Training the Concept of Innovate in Dolphins (Tursiops truncatus) Is Both Creative and Cognitively Stimulating.

Creative or novel behaviors in bottlenose dolphins (Tursiops truncatus) can be indicators of flexible thinking and problem solving. Over 50 years ago, two rough-tooth dolphins demonstrated creative novel behaviors acquired through reinforcement training in human care. Since this novel training, a variety of species have been trained to respond to this conceptual cue. The current study assessed the creativity of 12 bottlenose dolphins (5 females, 7 males) housed at the Roatan Institute for Marine Sciences (RIMS) in Roatan, Honduras. Individual differences were found across four constructs measured for creativity: fluency, flexibility, elaboration, and originality. Variability in performance occurred across test sessions. Animals with less experience with this task performed fewer "innovative" behaviors as compared to more experienced animals. Despite errors, dolphins continued to attempt the task during test sessions, suggesting the concept of "innovate" was intrinsically rewarding and cognitively engaging. This task may be utilized across species to promote the comparative study of innovative or creative behavior as well as to promote cognitive welfare.

Effect of red blood cell storage time in pediatric cardiac surgery patients: A subgroup analysis of a randomized controlled trial.

Objective: This study aimed to determine whether or not transfusion of fresh red blood cells (RBCs) reduced the incidence of new or progressive multiple organ dysfunction syndrome compared with standard-issue RBCs in pediatric patients undergoing cardiac surgery. Methods: Preplanned secondary analysis of the Age of Blood in Children in Pediatric Intensive Care Unit study, an international randomized controlled trial. This study included children enrolled in the Age of Blood in Children in Pediatric Intensive Care Unit trial and admitted to a pediatric intensive care unit after cardiac surgery with cardiopulmonary bypass. Patients were randomized to receive either fresh (stored ≤7 days) or standard-issue RBCs. The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured up to 28 days postrandomization or at pediatric intensive care unit discharge, or death. Results: One hundred seventy-eight patients (median age, 0.6 years; interquartile range, 0.3-2.6 years) were included with 89 patients randomized to the fresh RBCs group (median length of storage, 5 days; interquartile range, 4-6 days) and 89 to the standard-issue RBCs group (median length of storage, 18 days; interquartile range, 13-22 days). There were no statistically significant differences in new or progressive multiple organ dysfunction syndrome between fresh (43 out of 89 [48.3%]) and standard-issue RBCs groups (38 out of 88 [43.2%]), with a relative risk of 1.12 (95% CI, 0.81 to 1.54; P = .49) and an unadjusted absolute risk difference of 5.1% (95% CI, -9.5% to 19.8%; P = .49). Conclusions: In neonates and children undergoing cardiac surgery with cardiopulmonary bypass, the use of fresh RBCs did not reduce the incidence of new or progressive multiple organ dysfunction syndrome compared with the standard-issue RBCs. A larger trial is needed to confirm these results.

PTEN inhibitor and kit ligand increase in vitro activation and survival of primordial follicles in alpaca.

In mammals, activation of primordial follicles to primary follicle is a progressive and highly regulated process. There is evidence in mice that phosphatase and tensin homologue deleted on Chromosome 10 (PTEN) silencing is an important negative regulator of phosphatidylinositol 3-kinase (PI3K), which initiates activation of dormant follicles. The objective of the study was to evaluate the effect of the addition of PTEN inhibitor (bpV(HOpic)) (10 µM) and/or Kit Ligand (KL) (100 ng/mL) on the in vitro activation and survival of alpaca primordial follicles. Ovarian cortical fragments from 11 adult alpacas were cultured for 24 h in tissue culture medium (α-MEM+ ) supplemented with KL and bpV or the association of both. Subsequently, each sample was processed by classical histology and follicular counting and classification were performed. The results obtained show a reduction (p < 0.05) of primordial follicles in more than 50% in follicular tissue cultured in vitro in α-MEM+ or supplemented with bpV and/or KL versus the control (not cultured). Further, >25% increase in primary follicles in follicular tissue cultured in vitro in α-MEM+ or supplemented with KL and/or bpV versus control. However, the follicular survival rate showed a decrease of 20% in the cultured tissues, except for the α-MEM+ supplemented with KL and bpV. In conclusion, supplementation of bpV (HOpic) (10 µM) and KL (100 ng/mL) increased the activation in vitro of primordial follicles and survival after in vitro culture of alpaca ovarian tissue.

