Rapid normalization of vitamin D deficiency in PICU (VITdALIZE-KIDS): study protocol for a phase III, multicenter randomized controlled trial.

BACKGROUND: The rate of vitamin D deficiency (VDD) in critically ill children worldwide has been estimated at 50%. These children are at risk of multiple organ dysfunction, chronic morbidity, and decreased health related quality of life (HRQL). Pediatric and adult ICU clinical trials suggest that VDD is associated with worse clinical outcomes, although data from supplementation trials are limited and inconclusive. Our group's phase II multicenter dose evaluation pilot study established the efficacy and safety of an enteral weight-based cholecalciferol loading dose to rapidly restore vitamin D levels in critically ill children. METHODS: Our aim is to evaluate the impact of this dosing regimen on clinical outcomes. VITdALIZE-KIDS is a pragmatic, phase III, multicenter, double-blind RCT aiming to randomize 766 critically ill children from Canadian PICUs. Participants are randomized using a 1:1 scheme to receive a single dose at enrollment of enteral cholecalciferol (10,000 IU/kg, max 400,000 IU) or placebo. Eligibility criteria include critically ill children aged newborn (> 37 weeks corrected gestational age) to < 18 years who have blood total 25-hydroxyvitamin D < 50 nmol/L. The primary objective is to determine if rapid normalization of vitamin D status improves HRQL at 28 days following enrollment. The secondary objective is to evaluate the impact of rapid normalization of vitamin D status on multiple organ dysfunction. The study includes additional tertiary outcomes including functional status, HRQL and mortality at hospital discharge and 90 days, PICU and hospital length of stay, and adverse events related to vitamin D toxicity. Additionally, we are performing comprehensive vitamin D speciation and non-targeted metabolite profiling as part of a sub-study for the first 100 participants from whom an enrollment and at least one post-intervention blood and urine sample were obtained. DISCUSSION: The VITdALIZE-KIDS trial is the first phase III, multicenter trial to evaluate whether rapid normalization of vitamin D status could represent a simple, inexpensive, and safe means of improving outcomes following pediatric critical illness. Recruitment was initiated in June 2019 and is expected to continue to March 2026. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03742505. Study first submitted on November 12, 2018 https://clinicaltrials.gov/study/NCT03742505.

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.

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.

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.

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.

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.

Long-term developmental effect of withholding parenteral nutrition in paediatric intensive care units: a 4-year follow-up of the PEPaNIC randomised controlled trial.

BACKGROUND: The PEPaNIC randomised controlled trial, which recruited 1440 critically ill infants and children in 2012-15, showed that withholding parenteral nutrition for 1 week (late-parenteral nutrition), compared with early supplementation within 24 h of admission to the paediatric intensive care unit (early-parenteral nutrition), prevented infections, accelerated recovery, and improved neurocognitive development assessed 2 years later. Because several neurocognitive domains can only be thoroughly assessed from age 4 years onwards, we aimed to determine the effect of late-parenteral nutrition versus early-parenteral nutrition on physical, neurocognitive, and emotional and behavioural development 4 years after randomisation. METHODS: This is a preplanned, blinded, 4-year follow-up study of participants included in the PEPaNIC trial (done at University Hospitals Leuven, Belgium; Erasmus Medical Centre Sophia Children's Hospital, Rotterdam, Netherlands; and Stollery Children's Hospital, Edmonton, AB, Canada) and of matched healthy children. Studied outcomes were anthropometrics; health status; parent-reported or caregiver-reported executive functions, and emotional and behavioural problems; and clinical tests for intelligence, visual-motor integration, alertness, motor coordination, and memory. Through multivariable linear and logistic regression analyses, after imputation for missing values (≤30%) and adjustment for risk factors, we investigated the effect of early-parenteral nutrition versus late-parenteral nutrition. This trial is registered with ClinicalTrials.gov, NCT01536275. FINDINGS: Between March 8, 2016, and Nov 8, 2019, 684 children from the original PEPaNIC trial (356 from the late-parenteral nutrition group and 328 from the early-parenteral nutrition group) were assessed for neurocognitive development at 4-years follow-up. Compared with the control group (369 healthy children), children who had critical illness had lower height (ß-estimate -2·11 [95% CI -3·15 to -1·06]; p<0·0001) and head circumference (-0·42 [-0·67 to -0·18]; p=0.00077); and worse health status (eg, hospital admission odds ratio 4·27 [95% CI 3·12 to 5·84]; p<0·0001), neurocognitive (eg, parent-reported or caregiver-reported total executive functioning ß-estimate 3·57 [95% CI 1·95 to 5·18], p<0·0001; total intelligence quotient -7·35 [-9·31 to -5·39], p<0·0001), and parent-reported or caregiver-reported emotional and behavioural developmental outcomes (internalising 2·73 [1·19 to 4·28], p=0·00055; externalising 1·63 [0·19 to 3·08], p=0·027; and total behavioural problems 2·95 [1·44 to 4·46], p=0·00013), adjusted for risk factors. Outcomes were never worse in the late-parenteral nutrition group compared with the early-parenteral nutrition group, but patients in the late-parenteral nutrition group had fewer parent-reported or caregiver-reported internalising (ß-estimate -1·88 [95% CI -3·69 to -0·07]; p=0·042), externalising (-1·73 [-3·43 to -0·03]; p=0·046), and total emotional and behavioural problems (-2·44 [-4·22 to -0·67]; p=0·0070) than patients who had received early-parenteral nutrition, after adjusting for risk factors, and were no longer different from healthy controls for these outcomes. INTERPRETATION: Omitting early parenteral nutrition use for critically ill children did not adversely affect long-term outcomes 4 years after randomisation and protected against emotional and behavioural problems, further supporting the deimplementation of early parenteral nutrition. FUNDING: European Research Council, Methusalem, Flanders Institute for Science and Technology, Research Foundation Flanders, Sophia Foundation, Stichting Agis Zorginnovatie, Erasmus Trustfonds, and the European Society for Clinical Nutrition and Metabolism.

