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In this randomized, controlled trial involving critically ill patients not receiving early parenteral nutrition, tight glucose control did not affect the length of time that ICU care was needed or mortality.

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.

Background In critically ill patients, measured creatinine clearance (CrCl) is the most reliable method to evaluate glomerular filtration rate in routine clinical practice and may vary subsequently on a day-to-day basis. We developed and externally validated models to predict CrCl one day ahead and compared them with a reference reflecting current clinical practice. Methods A gradient boosting method (GBM) machine-learning algorithm was used to develop the models on data from 2825 patients from the EPaNIC multicenter randomized controlled trial database. We externally validated the models on 9576 patients from the University Hospitals Leuven, included in the M@tric database. Three models were developed: a “Core” model based on demographic, admission diagnosis, and daily laboratory results; a “Core + BGA” model adding blood gas analysis results; and a “Core + BGA + Monitoring” model also including high-resolution monitoring data. Model performance was evaluated against the actual CrCl by mean absolute error (MAE) and root-mean-square error (RMSE). Results All three developed models showed smaller prediction errors than the reference. Assuming the same CrCl of the day of prediction showed 20.6 (95% CI 20.3–20.9) ml/min MAE and 40.1 (95% CI 37.9–42.3) ml/min RMSE in the external validation cohort, while the developed model having the smallest RMSE (the Core + BGA + Monitoring model) had 18.1 (95% CI 17.9–18.3) ml/min MAE and 28.9 (95% CI 28–29.7) ml/min RMSE. Conclusions Prediction models based on routinely collected clinical data in the ICU were able to accurately predict next-day CrCl. These models could be useful for hydrophilic drug dosage adjustment or stratification of patients at risk. Trial registration . Not applicable.

Background Many critically ill children face long-term developmental impairments. The PEPaNIC trial attributed part of the problems at the level of neurocognitive and emotional/behavioral development to early use of parenteral nutrition (early-PN) in the PICU, as compared with withholding it for 1 week (late-PN). Insight in long-term daily life physical functional capacity after critical illness is limited. Also, whether timing of initiating PN affects long-term physical function of these children remained unknown. Methods This preplanned follow-up study of the multicenter PEPaNIC randomized controlled trial subjected 521 former critically ill children (253 early-PN, 268 late-PN) to quantitative physical function tests 4 years after PICU admission in Leuven or Rotterdam, in comparison with 346 age- and sex-matched healthy children. Tests included handgrip strength measurement, timed up-and-go test, 6-min walk test, and evaluation of everyday overall physical activity with an accelerometer. We compared these functional measures for the former critically ill and healthy children and for former critically ill children randomized to late-PN versus early-PN, with multivariable linear or logistic regression analyses adjusting for risk factors. Results As compared with healthy children, former critically ill children showed less handgrip strength ( p  < 0.0001), completed the timed up-and-go test more slowly ( p  < 0.0001), walked a shorter distance in 6 min ( p  < 0.0001) during which they experienced a larger drop in peripheral oxygen saturation ( p  ≤ 0.026), showed a lower energy expenditure ( p  ≤ 0.024), performed more light and less moderate physical activity ( p  ≤ 0.047), and walked fewer steps per day ( p  = 0.0074). Late-PN as compared with early-PN did not significantly affect these outcomes. Conclusions Four years after PICU admission, former critically ill children showed worse physical performance as compared with healthy children, without impact of timing of supplemental PN in the PICU. This study provides further support for de-implementing the early use of PN in the PICU. Trial registration ClinicalTrials.gov, NCT01536275 ; registered on February 22, 2012.

Background In severe traumatic brain injury (TBI), sedatives are often used to control intracranial pressure (ICP), to reduce brain metabolism, to allow for other treatments such as mechanical ventilation or targeted temperature management, or to control paroxysmal sympathetic hyperactivity. Prolonged sedation is often necessary. The most commonly used sedatives in TBI are propofol and midazolam, often in combination, but both have significant side effects when used at high doses for several days. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, provides sedation and analgesia with minimal respiratory depression or haemodynamic instability. However, ketamine carries a US Food and Drug Administration (FDA) precaution regarding its use in patients with pre-anaesthetic elevated cerebrospinal fluid pressure, which discourages its use in TBI patients. Several observational studies and two large meta-analyses do not suggest that the use of ketamine as an induction agent or sedative in sedated and mechanically ventilated TBI patients would increase the ICP. Off-label use of ketamine for this indication is increasing worldwide. To date, no prospective randomized clinical trial (RCT) has demonstrated the safety of ketamine in TBI patients. Methods The Brain Injury and Ketamine (BIKe) study is a prospective multicentre double-blind placebo-controlled RCT, to evaluate the safety, and effect on therapeutic intensity to reduce ICP, of ketamine as an adjunct to a standard sedation regimen in patients with severe TBI. Adult TBI patients, admitted to the intensive care unit (ICU), requiring sedation and ICP monitoring within 72 h of admission, will be randomized to ketamine or placebo. The study drug will be started within 6 h of randomization. The dose of the investigational medicinal product (IMP) is 1 mg/kg/h, by continuous infusion. The IMP will be stopped when the last ICP control sedative is discontinued. Data collection will stop when the patient is discharged from the ICU. All patients will be followed for 6 months post-trauma. The study is powered for the safety endpoint of detecting a clinically relevant increase of two episodes in the median number of episodes of high intracranial pressure episodes per ICU stay. A total of 100 patients are required to meet these objectives. We hypothesize a clinically relevant reduction in the therapeutic intensity level (TIL) score of at least 3 points. Discussion This study is the first prospective RCT to investigate the safety of ketamine as an adjunct to a standard sedation regimen in TBI patients. Trial registration ClinicalTrials.gov NCT05097261. Registered on October 28, 2021.