Neurodevelopmental Outcomes of Infants after Neonatal Surgical Intervention for Tetralogy of Fallot or Pulmonary Atresia.

OBJECTIVE: To determine the 2-year neurodevelopmental outcomes for survivors of neonatal cardiac surgery for the most common right ventricular outflow tract obstructive lesions: tetralogy of Fallot and pulmonary atresia with a ventricular septal defect. STUDY DESIGN: A single-center consecutive cohort of 77 children underwent neonatal surgery for tetralogy of Fallot or pulmonary atresia with a ventricular septal defect at ≤6 weeks of age between 2006 and 2017. The patients underwent a multidisciplinary neurodevelopmental assessment at 18-24 months of age. Survivor outcomes were compared by univariable and multivariable analyses. RESULTS: The 2-year mortality was 7.8% (6/77) with a postoperative in-hospital mortality of 3.9% (3/77). Freedom from reintervention by cardiac catheterization or surgical intervention at 2 years was 36%. Functional and neurodevelopmental assessment for 69 of 71 survivors was completed at a mean age of 22.6 ± 4.0 months using the Bayley Scales of Infant and Toddler Development III. The mean neurodevelopmental outcome scores were 83.4 ± 16.5 for cognitive skills, 82.2 ± 18.7 for language skills, and 81.4 ± 18.1 for motor skills. Cognitive, language, and motor delay, defined as a score of <70, was identified in 25%, 25%, and 23% of patients, respectively. Multivariable analyses for factors associated with worse neurodevelopmental outcomes identified chromosomal anomalies (P < .001) and postoperative complications (P < .03). CONCLUSIONS: Cyanotic tetralogy of Fallot and pulmonary atresia with ventricular septal defect requiring neonatal repair showed similar 2-year neurodevelopmental outcomes below normative values and a high prevalence of cognitive, language and motor delays.

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.

Perspectives of Pediatric Nephrologists, Intensivists and Nurses Regarding AKI Management and Expected Outcomes.

Background: Acute kidney injury (AKI) in critically ill children is associated with increased risk for short- and long-term adverse outcomes. Currently, there is no systematic follow-up for children who develop AKI in intensive care unit (ICU). Objective: This study aimed to assess variation regarding management, perceived importance, and follow-up of AKI in the ICU setting within and between healthcare professional (HCP) groups. Design: Anonymous, cross-sectional, web-based surveys were administered nationally to Canadian pediatric nephrologists, pediatric intensive care unit (PICU) physicians, and PICU nurses, via professional listservs. Setting: All Canadian pediatric nephrologists, PICU physicians, and nurses treating children in the ICU were eligible for the survey. Patients: N/A. Measurements: Surveys included multiple choice and Likert scale questions on current practice related to AKI management and long-term follow-up, including institutional and personal practice approaches, and perceived importance of AKI severity with different outcomes. Methods: Descriptive statistics were performed. Categorical responses were compared using Chi-square or Fisher's exact tests; Likert scale results were compared using Mann-Whitney and Kruskal-Wallis tests. Results: Surveys were completed by 34/64 (53%) pediatric nephrologists, 46/113 (41%) PICU physicians, and 82 PICU nurses (response rate unknown). Over 65% of providers reported hemodialysis to be prescribed by nephrology; a mix of nephrology, ICU, or a shared nephrology-ICU model was reported responsible for peritoneal dialysis and continuous renal replacement therapy (CRRT). Severe hyperkalemia was the most important renal replacement therapy (RRT) indication for both nephrologists and PICU physicians (Likert scale from 0 [not important] to 10 [most important]; median = 10, 10, respectively). Nephrologists reported a lower threshold of AKI for increased mortality risk; 38% believed stage 2 AKI was the minimum compared to 17% of PICU physicians and 14% of nurses. Nephrologists were more likely than PICU physicians and nurses to recommend long-term follow-up for patients who develop any AKI during ICU stay (Likert scale from 0 [none] to 10 [all patients]; mean=6.0, 3.8, 3.7, respectively) (P < .05). Limitations: Responses from all eligible HCPs in the country could not obtained. There may be differences in opinions between HCPs that completed the survey compared to those that did not. Additionally, the cross-sectional design of our study may not adequately reflect changes in guidelines and knowledge since survey completion, although no specific guidelines have been released in Canada since survey dissemination. Conclusions: Canadian HCP groups have variable perspectives on pediatric AKI management and follow-up. Understanding practice patterns and perspectives will help optimize pediatric AKI follow-up guideline implementation.