Effect of Fresh vs Standard-issue Red Blood Cell Transfusions on Multiple Organ Dysfunction Syndrome in Critically Ill Pediatric Patients: A Randomized Clinical Trial.

Importance: The clinical consequences of red blood cell storage age for critically ill pediatric patients have not been examined in a large, randomized clinical trial. Objective: To determine if the transfusion of fresh red blood cells (stored ≤7 days) reduced new or progressive multiple organ dysfunction syndrome compared with the use of standard-issue red blood cells in critically ill children. Design, Setting, and Participants: The Age of Transfused Blood in Critically-Ill Children trial was an international, multicenter, blinded, randomized clinical trial, performed between February 2014 and November 2018 in 50 tertiary care centers. Pediatric patients between the ages of 3 days and 16 years were eligible if the first red blood cell transfusion was administered within 7 days of intensive care unit admission. A total of 15 568 patients were screened, and 13 308 were excluded. Interventions: Patients were randomized to receive either fresh or standard-issue red blood cells. A total of 1538 patients were randomized with 768 patients in the fresh red blood cell group and 770 in the standard-issue group. Main Outcomes and Measures: The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured for 28 days or to discharge or death. Results: Among 1538 patients who were randomized, 1461 patients (95%) were included in the primary analysis (median age, 1.8 years; 47.3% girls), in which there were 728 patients randomized to the fresh red blood cell group and 733 to the standard-issue group. The median storage duration was 5 days (interquartile range [IQR], 4-6 days) in the fresh group vs 18 days (IQR, 12-25 days) in the standard-issue group (P < .001). There were no significant differences in new or progressive multiple organ dysfunction syndrome between fresh (147 of 728 [20.2%]) and standard-issue red blood cell groups (133 of 732 [18.2%]), with an unadjusted absolute risk difference of 2.0% (95% CI, -2.0% to 6.1%; P = .33). The prevalence of sepsis was 25.8% (160 of 619) in the fresh group and 25.3% (154 of 608) in the standard-issue group. The prevalence of acute respiratory distress syndrome was 6.6% (41 of 619) in the fresh group and 4.8% (29 of 608) in the standard-issue group. Intensive care unit mortality was 4.5% (33 of 728) in the fresh group vs 3.5 % (26 of 732) in the standard-issue group (P = .34). Conclusions and Relevance: Among critically ill pediatric patients, the use of fresh red blood cells did not reduce the incidence of new or progressive multiple organ dysfunction syndrome (including mortality) compared with standard-issue red blood cells. Trial Registration: ClinicalTrials.gov Identifier: NCT01977547.

Effect of early supplemental parenteral nutrition in the paediatric ICU: a preplanned observational study of post-randomisation treatments in the PEPaNIC trial.