Background It remains controversial whether critical illness-related hyperglycemia should be treated or not, since randomized controlled trials (RCTs) have shown context-dependent outcome effects. Whereas pioneer RCTs found improved outcome by normalizing blood glucose in patients receiving early parenteral nutrition (PN), a multicenter RCT revealed increased mortality in patients not receiving early PN. Although withholding early PN has become the feeding standard, the multicenter RCT showing harm by tight glucose control in this context has been criticized for its potentially unreliable glucose control protocol. We hypothesize that tight glucose control is effective and safe using a validated protocol in adult critically ill patients not receiving early PN. Methods The TGC-fast study is an investigator-initiated, multicenter RCT. Patients unable to eat, with need for arterial and central venous line and without therapy restriction, are randomized upon ICU admission to tight (80–110 mg/dl) or liberal glucose control (only initiating insulin when hyperglycemia >215 mg/dl, and then targeting 180–215 mg/dl). Glucose measurements are performed on arterial blood by a blood gas analyzer, and if needed, insulin is only administered continuously through a central venous line. If the arterial line is no longer needed, glucose is measured on capillary blood. In the intervention group, tight control is guided by the validated LOGIC-Insulin software. In the control arm, a software alert is used to maximize protocol compliance. The intervention is continued until ICU discharge, until the patient is able to eat or no longer in need of a central venous line, whatever comes first. The study is powered to detect, with at least 80% power and a 5% alpha error rate, a 1-day difference in ICU dependency (primary endpoint), and a 1.5% increase in hospital mortality (safety endpoint), for which 9230 patients need to be included. Secondary endpoints include acute and long-term morbidity and mortality, and healthcare costs. Biological samples are collected to study potential mechanisms of organ protection. Discussion The ideal glucose target for critically ill patients remains debated. The trial will inform physicians on the optimal glucose control strategy in adult critically ill patients not receiving early PN. Trial registration ClinicalTrials.gov NCT03665207. Registered on 11 September 2018.

Background Carnitine deficiency affects mitochondrial and muscle function, but its relevance during critical illness remains unknown. Our aim was to investigate the relationship between plasma free carnitine concentrations and outcome in prolonged critical illness. Methods In this secondary analysis of the EPaNIC randomised controlled trial, abnormal plasma free carnitine concentrations, measured on ICU-day-6 ( N  = 1600), were defined by their association with a lower likelihood of an earlier alive ICU discharge (the primary endpoint) in a Cox proportional hazards model. Subsequently, they were binned based on their distribution and partial residuals in the Cox-model. Adjusted multivariable Cox-model and logistic regression analysed both association of abnormal carnitinemia with acute and long-term morbidity and mortality, and predictive risk factors. Results The median plasma free carnitine concentration on ICU-day-6 was 34.8 (IQR 24.4–49.8 µmol/L). Surprisingly, higher concentrations associated with a lower likelihood of an earlier alive ICU discharge (HR [95% CI] (per 10 µmol/L increase): 0.97 [0.95–0.99]). Yet, the partial residuals plot revealed this likelihood to be lower for patients with concentrations corresponding to the lowest (< 24 µmol/L; N  = 374) and highest quartiles (> 50 µmol/L; N  = 395) as compared to intermediate quartiles (24–50 µmol/L; N  = 831). Both low and high carnitine concentrations were associated with a prolonged ICU and hospital dependency, a prolonged need for life-supporting therapies, and increased mortality at 90-days. Carnitine concentrations above 50 µmol/L also associated with muscle weakness and increased two and five year-mortality. Conclusion On ICU-day-6, both low and high free carnitine concentrations associated with delayed ICU-recovery, and excess morbidity and mortality, suggesting a U-shaped relationship.