Contexte: L'insuffisance rénale aiguë (IRA) chez les enfants gravement malades est associée à un risque accru d'issues défavorables à court et à long terme. En ce moment, il n'existe aucun suivi systématique pour les enfants qui développent une IRA pendant un séjour à l'unité des soins intensifs (USI). Objectif: Cette étude visait à évaluer les variations dans la prise en charge de l'IRA, de son importance perçue et de son suivi, tant au sein des groupes de professionnels de la santé (PS) qu'entre les différents groupes de PS. Conception: Des sondages transversaux à remplir de façon anonyme en ligne ont été menés à l'échelle nationale auprès de néphrologues pédiatriques canadiens, de médecins des unités de soins intensifs pédiatriques (USIP) et de membres du personnel infirmier des USIP ayant été répertoriés à partir de listes professionnelles. Cadre: Tous les néphrologues pédiatriques canadiens, médecins et membres du personnel infirmier qui traitent des enfants en USI étaient admissibles à répondre au sondage. Patients: S/O. Mesures: Les sondages comportaient des questions à choix multiples et des questions de type échelle de Likert qui portaient sur les pratiques actuelles de la gestion et de suivi à long terme de l'IRA, notamment sur les approches institutionnelles et personnelles de pratique et sur l'importance perçue de la gravité de l'IRA avec différents résultats. Méthodologie: Des statistiques descriptives ont été réalisées. Les réponses catégorielles ont été comparées à l'aide du chi-carré ou de tests exacts de probabilité de Fisher; les résultats des échelles de Likert ont été comparés à l'aide de tests de Mann-Whitney et de Kruskal-Wallis. Résultats: Les sondages ont été complétés par 53 % des néphrologues pédiatriques (34/64), 41 % des médecins d'USIP (46/113) et par 82 membres du personnel infirmier d'USIP (taux de réponse inconnu). Plus de 65 % des prestataires de soins ont déclaré que l'hémodialyse était prescrite par le service de néphrologie, alors que la dialyze péritonéale et la thérapie de remplacement rénal continu (TRRC) étaient confiées à la fois à la néphrologie, à l'USI ou à un modèle partagé néphrologie-USI. L'hyperkaliémie grave était l'indication la plus importante de la TRR pour les néphrologues et les médecins en USIP (échelle de Likert de 0 [pas important] à 10 [le plus important]; médiane = 10, 10, respectivement). Les néphrologues ont signalé un seuil inférieur d'IRA pour l'augmentation du risque de mortalité; 38 % d'entre eux estimaient que l'IRA de stade 2 était le seuil minimum, contre 17 % des médecins en USI et 14 % du personnel infirmier. Les néphrologues étaient plus susceptibles que les médecins et le personnel infirmier des USIP de recommander un suivi à long terme pour les patients qui développent une IRA pendant leur séjour en USI (échelle Likert de 0 [aucun] à 10 [tous les patients]; moyennes respectives = 6,0; 3,8 et 3,7 [p < 0,05]). Limites: Il n'a pas été possible d'obtenir les réponses de tous les PS admissibles au pays. Des différences d'opinions sont possibles entre les PS qui ont répondu au sondage et ceux qui ne l'ont pas fait. De plus, la conception transversale de notre étude pourrait ne pas refléter adéquatement les changements apportés aux lignes directrices et aux connaissances depuis la fin de cette enquête, bien qu'aucune ligne directrice particulière n'ait été publiée au Canada depuis la diffusion du sondage. Conclusion: Les divers groupes de professionnels de la santé canadiens ont des points de vue différents en ce qui concerne la prise en charge et le suivi de l'IRA chez les enfants. La compréhension des modèles de pratique et des perspectives permettra d'optimiser la mise en œuvre de directives de suivi de l'IRA pédiatrique.

