Tight Blood-Glucose Control without Early Parenteral Nutrition in the ICU.

BACKGROUND: Randomized, controlled trials have shown both benefit and harm from tight blood-glucose control in patients in the intensive care unit (ICU). Variation in the use of early parenteral nutrition and in insulin-induced severe hypoglycemia might explain this inconsistency. METHODS: We randomly assigned patients, on ICU admission, to liberal glucose control (insulin initiated only when the blood-glucose level was >215 mg per deciliter [>11.9 mmol per liter]) or to tight glucose control (blood-glucose level targeted with the use of the LOGIC-Insulin algorithm at 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]); parenteral nutrition was withheld in both groups for 1 week. Protocol adherence was determined according to glucose metrics. The primary outcome was the length of time that ICU care was needed, calculated on the basis of time to discharge alive from the ICU, with death accounted for as a competing risk; 90-day mortality was the safety outcome. RESULTS: Of 9230 patients who underwent randomization, 4622 were assigned to liberal glucose control and 4608 to tight glucose control. The median morning blood-glucose level was 140 mg per deciliter (interquartile range, 122 to 161) with liberal glucose control and 107 mg per deciliter (interquartile range, 98 to 117) with tight glucose control. Severe hypoglycemia occurred in 31 patients (0.7%) in the liberal-control group and 47 patients (1.0%) in the tight-control group. The length of time that ICU care was needed was similar in the two groups (hazard ratio for earlier discharge alive with tight glucose control, 1.00; 95% confidence interval, 0.96 to 1.04; P = 0.94). Mortality at 90 days was also similar (10.1% with liberal glucose control and 10.5% with tight glucose control, P = 0.51). Analyses of eight prespecified secondary outcomes suggested that the incidence of new infections, the duration of respiratory and hemodynamic support, the time to discharge alive from the hospital, and mortality in the ICU and hospital were similar in the two groups, whereas severe acute kidney injury and cholestatic liver dysfunction appeared less prevalent with tight glucose control. CONCLUSIONS: In critically ill patients who were not receiving early parenteral nutrition, tight glucose control did not affect the length of time that ICU care was needed or mortality. (Funded by the Research Foundation-Flanders and others; TGC-Fast ClinicalTrials.gov number, NCT03665207.).

The association of hypoglycemia with outcome of critically ill children in relation to nutritional and blood glucose control strategies.

BACKGROUND: Withholding parenteral nutrition (PN) until one week after PICU admission facilitated recovery from critical illness and protected against emotional and behavioral problems 4 years later. However, the intervention increased the risk of hypoglycemia, which may have counteracted part of the benefit. Previously, hypoglycemia occurring under tight glucose control in critically ill children receiving early PN did not associate with long-term harm. We investigated whether hypoglycemia in PICU differentially associates with outcome in the context of withholding early PN, and whether any potential association with outcome may depend on the applied glucose control protocol. METHODS: In this secondary analysis of the multicenter PEPaNIC RCT, we studied whether hypoglycemia in PICU associated with mortality (N = 1440) and 4-years neurodevelopmental outcome (N = 674) through univariable comparison and multivariable regression analyses adjusting for potential confounders. In patients with available blood samples (N = 556), multivariable models were additionally adjusted for baseline serum NSE and S100B concentrations as biomarkers of neuronal, respectively, astrocytic damage. To study whether an association of hypoglycemia with outcome may be affected by the nutritional strategy or center-specific glucose control protocol, we further adjusted the models for the interaction between hypoglycemia and the randomized nutritional strategy, respectively, treatment center. In sensitivity analyses, we studied whether any association with outcome was different in patients with iatrogenic or spontaneous/recurrent hypoglycemia. RESULTS: Hypoglycemia univariably associated with higher mortality in PICU, at 90 days and 4 years after randomization, but not when adjusted for risk factors. After 4 years, critically ill children with hypoglycemia scored significantly worse for certain parent/caregiver-reported executive functions (working memory, planning and organization, metacognition) than patients without hypoglycemia, also when adjusted for risk factors including baseline NSE and S100B. Further adjustment for the interaction of hypoglycemia with the randomized intervention or treatment center revealed a potential interaction, whereby tight glucose control and withholding early PN may be protective. Impaired executive functions were most pronounced in patients with spontaneous or recurrent hypoglycemia. CONCLUSION: Critically ill children exposed to hypoglycemia in PICU were at higher risk of impaired executive functions after 4 years, especially in cases of spontaneous/recurrent hypoglycemia.

