Health-related quality of life of children and their parents 2 years after critical illness

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, childre

Time course of altered DNA methylation evoked by critical illness and by early administration of parenteral nutrition in the paediatric ICU

Background: A genome-wide study identifed de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, ofering a biological basis for their impaired long-term development. Early parenteral nutrition (early-PN) in PICU, compared with omitting PN in the frst week (late-PN), explained diferential methylation of 23% of the afected CpG-sites. We documented the time course of altered DNA methylation in PICU and the impact hereon of early nutritional management. Results: We selected 36 early-PN and 36 late-PN matched patients, and 42 matched healthy children. We quantifed DNA methylation on days 3, 5 and 7 for the 147 CpG-sites of which methylation was normal upon PICU admission in this subset and altered by critical illness at PICU discharge. Methylation in patients difered from healthy children for 64.6% of the 147 CpG-sites on day 3, for 72.8% on day 5 and for 90.5% on day 7 as revealed by ANOVA at each time point. Within-patients methylation time course analyses for each CpG-site identifed diferent patterns based on paired t test p value and direction of change. Rapid demethylation from admission to day 3 occurred for 76.2% of the CpG-sites, of which 67.9% remained equally demethylated or partially remethylated and 32.1% further demethylated beyond day 3. From admission to day 3, 19.7% of the CpG-sites became hypermethylated, of which, beyond day 3, 34.5% remained equally hypermethylated or partially demethylated again and 65.5% further hypermethylated. For 4.1% of the CpG-sites, changes only appeared beyond day 3. Finally, for the CpG-sites afected by early-PN on the last PICU day, earlier changes in DNA methylation were compared for early-PN and late-PN patients, revealing that 38.9% were already diferentially methylated by day 3, another 25.0% by day 5 and another 13.9% by day 7. Conclusions: Critical illness- and early-PN-induced changes in DNA methylation occurred mainly within 3 days. Most abnormalities were at least partially maintained or got worse with longer time in PICU. Interventions targeting aberrant DNA methylation changes should be initiated earl

Cost-effectiveness study of early versus late parenteral nutrition in critically ill children (PEPaNIC)

__Background:__ The multicentre randomised controlled PEPaNIC trial showed that withholding parenteral nutrition (PN) during the first week of critical illness in children was clinically superior to providing early PN. This study describes the cost-effectiveness of this new nutritional strategy. __Methods:__ Direct medical costs were calculated with use of a micro-costing approach. We compared the costs of late versus early initiation of PN (n = 673 versus n = 670 pa

Leukocyte telomere length in paediatric critical illness

__Background:__ Children who have suffered from critical illnesses that required treatment in a paediatric intensive care unit (PICU) have long-term physical and neurodevelopmental impairments. The mechanisms underlying this legacy remain largely unknown. In patients suffering from chronic diseases hallmarked by inflammation and oxidative stress, poor long-term outcome has been associated with shorter telomeres. Shortened telomeres have also been reported to result from excessive food consumption and/or unhealthy nutrition. We investigated whether critically ill children admitted to the PICU have shorter-than-normal telomeres, and whether early parenteral nutrition (PN) independently affects telomere length when adjusting for known determinants of telomere length. __Methods:__ Telomere length was quantified in leukocyte DNA from 342 healthy children and from 1148 patients who had been enrolled in the multicenter, randomised controlled trial (RCT), PEPaNIC. These patients were randomly allocated to initiation of PN within 24 h (early PN) or to withholding PN for one week in PICU (late PN). The impact of early PN versus late PN on the change in telomere length from the first to last PICU-day was investigated with multivariable linear regression analyses. __Results:__ Leukocyte telomeres were 6% shorter than normal upon PICU admission (median 1.625 (IQR 1.446-1.825) telomere/single-copy-gene ratio (T/S) units vs. 1.727 (1.547-1.915) T/S-units in healthy children (P < 0.0001)). Adjusted for potential baseline determinants and leukocyte composition, early PN was associated with telomere shortening during PICU stay as compared with late PN (estimate early versus late PN -0.021 T/S-units, 95% CI -0.038; 0.004, P = 0.01). Other independent determinants of telomere length identified in this model were age, gender, baseline telomere length and fraction of neutrophils in the sample from which the DNA was extracted. Telomere shortening with early PN was independent of post-randomisation factors affected by early PN, including longer length of PICU stay, larger amounts of insulin and higher risk of infection. __Conclusions:__ Shorter than normal leukocyte telomeres are present in critically ill children admitted to the PICU. Early initiation of PN further shortened telomeres, an effect that was independent of other determinants. Whether such telomere-shortening predisposes to long-term consequences of paediatric critical illness should be further investigated in a prospective follow-up study