Standard Versus Restrictive Transfusion Strategy for Pediatric Cardiac ECLS Patients: Single Center Retrospective Cohort Study.

This retrospective cohort study aimed to compare blood component transfusion before and after the implementation of a restrictive transfusion strategy (RTS) in pediatric cardiac Extracorporeal Life Support (ECLS) patients. The study included children admitted to the pediatric cardiac intensive care unit (PCICU) at the Stollery Children's Hospital who received ECLS between 2012 and 2020. Children on ECLS between 2012 and 2016 were treated with standard transfusion strategy (STS), while those on ECLS between 2016 and 2020 were treated with RTS. During the study, 203 children received ECLS. Daily median (interquartile range [IQR]) packed red blood cell (PRBC) transfusion volume was significantly lower in the RTS group; 26.0 (14.4-41.5) vs. 41.5 (26.6-64.4) ml/kg/day, p value <0.001. The implementation of a RTS led to a median reduction of PRBC transfusion of 14.5 (95% CI: 6.70-21.0) ml/kg/day. Similarly, the RTS group received less platelets: median (IQR) 8.4 (4.50-15.0) vs. 17.5 (9.40-29.0) ml/kg/day, p value <0.001. The implementation of a RTS resulted in a median reduction of platelet transfusion of 9.2 (95% CI: 5.45-13.1) ml/kg/day. The RTS resulted in less median (IQR) fluid accumulation in the first 48 hours: 56.7 (2.30-121.0) vs. 140.4 (33.8-346.2) ml/kg, p value = 0.001. There were no significant differences in mechanical ventilation days, PCICU/hospital days, or survival. The use of RTS resulted in lower blood transfusion volumes, with similar clinical outcomes.

A complicated Glenn procedure: risk factors and association with adverse long-term neurodevelopmental and functional outcomes.

OBJECTIVES: To determine potentially modifiable risk factors for a complicated Glenn procedure (cGP) and whether a cGP predicted adverse neurodevelopmental and functional outcomes. A cGP was defined as post-operative death, heart transplant, extracorporeal life support, Glenn takedown, or prolonged ventilation. METHODS: All 169 patients having a Glenn procedure from 2012 to 2017 were included. Neurodevelopmental assessments were performed at age 2 years in consenting survivors (n = 156/159 survivors). The Bayley Scales of Infant and Toddler Development-3rd Edition (Bayley-III) and the Adaptive Behavior Assessment System-2nd Edition (ABAS-II) were administered. Adaptive functional outcomes were determined by the General Adaptive Composite (GAC) score from the ABAS-II. Predictors of outcomes were determined using univariate and multiple variable linear or Cox regressions. RESULTS: Of patients who had a Glenn procedure, 10/169 (6%) died by 2 years of age and 27/169 (16%) had a cGP. Variables statistically significantly associated with a cGP were the inotrope score on post-operative day 1 (HR 1.04, 95%CI 1.01, 1.06; p = 0.010) and use of inhaled nitric oxide post-operatively (HR 7.31, 95%CI 3.19, 16.76; p < 0.001). A cGP was independently statistically significantly associated with adverse Bayley-III Cognitive (ES -10.60, 95%CI -17.09, -4.11; p = 0.002) and Language (ES -11.43, 95%CI -19.25, -3.60; p = 0.004) scores and adverse GAC score (ES -14.89, 95%CI -22.86, -6.92; p < 0.001). CONCLUSIONS: Higher inotrope score and inhaled nitric oxide used post-operatively were associated with a cGP. A cGP was independently associated with adverse 2-year neurodevelopmental and functional outcomes. Whether early recognition and intervention for risk of a cGP can prevent adverse outcomes warrants study.

Early hypophosphatemia in critically ill children and the effect of parenteral nutrition: A secondary analysis of the PEPaNIC RCT.