Development and validation of the creatinine clearance predictor machine learning models in critically ill adults.

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.

Development and validation of clinical prediction models for acute kidney injury recovery at hospital discharge in critically ill adults.

PURPOSE: Acute kidney injury (AKI) recovery prediction remains challenging. The purpose of the present study is to develop and validate prediction models for AKI recovery at hospital discharge in critically ill patients with ICU-acquired AKI stage 3 (AKI-3). METHODS: Models were developed and validated in a development cohort (n = 229) and a matched validation cohort (n = 244) from the multicenter EPaNIC database to create prediction models with the least absolute shrinkage and selection operator (Lasso) machine-learning algorithm. We evaluated the discrimination and calibration of the models and compared their performance with plasma neutrophil gelatinase-associated lipocalin (NGAL) measured on first AKI-3 day (NGAL_AKI3) and reference model that only based on age. RESULTS: Complete recovery and complete or partial recovery occurred in 33.20% and 51.23% of the validation cohort patients respectively. The prediction model for complete recovery based on age, need for renal replacement therapy (RRT), diagnostic group (cardiac/surgical/trauma/others), and sepsis on admission had an area under the receiver operating characteristics curve (AUROC) of 0.53. The prediction model for complete or partial recovery based on age, need for RRT, platelet count, urea, and white blood cell count had an AUROC of 0.61. NGAL_AKI3 showed AUROCs of 0.55 and 0.53 respectively. In cardiac patients, the models had higher AUROCs of 0.60 and 0.71 than NGAL_AKI3's AUROCs of 0.52 and 0.54. The developed models demonstrated a better performance over the reference models (only based on age) for cardiac surgery patients, but not for patients with sepsis and for a general ICU population. CONCLUSION: Models to predict AKI recovery upon hospital discharge in critically ill patients with AKI-3 showed poor performance in the general ICU population, similar to the biomarker NGAL. In cardiac surgery patients, discrimination was acceptable, and better than NGAL. These findings demonstrate the difficulty of predicting non-reversible AKI early.

Physical, Emotional/Behavioral, and Neurocognitive Developmental Outcomes From 2 to 4 Years After PICU Admission: A Secondary Analysis of the Early Versus Late Parenteral Nutrition Randomized Controlled Trial Cohort.

OBJECTIVES: PICU patients face long-term developmental impairments, partially attributable to early parenteral nutrition (PN) versus late-PN. We investigated how this legacy and harm by early-PN evolve over time. DESIGN: Preplanned secondary analysis of the multicenter PEPaNIC-RCT (ClinicalTrials.gov, NCT01536275) that enrolled 1,440 critically ill children from 2012 to 2015 and its 2- (2014-2018) and 4-year (2016-2019) cross-sectional follow-up studies. SETTING: PICUs of Leuven (Belgium), Rotterdam (The Netherlands), and Edmonton (Canada). PATIENTS: Patients and demographically matched healthy control children that underwent longitudinal assessment for physical/emotional/behavioral/neurocognitive functions at both follow-up time points. INTERVENTIONS: In the PEPaNIC-RCT, patients were randomly allocated to early-PN versus late-PN. MEASUREMENTS AND MAIN RESULTS: This within-individual longitudinal study investigated changes in physical/emotional/behavioral/neurocognitive functions from 2 to 4 years after PICU admission for 614 patients (297 early-PN and 317 late-PN, tested at mean ± sd age 5.4 ± 4.2 and 7.3 ± 4.3 yr) and for 357 demographically matched healthy children tested at age 5.6 ± 4.3 and 7.5 ± 4.3 years. We determined within-group time-courses, interaction between time and group, and independent impact of critical illness and early-PN on these time-courses. Most deficits in patients versus healthy children remained prominent over the 2 years ( p ≤ 0.01). Deficits further aggravated for height, body mass index, the executive function metacognition, intelligence, motor coordination (alternating/synchronous tapping), and memory learning-index, whereas verbal memory deficits became smaller (working/immediate/delayed memory) ( p ≤ 0.05). Adjustment for risk factors confirmed most findings and revealed that patients "grew-into-deficit" for additional executive functions (flexibility/emotional control/total executive functioning) and "grew-out-of-deficit" for additional memory functions (recognition/pictures) ( p ≤ 0.05). Time-courses were largely unaffected by early-PN versus late-PN, except for weight loss and limited catch-up for visual-motor integration and alertness in early-PN patients ( p ≤ 0.05). CONCLUSIONS: From 2- to 4-year post-PICU admission, developmental impairments remained prominent. Within that time-window, impaired growth in height, executive functioning and intelligence aggravated, and impaired memory and harm by early-PN only partially recovered. Impact on development into adulthood requires further investigation.