Background The PEPaNIC RCT showed that early supplementation of insufficient enteral nutrition by parenteral nutrition (early-PN) worsened outcome of critically ill children as compared with withholding PN for 1 week (late-PN). The best timing to initiate nutritional support in the pediatric intensive care unit (PICU) remains unclear. In adults, declining phosphate levels may identify patients who are particularly harmed by early-PN. We therefore assessed whether early hypophosphatemia in critically ill children may indicate metabolic intolerance to nutrition. Methods In this secondary analysis of the PEPaNIC RCT ( n  = 1440), we investigated whether development of hypophosphatemia statistically interacts with the randomized intervention for its impact on clinical outcome, adjusting for baseline risk factors. Outcomes of interest included the incidence of new infections and the duration of PICU dependency as primary endpoints, 90-day mortality as safety endpoint, and duration of mechanical ventilation and of hospital stay as secondary endpoints. Subsequently, the impact of early-PN vs. late-PN in patients with and without early hypophosphatemia was assessed. Analyses were performed for phosphate abnormalities on PICU day 1 and 2, with and without imputing 20.3% (day 1) or 22.0% (day 2) missing phosphate data. Results Of patients with available phosphate measurements, 19.9% (211/1060) and 27.5% (243/883) developed hypophosphatemia on day 1 and day 2, respectively. Day 1 hypophosphatemia did not interact with the randomized intervention for any studied outcome. On day 2, hypophosphatemia interacted with randomization for risk of new infection ( P  = 0.031), likelihood of earlier live PICU discharge ( P  = 0.030), and time to live weaning from mechanical ventilation ( P  = 0.025). Harm by early-PN was more pronounced in patients with hypophosphatemia than in those without. Results after imputing missing phosphate data were similar, with an additional interaction for 90-day mortality ( P  = 0.038) revealing higher mortality with early-PN in patients with hypophosphatemia. Conclusions Development of hypophosphatemia may identify critically ill children who are particularly harmed by early-PN. This opens perspectives for its use as a biomarker of metabolic intolerance to enhanced nutrition, which requires further investigation. Trial registration ClinicalTrials.gov NCT01536275, registered February 2012.

Aim: Between 2012-2015, the PEPaNIC randomized controlled trial, which included 1440 critically ill infants and children, showed that withholding parenteral nutrition during the first week in the pediatric intensive care unit (PICU) (late-PN), as compared with initiating supplemental PN early (early-PN), improved PICU outcomes (1) and improved neurocognitive development assessed 2 years later (2). The latter was explained by avoiding early-PN induced adversely altered DNA-methylation of 37 CpG sites (3). As a large number of patients were younger than 1 year of age at randomization and given that assessment of most neurocognitive domains is only possible from 4 years of age onwards, we performed a 4-year follow-up to determine the impact of late-PN versus early-PN on physical, neurocognitive, and emotional/behavioral development. This pre-planned, 4-year follow-up study of the 1440 PEPaNIC patients and of 369 matched healthy children was blinded for treatment allocation (ClinicalTrials.gov-NCT01536275). Methods: Studied clinical outcomes included anthropometrics, health status, parent/caregiver-reported executive functions, and emotional/behavioral problems, and clinical tests for intelligence, visual-motor integration, alertness, motor coordination and memory. Univariable and multivariable linear and logistic regression analyses adjusted for risk factors assessed the impact of late-PN versus early-PN on the outcomes and investigated a potential mediation role of the adversely altered DNA-methylation of 37 CpG sites previously shown to be evoked by late-PN as compared with early-PN (3). Results: Overall, at 4 years follow-up, patients (356 late-PN patients, 328 early-PN patients) could be tested neurocognitively. They revealed worse anthropometric, health status, neurocognitive and emotional/behavioral developmental outcomes than the healthy control children. Outcomes of late-PN patients were never worse than those of early-PN patients. In contrast, late-PN patients had fewer internalizing (P=0.042) and externalizing problems (P=0.046), and fewer total emotional/behavioral problems (P=0.007) than early-PN patients, which were normalized by late-PN. Avoiding the early-PN induced adversely altered DNA-methylation status of the 37 CpG sites statistically explained its impact on the behavioral outcomes. Conclusion: Four years after randomization to late-PN or early-PN in the PICU, late-PN did not show harm, and was found to protect against emotional/behavioral problems, with altered DNA-methylation as a potential biological mediator hereof. These data further support de-implementation of PN-use early during critical illness in infants and children. (1) Fivez et al. N Eng J Med 2016 (2) Verstraete et al. Lancet Respir Med 2019 (3) Guiza et al. Lancet Respir Med 2020 (in press)