BACKGROUND & AIMS: Hypophosphatemia during critical illness has been associated with adverse outcome. The reintroduction of enteral or parenteral nutrition, leading to refeeding hypophosphatemia (RFH), has been presented as potential risk factor. We investigated the occurrence of early RFH, its association with clinical outcome, and the impact of early parenteral nutrition (PN) on the development of early RFH in pediatric critical illness. METHODS: This is a secondary analysis of the PEPaNIC randomized controlled trial (N = 1440), which showed that withholding supplemental parenteral nutrition (PN) for 1 week (late-PN) in the pediatric intensive care unit (PICU) accelerated recovery and reduced new infections compared to early-PN (<24 h). Patients with renal replacement therapy or unavailable phosphate concentrations were excluded from this analysis. Early RFH was defined as serum/plasma phosphate <0.65 mmol/L and a drop of >0.16 mmol/L within 3 days of admission to the PICU. The association between baseline characteristics and early RFH, and the association of early RFH with clinical outcome were investigated using logistic and linear regression models, both uncorrected and corrected for possible confounders. To examine the impact of nutritional intake on phosphate concentrations, structural nested mean models with propensity score and censoring models were used. RESULTS: A total of 1247 patients were eligible (618 early-PN, 629 late-PN). Early RFH occurred in 40 patients (3%) in total, significantly more in the early-PN group (n = 31, within-group occurrence 5%) than in the late-PN-group (n = 9, within-group occurrence 1%, p < 0.001). Patients who were older (OR 1.14 (95% CI 1.08; 1.21) per year added, p < 0.001) and who had a higher Pediatric Risk of Mortality (PIM3) score had a higher risk of developing early RFH (OR 1.36 (95% CI 1.15; 1.59) per unit added, p < 0.001), whereas patients in the late-PN group had a lower risk of early RFH (OR 0.24 (95% CI 0.10; 0.49), p < 0.001). Early RFH was significantly associated with a 56% longer PICU stay (p = 0.003) and 42% longer hospital stay (p = 0.007), but not with new infections (OR 2.01 (95% CI 0.90; 4.30), p = 0.08) or length of mechanical ventilatory support (OR 1.05 (95% CI -3.92; 6.03), p = 0.68), when adjusted for possible confounders. Increase of parenteral nutrition intake (in % kcal of predicted resting energy expenditure) decreased phosphate concentrations (c = -0.002 (95% CI -0.002; -0.001). CONCLUSIONS: Early RFH occurred in 3% of critically ill children. Patients randomized to late-PN had a lower chance of developing early RFH, which may be explained by the more gradual build-up of nutrition. As early RFH might impact recovery, it is important to closely monitor phosphate concentrations in patients, especially of those at risk for early RFH.

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.

Pediatric Extracorporeal Life Support Transport in Western Canada: Experience over 14 years.

This retrospective cohort study describes all children transported on extracorporeal life support (ECLS) by the Stollery Children's Hospital Pediatric Transport team (SCH-PTT) between 2004 and 2018. We compared outcomes and complications between primary (SCH-PTT performed ECLS cannulation) vs. secondary (cannulation performed by referring facility) transports, as well as secondary transports from referring centers with and without an established ECLS cannulation program. SCH-PTT performed 68 ECLS transports during the study period. Median (IQR) transport distance was 298 (298-1,068) kilometers. Mean (SD) times from referral call to ECLS-initiation were: primary transports 7.8 (2.9) vs. 2.5(3.5) hours for secondary transports, p value < 0.001. Complications were common (n = 65, 95%) but solved without leading to adverse outcomes. There were no significant differences in the number of complications between primary and secondary transports. There was no significant difference in survival to ECLS decannulation between primary 9 (90%) and secondary transports 43 (74%), p value = 0.275. ECLS survival was higher for children cannulated by the SCH-PTT or a center with an ECLS cannulation program: 42 (82%) vs. 10 (59%), p value = 0.048. Critically ill children on ECLS can be safely transported by a specialized pediatric ECLS transport team. Secondary transports from a center with an ECLS cannulation program are also safe and have similar results as primary transports.

Differential DNA methylation by early versus late parenteral nutrition in the PICU: a biological basis for its impact on emotional and behavioral problems documented 4 years later.