BACKGROUND: Large randomised controlled trials have shown that early supplemental parenteral nutrition in patients admitted to adult and paediatric intensive care units (PICUs) is harmful. Overdosing of energy with too little protein was suggested as a potential reason for this. This study analysed which macronutrient was associated with harm caused by early supplemental parenteral nutrition in the Paediatric Early versus Late Parenteral Nutrition In Critical Illness (PEPaNIC) randomised trial. METHODS: Patients in the initial randomised controlled trial were randomly assigned to receive suppplemental parenteral nutrition (PN) within 24 h of PICU admission (early PN) or to receive such PN after 1 week (late PN) when enteral nutrition was insufficient. In this post-randomisation, observational study, doses of glucose, lipids, and aminoacids administered during the first 7 days of PICU stay were expressed as % of reference doses from published clinical guidelines for age and weight. Independent associations between average macronutrient doses up to each of the first 7 days and likelihood of acquiring an infection in the PICU, of earlier live weaning from mechanical ventilation, and of earlier live PICU discharge were investigated using multivariable Cox proportional hazard analyses. The three macronutrients were included in the analysis simultaneously and baseline risk factors were adjusted for. FINDINGS: From June 18, 2012, to July 27, 2015, 7519 children aged between newborn and 17 years were assessed for eligibility. 6079 patients were excluded, and 1440 children were randomly assigned to receive either early PN (n=723) or late PN (n=717). With increasing doses of aminoacids, the likelihood of acquiring a new infection was higher (adjusted hazard ratios [HRs] per 10% increase between 1·043-1·134 for days 1-5, p≤0·029), while the likelihood of earlier live weaning from mechanical ventilation was lower (HRs 0·950-0·975 days 3-7, p≤0·045), and the likelihood of earlier live PICU discharge was lower (HRs 0·943-0·972 days 1-7, p≤0·030). By contrast, more glucose during the first 3 days of PICU stay was independently associated with fewer infections (HRs 0·870-0·913, p≤0·036), whereas more lipids was independently associated with earlier PICU discharge (HRs 1·027-1·050, p≤0·043 days 4-7). Risk of harm with aminoacids was also shown for low doses. INTERPRETATION: These associations suggest that early administration of aminoacids, but not glucose or lipids, could explain harm caused by early supplemental parenteral nutrition in critically ill children. FUNDING: Flemish Agency for Innovation through Science and Technology; UZLeuven Clinical Research Fund; Research Foundation Flanders; Methusalem Programme Flemish Government; European Research Council; Fonds-NutsOhra; Erasmus-MC Research Grant; Erasmus Trustfonds.

Pilot randomized controlled trial on early and late remote ischemic preconditioning prior to complex cardiac surgery in young infants.

BACKGROUND: Remote ischemic preconditioning involves providing a brief ischemia-reperfusion event to a tissue to create subsequent protection from a more severe ischemia-reperfusion event to a different tissue/organ. The few pediatric remote ischemic preconditioning studies in the literature show conflicting results. AIM: We conducted a pilot randomized controlled trial to determine the feasibility of conducting a larger trial and to gather provisional data on the effect of early and late remote ischemic preconditioning on outcomes of infants after surgery for congenital heart disease. METHODS: This single-center, double-blind randomized controlled trial of remote ischemic preconditioning vs control (sham-remote ischemic preconditioning) in young infants going for surgery for congenital heart disease at the Stollery Children's Hospital. Remote ischemic preconditioning was performed at 24-48 h preoperatively and immediately prior to cardiopulmonary bypass. Remote ischemic preconditioning stimulus was performed with blood pressure cuffs around the thighs. Primary outcomes were feasibility and peak blood lactate level on day 1 postoperatively. RESULTS: Fifty-two patients were randomized but seven patients became ineligible after randomization leaving 45 patients included in the study. In the included patients, 7 (15%) had protocol deviations (five infants did not have the preoperative intervention and two did not receive the intervention in the operating room). From a comfort point of view, only one subject in the control group and two in the Remote ischemic preconditioning group received sedation during the preoperative intervention. There were no study-related adverse events and no complications to the limbs subjected to preconditioning. There were no significant differences between the Remote ischemic preconditioning group and the control group in the highest blood lactate level on day 1 postoperatively (mean difference, 1.28; 95%CI, -0.22, 2.78; P-value = 0.093). CONCLUSION: In infants who underwent surgery for congenital heart disease, our pilot randomized controlled trial on early and late remote ischemic preconditioning proved to be feasible but did not find any significant difference in acute outcomes. A larger trial may be necessary.

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. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01536275 on 16 February 2012.

Survival and neurocognitive outcomes after cardiac extracorporeal life support in children less than 5 years of age: a ten-year cohort.