Outcomes of Delaying Parenteral Nutrition for 1 Week vs Initiation Within 24 Hours Among Undernourished Children in Pediatric Intensive Care

_IMPORTANCE_ Undernourishment has been associated with poor outcomes of critical illness in children. The effects of withholding parenteral nutrition (PN) for 1 week in undernourished critically ill children are unknown. _OBJECTIVE_ To assess the outcome effects of withholding PN for 1 week in undernourished critically ill children. _DESIGN, SETTING, AND PARTICIPANTS_ This is a subanalysis of the randomized clinical trial Pediatric Early vs Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC; N = 1440), which focused on the subgroup of pediatric intensive care unit (PICU) patients identified as undernourished on admission. Children included in the PEPaNIC trial were enrolled between June 18, 2012, and July 27, 2015. Undernourishment was defined as weight-for-age z score less than −2 in children younger than 1 year, and body mass index–for-age z score less than −2 in children 1 year or older. Data analysis was conducted from August 3, 2017, to July 6, 2018. _INTERVENTIONS_ Patients were randomized to initiation of supplemental PN within 24 hours (early PN) or after 1 week (late PN) when enteral nutrition was insufficient. _MAIN OUTCOMES AND MEASURES_ Primary end points were risk of new infections acquired in the PICU and time to live PICU discharge, assessed via multivariable logistic regression and Cox proportional hazard analyses, adjusted for risk factors. _RESULTS_ A total of 289 of 1440 children (20.1%), term newborn to age 17 years, were identified as undernourished, of whom 150 of 717 patients (20.9%) were in the late PN group and 139 of 723 patients (19.2%) were in the early PN group. On admission, characteristics were similar among the treatment groups. Mean (SD)weight z scoreswere −3.33 (1.18) in the late PN group and −3.21 (1.09) in the early PN group. Compared with well-nourished PICU patients, undernourishment on admission was associated with lower likelihood of an earlier live PICU discharge. Among undernourished PICU patients, late PN reduced the risk of new infections by 11.0%, and shortened the duration of PICU stay by a median of 2 days. The safety outcomes mortality, incidence of hypoglycemia during the first week, and incidence of weight deterioration during PICU stay were similar between the treatment groups. _CONCLUSIONS AND RELEVANCE_ In undernourished critically ill children, withholding PN for 1week was clinically superior to early PN

Impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients (PEPaNIC trial): Study protocol for a randomized controlled trial

Background: The state-of-the-art nutrition used for critically ill children is based essentially on expert opinion and extrapolations from adult studies or on studies in non-critically ill children. In critically ill adults, withholding parenteral nutrition (PN) during the first week in ICU improved outcome, as compared with early supplementation of insufficient enteral nutrition (EN) with PN. We hypothesized that withholding PN in children early during critical illness reduces the incidence of new infections and accelerates recovery. Methods/Design: The Pediatric Early versus Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC) study is an investigator-initiated, international, multicenter, randomized controlled trial (RCT) in three tertiary referral pediatric intensive care units (PICUs) in three countries on two continents. This study compares early versus late initiation of PN when EN fails to reach preset caloric targets in critically ill children. In the early-PN (control, standard of care) group, PN comprising glucose, lipids and amino acids is administered within the first days to reach the caloric target. In the late-PN (intervention) group, PN completing EN is only initiated beyond PICU-day 7, when EN fails. For both study groups, an early EN protocol is applied and micronutrients are administered intravenously. The primary assessor-blinded outcome measures are the incidence of new infections during PICU-stay and the duration of intensive care dependency. The sample size (n = 1,440, 720 per arm) was determined in order to detect a 5% absolute reduction in PICU infections, with at least 80% 1-tailed power (70% 2-tailed) and an alpha error rate of 5%. Based on the actual incidence of new PICU infections in the control group, the required sample size was confirmed at the time of an a priori- planned interim-analysis focusing on the incidence of new infections in the control group only. Discussion: Clinical evidence in favor of early administration of PN in critically ill children is currently lacking, despite potential benefit but also known side effects. This large international RCT will help physicians to gain more insight in the clinical effects of omitting PN during the first week of critical illness in children

Dynamics and prognostic value of the hypothalamus–pituitary–adrenal axis responses to pediatric critical illness and association with corticosteroid treatment: a prospective observational study