BACKGROUND: The PEPaNIC multicenter randomized controlled trial (RCT) has shown that early administration of supplemental parenteral nutrition (early-PN) as compared with withholding PN for 1 week (late-PN) induced long-term internalizing, externalizing and total emotional/behavioral problems in critically ill children, as observed 4 years later. Early-PN was further shown to alter the methylation status of 37 CpG-sites in leukocyte DNA between admission and discharge from the pediatric intensive care unit (PICU). In a preplanned subanalysis of the PEPaNIC trial, we now investigated whether the altered methylation of these CpG-sites could statistically explain the negative impact of early-PN on emotion/behavior documented 4 years after PICU admission. RESULTS: The combination of DNA methylation data and data on behavior 4 years after PICU admission was available for 403 of the 1440 patients (aged 0-17 years at PICU admission) who were included in the PEPaNIC RCT (192 early-PN and 211 late-PN patients). Mediation analyses with use of bootstrapped multivariable non-linear regression analyses adjusted for baseline risk factors revealed that the adverse alterations by early-PN in methylation of the 37 CpG-sites together statistically explained its harmful impact on internalizing, externalizing and total emotional/behavioral problems. When adding the methylation status of the 37 CpG-sites to the models, the explanatory power improved with a 1.710 to 1.851-fold increase, and the impact of the altered methylation status of the CpG-sites explained the impact of the randomization to early-PN versus late-PN. CONCLUSIONS: Abnormal DNA methylation induced by the early use of PN in the PICU provides a biological basis for its long-term harmful effect on emotion/behavior of critically ill children 4 years after PICU admission. Trial Registration ClinicalTrials.gov NCT01536275, registered February 17, 2012, https://clinicaltrials.gov/ct2/show/NCT01536275 .

Remote triage in paediatric critical care: A Canadian provincial-wide cohort study.

OBJECTIVE: To describe remote triage of 'potentially' critically ill or injured children in a western Canadian province and to examine the associated factors with 'missings' in vital sign items recorded in centralized telephone triage consultations. METHODS: This is a provincial-wide prospective cohort study. We included all children under 17 years of age consulted through the central transport coordination centres in Alberta from June 2016 to July 2017. We labeled a value as 'missing' when the actual value was not identified in the audio records. RESULTS: In total, 429 cases were included in this study. The median duration of triage calls was 6.8 minutes. Although the patients' demographics and primary diagnoses were similar, backgrounds of the referring physicians and hospitals were significantly different between the two cohorts (i.e., patients referred to Calgary versus Edmonton). The proportion of 'missings' among the vital sign items varied significantly, in which capillary refilling time (60%), pupils (86%), Glasgow Coma Scale (GCS) (79%), and level of respiratory effort (50%) were not well recorded, whereas heart rate (proportion of 'missings': 12%), SpO2 (20%), and respiratory rate (26%) were recorded reasonably well. The lower proportion of 'missings' was observed in older aged patients for several vital sign items including systolic blood pressure and GCS. CONCLUSIONS: The proportion of missing vital signs recorded varied significantly. The 'missings' could be associated with referring physician's background and patients' demographics such as 'age' that should be considered for the improvement of triage quality in the future.

Supplementation of vitamins, trace elements and electrolytes in the PEPaNIC Randomised Controlled Trial: Composition and preparation of the prescription.