Postoperative Cerebral Oxygen Saturation in Children After Congenital Cardiac Surgery and Long-Term Total Intelligence Quotient: A Prospective Observational Study.

OBJECTIVES: During the early postoperative period, children with congenital heart disease can suffer from inadequate cerebral perfusion, with possible long-term neurocognitive consequences. Cerebral tissue oxygen saturation can be monitored noninvasively with near-infrared spectroscopy. In this prospective study, we hypothesized that reduced cerebral tissue oxygen saturation and increased intensity and duration of desaturation (defined as cerebral tissue oxygen saturation < 65%) during the early postoperative period, independently increase the probability of reduced total intelligence quotient, 2 years after admission to a PICU. DESIGN: Single-center, prospective study, performed between 2012 and 2015. SETTING: The PICU of the University Hospitals Leuven, Belgium. PATIENTS: The study included pediatric patients after surgery for congenital heart disease admitted to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Postoperative cerebral perfusion was characterized with the mean cerebral tissue oxygen saturation and dose of desaturation of the first 12 and 24 hours of cerebral tissue oxygen saturation monitoring. The independent association of postoperative mean cerebral tissue oxygen saturation and dose of desaturation with total intelligence quotient at 2-year follow-up was evaluated with a Bayesian linear regression model adjusted for known confounders. According to a noninformative prior, reduced mean cerebral tissue oxygen saturation during the first 12 hours of monitoring results in a loss of intelligence quotient points at 2 years, with a 90% probability (posterior ß estimates [80% credible interval], 0.23 [0.04-0.41]). Similarly, increased dose of cerebral tissue oxygen saturation desaturation would result in a loss of intelligence quotient points at 2 years with a 90% probability (posterior ß estimates [80% credible interval], -0.009 [-0.016 to -0.001]). CONCLUSIONS: Increased dose of cerebral tissue oxygen saturation desaturation and reduced mean cerebral tissue oxygen saturation during the early postoperative period independently increase the probability of having a lower total intelligence quotient, 2 years after PICU admission.

Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver.

Liver injury triggers adaptive remodeling of the hepatic transcriptome for repair/regeneration. We demonstrate that this involves particularly profound transcriptomic alterations where acute induction of genes involved in handling of endoplasmic reticulum stress (ERS) is accompanied by partial hepatic dedifferentiation. Importantly, widespread hepatic gene downregulation could not simply be ascribed to cofactor squelching secondary to ERS gene induction, but rather involves a combination of active repressive mechanisms. ERS acts through inhibition of the liver-identity (LIVER-ID) transcription factor (TF) network, initiated by rapid LIVER-ID TF protein loss. In addition, induction of the transcriptional repressor NFIL3 further contributes to LIVER-ID gene repression. Alteration to the liver TF repertoire translates into compromised activity of regulatory regions characterized by the densest co-recruitment of LIVER-ID TFs and decommissioning of BRD4 super-enhancers driving hepatic identity. While transient repression of the hepatic molecular identity is an intrinsic part of liver repair, sustained disequilibrium between the ERS and LIVER-ID transcriptional programs is linked to liver dysfunction as shown using mouse models of acute liver injury and livers from deceased human septic patients.

Visualization of Intracranial Pressure Insults After Severe Traumatic Brain Injury: Influence of Individualized Limits of Reactivity.

Cerebral perfusion pressure (CPP) lower limits of reactivity can be determined almost continuously after severe traumatic brain injury (TBI), and deviation below the lower limit carries important prognostic information. In this study, we used a recently derived coloured contour method for visualizing intracranial pressure (ICP) insults to describe the influence of having a CPP above the CPP lower limits of reactivity after severe TBI. In a cohort of 729 patients, we examined the relationship between ICP insults and the 6-month Glasgow Outcome Scale score, using colour-coded plots, as described previously. We then assessed this relationship when ICP insults were above or below the CPP lower limit of reactivity. We found a curvilinear relationship whereby even prolonged durations of low-intensity ICP insults were not associated with poor outcomes but short durations of high-intensity insults were. When only ICP insults with a CPP below the CPP lower limit of reactivity were considered, a much lower intensity of ICP insults could be tolerated. A CPP above the lower limits of reactivity exerts a protective effect, whereas a CPP below the lower reactivity limits renders the patient vulnerable to increased morbidity from intracranial hypertension.