BACKGROUND: Survival after pediatric cardiac extracorporeal life support (ECLS) is guarded, and neurological morbidity varies widely. Our objective is to report our 10-year experience with cardiac ECLS, including survival and kindergarten entry neurocognitive outcomes; to identify predictors of mortality or adverse neurocognitive outcomes; and to compare 2 eras, before and after 2005. METHODS AND RESULTS: From 2000 to 2009, 98 children had venoarterial cardiac ECLS. Sixty-four patients (65%) survived to hospital discharge, and 50 (51%) survived ≤5 years of age. Neurocognitive follow-up of survivors was completed at mean (SD) age of 52.9 (8) months using Wechsler Preschool and Primary Scale of Intelligence. Logistic regression analysis found the longer time (hours) for lactate to fall below 2 mmol/L on ECLS (hazard ratio, 1.39; 95% confidence interval, 1.05, 1.84; P=0.022), and the amount of platelets (mL/kg) given in the first 48 hours (hazard ratio, 1.18; 95% confidence interval, 1.06, 1.32; P=0.002) was independently associated with higher in-hospital mortality. Receiving ECLS after the year 2005 was independently associated with lower risk of in-hospital mortality (hazard ratio, 0.36; 95% confidence interval, 0.13, 0.99; P=0.048). Extracorporeal cardiopulmonary resuscitation was not independently associated with mortality or neurocognitive outcomes. Era was not independently associated with neurocognitive outcomes. The full-scale intelligence quotient of survivors without chromosomal abnormalities was 79.7 (16.6) with 25% below 2 SD of the population mean. CONCLUSIONS: Mortality has improved over time; time for lactate to fall on ECLS and volume of platelets transfused are independent predictors of mortality. Extracorporeal cardiopulmonary resuscitation and era were not independently associated with neurocognitive outcomes.

Hemodynamic changes in child acute respiratory distress syndrome with airway pressure release ventilation: a case series.

BACKGROUND: Airway pressure release ventilation (APRV) is widely used in adult critical care settings. However, information on the use of APRV in the pediatric population is limited. METHODS: All patients admitted to the medical-surgical pediatric intensive care unit with a diagnosis of acute respiratory distress syndrome (ARDS) who received APRV for at least 12 h between 2007 and 2009 were reviewed. RESULTS: Thirteen patients with a variety of etiologies of ARDS were included, with a mean weight of 18.2 ± 15.0 kg, a mean age of 68 ± 57 months and a predicted mortality (based on Pediatric Index of Mortality version 2) of 23.9 ± 13.8%. Patients were placed on APRV for a median of 4 days (range 1-10 days). There was no change in blood gas parameters after 1 h or 12 h of APRV when compared with pre-APRV. There was no statistical difference in hemodynamic parameters, including mean arterial blood pressure, central venous blood pressure and heart rate, while the patients were on APRV. CONCLUSION: APRV could be safely used in pediatric ARDS patients, without significant hemodynamic compromise or side effects.

Is propofol a friend or a foe of the pediatric intensivist? Description of propofol use in a PICU*.

OBJECTIVE: The primary objective is to describe the practice patterns of nonprocedural propofol use in a single-center referral PICU. The secondary objective is to describe the rate of concordance of propofol use with the PICU local practice of a maximum mean rate of 4 mg/kg/hr and a maximum duration of 24 hours and to assess for signs and symptoms of propofol infusion syndrome. DESIGN: Retrospective descriptive cohort study. SETTING: PICU of a tertiary care teaching hospital and referral hospital for the Western Canada. PATIENTS: Children 1 month to 17 years old who received a nonprocedural propofol infusion between January 1, 2009, and December 31, 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred twenty-three infusions (representing 210 unique patients) were included in the study. The median average infusion rate (interquartile range) including boluses was 2.7 mg/kg/hr (1.9-3.6 mg/kg/hr), and the mean infusion duration (SD) was 10.3 hours (6.7 hr). Eighty-seven percent and 98% of infusions were concordant with PICU intensivists self-reported practice maximum rate and duration, respectively. No cases of propofol-related infusion syndrome or deaths associated with propofol infusions were identified. CONCLUSIONS: The use of propofol infusions was in concordance with PICU local practice, and propofol infusion syndrome did not developed in patients. In agreement with previous recommendations, propofol infusions in the PICU appear to be safe when limiting doses to 4 mg/kg/hr and for less than 24 hours; however, appropriate monitoring of adverse effects is still warranted due to absence of robust evidence.

A Canadian survey of perceived barriers to initiation and continuation of enteral feeding in PICUs.