BACKGROUND AND AIMS: Following the results of the paediatric early versus late parenteral nutrition in critical illness (PEPaNIC) multicentre, randomised, controlled trial, the new ESPGHAN/ESPEN/ESPR/CSPEN and ESPNIC guidelines recommend to consider withholding parenteral macronutrients for 1 week, while providing micronutrients, in critically ill children if enteral nutrition is insufficient. Critically ill children are suspected to be vulnerable to micronutrient deficiencies due to inadequate enteral nutrition, increased body's demands and excessive losses. Hitherto, micronutrient requirements in PICU are estimated based on recommended daily intakes for healthy children and expert opinion. We aimed to provide an overview of the current practice of micronutrient administration and practical considerations in the three participating centres of the PEPaNIC study, and compare these therapies with the recommendations in the new ESPGHAN/ESPEN/ESPR/CSPEN guidelines. METHODS: We describe the current composition and preparation of the prescribed parenteral micronutrients (consisting of vitamins, trace elements and electrolytes) in the three centres (Leuven, Rotterdam and Edmonton) that participated in the PEPaNIC RCT, and compare this per micronutrient with the ESPGHAN/ESPEN/ESPR/CSPEN guidelines recommendations. RESULTS: The three centres use a different micronutrient supplementation protocol during the first week of critical illness in children, with substantial differences regarding the amounts administered. Leuven administers commercial vitamins, trace elements and electrolytes in separate infusions both in 4 h. Rotterdam provides commercial vitamins and trace elements simultaneously via 8-h infusion and electrolytes continuously over 24 h. Lastly, Edmonton administers commercial vitamins and institutionally prepared trace elements solutions in 1 h and electrolytes on demand. Comparison with the ESPGHAN/ESPEN/ESPR/CSPEN guidelines yields in differences between the recommendations and the administered amounts, which are most substantial for vitamins. CONCLUSION: The practice of intravenous micronutrient administration differs substantially between the three PEPaNIC centres and in comparison with the current guideline recommendations. This deviation is at least partially explained by the inability to provide all recommended amounts with the currently available commercial products and by the lack of strong evidence supporting these recommendations.

Comparison of motor outcomes between preschool children with univentricular and biventricular critical heart disease not diagnosed with cerebral palsy or acquired brain injury.

This comparison study of two groups within an inception cohort aimed to compare the frequency of motor impairment between preschool children with univentricular and biventricular critical congenital heart disease (CHD) not diagnosed with cerebral palsy/acquired brain injury, describe and compare their motor profiles and explore predictors of motor impairment in each group.Children with an intellectual quotient <70 or cerebral palsy/acquired brain injury were excluded. Motor skills were assessed with the Movement Assessment Battery for Children-2. Total scores <5th percentile indicated motor impairment. Statistical analysis included χ2 test and multiple logistic regression analysis.At a mean age of 55.4 (standard deviation 3.77) months, motor impairment was present in 11.8% of those with biventricular critical CHD, and 32.4% (p < 0.001) of those with univentricular critical CHD. The greatest difference between children with biventricular and univentricular CHD was seen in total test scores 8.73(2.9) versus 6.44(2.8) (p < 0.01) and in balance skills, 8.84 (2.8) versus 6.97 (2.5) (p = 0.001). Manual dexterity mean scores of children with univentricular CHD were significantly below the general population mean (>than one standard deviation). Independent odds ratio for motor impairment in children with biventricular critical CHD was presence of chromosomal abnormality, odds ratio 10.9 (CI 2.13-55.8) (p = 0.004); and in children with univentricular critical CHD odds ratio were: postoperative day 1-5 highest lactate (mmol/L), OR: 1.65 (C1.04-2.62) (p = 0.034), and dialysis requirement any time before the 4.5-year-old assessment, OR: 7.8 (CI 1.08-56.5) (p = 0.042).Early assessment of motor skills, particularly balance and manual dexterity, allows for intervention and supports that can address challenges during the school years.

Association Between Acute Kidney Injury Duration and Outcomes in Critically Ill Children.