Association of Dose of Intracranial Hypertension with Outcome in Subarachnoid Hemorrhage.

BACKGROUND: In patients with aneurysmal subarachnoid hemorrhage (aSAH) the burden of intracranial pressure (ICP) and its contribution to outcomes remains unclear. In this multicenter study, the independent association between intensity and duration, or "dose," of episodes of intracranial hypertension and 12-month neurological outcomes was investigated. METHODS: This was a retrospective analysis of multicenter prospectively collected data of 98 adult patients with aSAH amendable to treatment. Patients were admitted to the intensive care unit of two European centers (Medical University of Innsbruck [Austria] and San Gerardo University Hospital of Monza [Italy]) from 2009 to 2013. The dose of intracranial hypertension was visualized. The obtained visualizations allowed us to investigate the association between intensity and duration of episodes of intracranial hypertension and the 12-month neurological outcomes of the patients, assessed with the Glasgow Outcome Score. The independent association between the cumulative dose of intracranial hypertension and outcome for each patient was investigated by using multivariable logistic regression models corrected for age, occurrence of delayed cerebral ischemia, and the Glasgow Coma Scale score at admission. RESULTS: The combination of duration and intensity defined the tolerance to intracranial hypertension for the two cohorts of patients. A semiexponential transition divided ICP doses that were associated with better outcomes (in blue) with ICP doses associated with worse outcomes (in red). In addition, in both cohorts, an independent association was found between the cumulative time that the patient experienced ICP doses in the red area and long-term neurological outcomes. The ICP pressure-time burden was a stronger predictor of outcomes than the cumulative time spent by the patients with an ICP greater than 20 mmHg. CONCLUSIONS: In two cohorts of patients with aSAH, an association between duration and intensity of episodes of elevated ICP and 12-month neurological outcomes could be demonstrated and was visualized in a color-coded plot.

Health-related quality of life of children and their parents 2 years after critical illness: pre-planned follow-up of the PEPaNIC international, randomized, controlled trial.

BACKGROUND: Pediatric intensive care unit (PICU) survivors are at risk for prolonged morbidities interfering with daily life. The current study examined parent-reported health-related quality of life (HRQoL) in former critically ill children and parents themselves and aimed to determine whether withholding parenteral nutrition (PN) in the first week of critical illness affected children's and parents' HRQoL 2 years later. METHODS: Children who participated in the pediatric early versus late parenteral nutrition in critical illness (PEPaNIC) trial and who were testable 2 years later (n = 1158) were included. Their HRQoL outcomes were compared with 405 matched healthy controls. At PICU admission, children had been randomly assigned to early-PN or late-PN. In the early-PN group, PN was initiated within 24 h after PICU admission. In the late-PN group, PN was withheld for up to 1 week in the PICU. Parents completed the Infant Toddler Quality of Life Questionnaire (ITQOL; age 2-3 years) or the Child Health Questionnaire-Parent Form 50 (CHQ-PF50; age 4-18 years). Besides, they completed the Health Utility Index (HUI) and the Short Form Health Survey (SF-12) regarding their child's and their own HRQoL, respectively. RESULTS: For the total age group of 786 post-PICU survivors, parents reported lower scores for almost all HRQoL scales compared to healthy children. Age-specifically, younger critically ill children (2.5 to 3 years old) scored worse for growth and development and older children (4-18 years old) scored worse for role functioning and mental health. Parents' own mental and physical HRQoL was comparable to that of healthy control parents. No HRQoL differences were found between children in the late-PN and those in the early-PN group. CONCLUSIONS: Parent-reported HRQoL of children 2 years after critical illness was impaired compared with healthy controls. In relation to their child's HRQoL, parents reported impairments in emotions, personal time, and family activities; however, their own HRQoL was not impaired. Withholding PN in the first week during critical illness had no impact on longer-term HRQoL of the child. TRIAL REGISTRATION: Clinical trials, NCT01536275. Registered 22 February 2012.