Purpose: Increased systemic cortisol availability during adult critical illness is determined by reduced binding-proteins and suppressed breakdown rather than elevated ACTH. Dynamics, drivers and prognostic value of hypercortisolism during pediatric critical illness remain scarcely investigated. Methods: This preplanned secondary analysis of the PEPaNIC-RCT (N = 1440), after excluding 420 children treated with corticosteroids before PICU-admission, documented (a) plasma ACTH, (free)cortisol and cortisol-metabolism at PICU-admission, day-3 and last PICU-day, their prognostic value, and impact of withholding early parenteral nutrition (PN), (b) the association between corticosteroid-treatment and these hormones, and (c) the association between corticosteroid-treatment and outcome. Results: ACTH was normal upon PICU-admission and low thereafte

Cortisol response to critical illness: Effect of intensive insulin therapy

Context: Both excessive and insufficient activation of the hypothalamic-pituitary-adrenal axis in response to critical illness is associated with increased mortality. Objective: The objective of the study was to study the effect of intensive insulin therapy, recently shown to reduce mortality and morbidity of critically ill patients, on the cortisol respon

Role of age of critically ill children at time of exposure to early or late parenteral nutrition in determining the impact hereof on long-term neurocognitive development: A secondary analysis of the PEPaNIC-RCT

Background & aims: Early use of parenteral nutrition (early-PN), as compared with withholding it for one week (late-PN), in the PICU, has shown to slow down recovery from critical illness and impair long-term development of 6 neurocognitive/behavioural/emotional functions assessed 2 years later. Given that key steps in brain maturation occur at different times during childhood, we hypothesised that age at time of exposure determines long-term developmental impact of early-PN. Methods: The 786 children who were neurocognitively tested 2 years after participation in the PEPaNIC-RCT were included in this study. First, for each studied long-term outcome, interaction between randomisation to early-PN versus late-PN and age was assessed with multivariable linear regression analysis. Subsequently, for outcomes with an interaction p ≤ 0.15, the impact of early-PN versus late-PN was analysed, after adjustment for risk factors, for 4 subgroups defined based on developmentally-relevant age at time of exposure [≤28 days (n = 121), 29 days to 11 months (n = 239), 11 months to <5 years (n = 223) and ≥5 years (n = 203)]. Results: Interaction between randomisation and age was present for weight, and parent-reported inhibitory control, cognitive flexibility, working memory, planning/organisation, metacognition, total executive functioning, and internalising and total behavioural/emotional problems. Subgroup analyses revealed that none of the age-groups revealed benefit, whereas children aged 29 days to <11 months were most vulnerable to harm by early-PN for development of inhibitory control (p = 0.008), working memory (p = 0.009), planning/organisation (p = 0.004), metacognition (p = 0.008), and total executive functioning (p = 0.004), and for internalising (p = 0.005) and total behavioural/emotional problems (p = 0.01). Children aged 11 months to <5 years revealed harm by early-PN for development of inhibitory control (p = 0.003). In contrast, children aged ≥5 years and neonates aged ≤28 days appeared less vulnerable. Conclusions: Critically ill children aged 29 days to 11 months at time of exposure were identified as most vulnerable to developmental harm evoked by early-PN. Clinical trials.gov: NCT01536275

Impact of hyperglycemia on neuropathological alterations during critical illness

Context: Although preventing excessive hyperglycemia during critical illness may provide clinical neuroprotection, it remains debated whether normoglycemia is without risk for the brain. Objective: To address this question, we compared the neuropathological alterations in microglia, astrocytes, and neurons, with uncontrolled hyperglycemia, moderately controlled hyperglycemia, and normoglycemia during human critical illness. We further investigated the time course in an animal model. Design and Setting: We analyzed brain specimens from patients who died in the intensive care unit and from critically ill rabbits randomized to hyper- or normoglycemia. Patients/Other Participants: We compared 10 critically ill patients randomized to normoglycemia (104 ±9 mg/dl) or moderate hyperglycemia (173 ±32 mg/dl), and five patients with uncontrolled hyperglycemia (254 ±83 mg/dl) with 16 controls (out of hospital sudden deaths). Critically ill rabbits were randomized to hyperglycemia (315 ±32 mg/dl) or normoglycemia (85 ±13 mg/dl) and studied after 3 and 7 d. Interventions: Insulin was infused to control blood glucose. Main Outcome Measures and Results: Patients with uncontrolled hyperglycemia showed 3.7- 6- fold increased microglial activation, 54-95% reduced number and activation of astrocytes, more than 9-fold increased neuronal and glial apoptosis, and a 1.5-2-fold increase in damaged neurons in hippocampus and frontal cortex (all P≤0.05). Most of these abnormalities were attenuated with moderate hyperglycemia and virtually absent with normoglycemia. Frontal cortex of hyperglycemic rabbits that had been critically ill for 3 d only revealed microglial activation, followed after 7 d by astrocyte and neuronal abnormalities similar to those observed in patients, all prevented by normoglycemia. Conclusions: Preventing hyperg