OBJECTIVES: Acute kidney injury occurs frequently in children during critical illness and is associated with increased morbidity, mortality, and health resource utilization. We aimed to examine the association between acute kidney injury duration and these outcomes. DESIGN: Retrospective cohort study. SETTINGS: PICUs in Alberta, Canada. PATIENTS: All children admitted to PICUs in Alberta, Canada between January 1, 2015, and December 31, 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 1,017 children were included, and 308 (30.3%) developed acute kidney injury during PICU stay. Acute kidney injury was categorized based on duration to transient (48 hr or less) or persistent (more than 48 hr). Transient acute kidney injury occurred in 240 children (77.9%), whereas 68 children (22.1%) had persistent acute kidney injury. Persistent acute kidney injury had a higher proportion of stage 2 and stage 3 acute kidney injury compared with transient acute kidney injury and was more likely to start within 24 hours from PICU admission. Persistent acute kidney injury occurred more frequently in those with higher illness severity and in those admitted with shock, sepsis, or with a history of transplant. Mortality varied significantly according to acute kidney injury status: 1.8% of children with no acute kidney injury, 5.4% with transient acute kidney injury, and 17.6% with persistent acute kidney injury died during hospital stay (p < 0.001). On multivariable analysis adjusting for illness and acute kidney injury severity, transient and persistent acute kidney injury were both associated with fewer ventilation-free days at 28 days (-1.28 d; 95% CI, -2.29 to -0.26 and -4.85 d; 95% CI, -6.82 to -2.88), vasoactive support-free days (-1.07 d; 95% CI, -2.00 to -0.15 and -4.24 d; 95% CI, -6.03 to -2.45), and hospital-free days (-1.93 d; 95% CI, -3.36 to -0.49 and -5.25 d; 95% CI, -8.03 to -2.47), respectively. CONCLUSIONS: In critically ill children, persistent and transient acute kidney injury have different clinical characteristics and association with outcomes. Acute kidney injury, even when its duration is short, carries significant association with worse outcomes. This risk increases further if acute kidney injury persists longer independent of the degree of its severity.

Music Use for Sedation in Critically ill Children (MUSiCC trial): a pilot randomized controlled trial.

OBJECTIVE: To demonstrate feasibility of a music medicine intervention trial in pediatric intensive care and to obtain information on sedation and analgesia dose variation to plan a larger trial. MATERIAL AND METHODS: Pilot randomized controlled trial (RCT) was conducted at the Stollery Children's Hospital general and cardiac intensive care units (PICU/PCICU). The study included children 1 month to 16 years of age on mechanical ventilation and receiving sedation drugs. Patients were randomized in a 1:1:1 ratio to music, noise cancellation or control. The music group received classical music for 30 min three times/day using headphones. The noise cancellation group received the same intervention but with no music. The control group received usual care. RESULTS: A total of 60 patients were included. Average enrollment rate was 4.8 patients/month, with a consent rate of 69%. Protocol adherence was achieved with patients receiving > 80% of the interventions. Overall mean (SD) daily Sedation Intensity Score was 52.4 (30.3) with a mean (SD) sedation frequency of 9.75 (7.21) PRN doses per day. There was a small but statistically significant decrease in heart rate at the beginning of the music intervention. There were no study related adverse events. Eighty-eight percent of the parents thought the headphones were comfortable; 73% described their child more settled during the intervention. CONCLUSIONS: This pilot RCT has demonstrated the feasibility of a music medicine intervention in critically ill children. The study has also provided the necessary information to plan a larger trial.

Impact of early surgical correction or palliation of congenital heart defects in infants with symptomatic viral respiratory tract infections in the current era.

Objective: This study investigates the influence of timing of surgery among infants with congenital heart disease and active respiratory tract infections in a contemporary Western Canadian cohort. Methods: This was a retrospective matched cohort study of infants aged 1 week to 6 months undergoing surgical repair of congenital heart disease between 2014 and 2017. Case patients had active respiratory tract infections preoperatively and were matched to control patients based on primary heart lesion. The primary outcome was time to extubation. Results: We identified 20 cases (median age, 3.4 months [range, 2.4-4.3 months]) that were matched to 40 controls (1:2 ratio). In case patients, surgery occurred at a median of 1 day after the positive viral testing. There were no statistically significant differences between cases and controls in time to extubation (59 vs 34 hours [P = .12]), postoperative vasoactive scores at 24 hours (0 vs 0 [P = .53]), 48 hours (0 vs 0 [P = .23]), maximum vasoactive score in postoperative period (5 vs 5.5 [P = .54]), or time to hospital discharge (13 vs 12 days [P = .39]). Case patients had increased duration of total respiratory support (including noninvasive ventilation, 3.5 vs 2 days [P = .02]) and postoperative intensive care unit length of stay (5.5 vs 3 days [P = .01]). Conclusions: Cardiac surgery on infants with congenital heart disease during an acute viral respiratory tract infection may yield a clinically relevant prolongation in time to extubation.

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.