OBJECTIVE: Clinicians believe nutrition support is important; however, delivery of enteral nutrition may be delayed or interrupted due to a lack of guidelines or perceived contraindications to administration. The aim of this national survey was to examine the knowledge and perceived barriers among clinicians which prevent enteral nutrition administration to PICU patients. DESIGN: The survey consisted of 23 questions (19 primary and four branching). The survey was validated using a semistructured pilot test by three pediatric critical care intensivists and two pediatric critical care registered dietitians external to the study team. SETTING: The survey was electronically distributed to clinicians in all PICUs across Canada. POPULATION: One hundred sixty-two PICU clinicians, including 96 staff intensivists, eight clinical assistants, 36 fellows, and 22 registered dietitians from PICUs across Canada. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The survey was administered from January to March 2013. The response rate was 50% (55 staff intensivists, two clinical assistants, nine fellows, and 15 registered dietitians). There was high variability among clinicians regarding reasons to delay the onset of enteral nutrition or interrupt enteral nutrition administration. High variability (> 70% agreement and < 10% disagreement or vice versa) was found for some reasons to delay or interrupt enteral nutrition, including lactates (rising or > 2 or > 4 mmol/L), high gastric residual volumes, CT/MRI scans, and hypoplastic left heart syndrome. Sixty-eight percent of PICU clinicians reported no written feeding protocol to be in place. CONCLUSIONS: Overall, there is high variability among clinicians regarding acceptable procedural and clinical barriers to enteral nutrition administration; this may be improved by a standardized feeding protocol. Therefore, further research must be conducted to provide clinicians with evidence to support their practices for enteral nutrition administration.

Indications and outcomes in children receiving renal replacement therapy in pediatric intensive care.

PURPOSE: We aimed to describe patient characteristics, indications for renal replacement therapy (RRT), and outcomes in children requiring RRT. We hypothesized that fluid overload, not classic blood chemistry indications, would be the most frequent reason for RRT initiation. MATERIALS AND METHODS: A retrospective cohort study of all patients receiving RRT at a single-center quaternary pediatric intensive care unit between January 2004 and December 2008 was conducted. RESULTS: Ninety children received RRT. The median age was 7 months (interquartile range, 1-83). Forty-six percent of patients received peritoneal dialysis, and 54% received continuous renal replacement therapy. The median (interquartile range) PRISM-III score was 14 (8-19). Fifty-seven percent had congenital heart disease, and 32% were on extracorporeal life support. The most common clinical condition associated with acute kidney injury was hemodynamic instability (57%; 95% confidence interval [CI], 46-67), followed by multiorgan dysfunction syndrome (17%; 95% CI, 10-26). The most common indication for RRT initiation was fluid overload (77%; 95% CI, 66-86). Seventy-three percent (95% CI, 62-82) of patients survived to hospital discharge. CONCLUSIONS: Hemodynamic instability and multiorgan dysfunction syndrome are the most common clinical conditions associated with acute kidney injury in our population. In the population studied, the mortality was lower than previously reported in children and much lower than in the adult population.

Diagnosis and management of circulatory arrest in pediatric ventricular assist device patients: presentation of two cases and suggested guidelines.

INTRODUCTION: Pediatric patients supported by ventricular assist devices (VADs) are becoming more common. No guidelines exist to provide an approach to diagnosis or management of circulatory arrest in these patients. We present two case reports of apparent circulatory arrest in pediatric VAD-supported patients at our institution. DISCUSSION: Diagnosis of circulatory arrest in VAD-supported patients can be challenging, especially with non-pulsatile flow devices. Traditional methods of diagnosis, such as pulse check and blood pressure, may be unreliable. Etiology may be primary device failure though other etiologies need to be considered. Treatment of the circulatory arrest depends on the etiology and type of VAD device being used. CONCLUSION: In the absence of strong literature on the approach to these patients, we present these case reports and our local institutional guidelines as a starting point for discussion.

Safety of Berlin Heart EXCOR pump changes in the PICU.

OBJECTIVE: To describe whether Berlin Heart EXCOR Pediatric pump changes in the ICU are associated with infection, hemodynamic and ventilatory instability, and neurologic injury. DESIGN: Retrospective, descriptive chart review. SETTING: PICU in a quaternary care children's hospital. PATIENTS: Eight patients were supported on Berlin Heart EXCOR Pediatric pumps due to cardiomyopathy or cardiogenic shock. Two patients were supported with left ventricular assist devices, five had biventricular assist devices, and one required a univentricular assist device. INTERVENTIONS: A team of cardiac surgeons, pediatric intensivists, and operating room nurses conducted sixteen pump changes in the pediatric intensive care unit. Patients were monitored for deleterious effects for 5 days following the change. MEASUREMENT AND MAIN RESULTS: For the first 48 hrs following the EXCOR pump change, no patients exhibited acute neurologic deficits or escalation of hemodynamic or ventilatory support. Over the first 5 days, no blood cultures were positive for microbes. CONCLUSIONS: Berlin Heart EXCOR Pediatric pump changes in the pediatric intensive care unit appear to be a safe procedure when conducted by a highly specialized team.