Prognostic and Diagnostic Utility of Serum Biomarkers in Pediatric Traumatic Brain Injury.

Traumatic brain injury (TBI) remains a major cause of morbidity and death among the pediatric population. Timely diagnosis, however, remains a complex task because of the lack of standardized methods that permit its accurate identification. The aim of this study was to determine whether serum levels of brain injury biomarkers can be used as a diagnostic and prognostic tool in this pathology. This prospective, observational study collected and analyzed the serum concentration of neuronal injury biomarkers at enrollment, 24h and 48h post-injury, in 34 children ages 0-18 with pTBI and 19 healthy controls (HC). Biomarkers included glial fibrillary acidic protein (GFAP), neurofilament protein L (NfL), ubiquitin-C-terminal hydrolase (UCH-L1), S-100B, tau and tau phosphorylated at threonine 181 (p-tau181). Subjects were stratified by admission Glasgow Coma Scale score into two categories: a combined mild/moderate (GCS 9-15) and severe (GCS 3-8). Glasgow Outcome Scale-Extended (GOS-E) Peds was dichotomized into favorable (≤4) and unfavorable (≥5) and outcomes. Data were analyzed utilizing Prism 9 and R statistical software. The findings were as follows: 15 patients were stratified as severe TBI and 19 as mild/moderate per GCS. All biomarkers measured at enrollment were elevated compared with HC. Serum levels for all biomarkers were significantly higher in the severe TBI group compared with HC at 0, 24, and 48h. The GFAP, tau S100B, and p-tau181 had the ability to differentiate TBI severity in the mild/moderate group when measured at 0h post-injury. Tau serum levels were increased in the mild/moderate group at 24h. In addition, NfL and p-tau181 showed increased serum levels at 48h in the aforementioned GCS category. Individual biomarker performance on predicting unfavorable outcomes was measured at 0, 24, and 48h across different GOS-E Peds time points, which was significant for p-tau181 at 0h at all time points, UCH-L1 at 0h at 6-9 months and 12 months, GFAP at 48h at 12 months, NfL at 0h at 12 months, tau at 0h at 12 months and S100B at 0h at 12 months. We concluded that TBI leads to increased serum neuronal injury biomarkers during the first 0-48h post-injury. A biomarker panel measuring these proteins could aid in the early diagnosis of mild to moderate pTBI and may predict neurological outcomes across the injury spectrum.

Impact of congenital heart disease on mortality and other associated outcomes in children hospitalised for acute asthma exacerbation.

BACKGROUND: Acute asthma exacerbation is one of the most common reasons for paediatric emergency room visits and hospital admissions in the United States of America. OBJECTIVE: To assess the impact of CHD on outcomes of children hospitalised for acute asthma exacerbation. METHODS: Children primarily admitted for acute asthma exacerbation were sampled from 2006, 2009, 2012, and 2016 kid inpatient database of the Healthcare Cost and Utilization Project using ICD codes. The disease outcomes were compared between those with and without CHD using multivariate logistic regressions in Stata version 17. RESULTS: There were a total of 639,280 acute asthma exacerbation admissions, of which 5,907 (0.92%) had CHD. The mortality rate was 0.079% for patients without CHD and 0.72% for those with co-existing CHD. Children with CHD had higher odds of mortality (5.51, CI 3.40-8.93, p < 0.001), acute respiratory failure (2.84, CI 2.53-3.20; p < 0.001), need for invasive mechanical ventilation (4.58, CI 3.80-5.52; p < 0.001), acute kidney injury (adjusted odds ratio 3.03, CI 3.03-7.44; p < 0.001), and in-hospital cardiac arrest (adjusted odds ratio 4.52, CI 2.49-8.19; p < 0.001) when compared with those without CHD. The adjusted mean length of hospital stays (CI 2.91-3.91; p < 0.001) and hospital charges (95% CI $31060-$47747) among children with acute asthma exacerbation and CHD were significantly higher than in those without CHD. CONCLUSION AND SIGNIFICANCE: CHD is an independent predictor of mortality, more severe disease course, and higher hospital resource utilisation. Strategies that improve CHD care will likely improve the overall health outcomes of children with CHD hospitalised for acute asthma exacerbation.

Utility of Brain Injury Biomarkers in Children With Congenital Heart Disease Undergoing Cardiac Surgery.

BACKGROUND: Congenital heart disease (CHD) affects roughly 40,000 children annually. Despite advancements, children undergoing surgery for CHD are at an increased risk for adverse neurological outcomes. At present, there is no gold standard for the diagnosis of cerebral injury during the perioperative period. OBJECTIVE: To determine the utility of brain injury biomarkers in children undergoing cardiac surgery. METHODS: We searched PUBMED, EMBASE, LILACS, EBSCO, ClinicalTrials.gov, Cochrane Databases, and OVID interface to search MEDLINE through July 2021 and assessed the literature following the snowball method. The search terms used were "congenital heart disease," "cardiopulmonary bypass," "biomarkers," "diagnosis," "prognosis," and "children." No language or publication date restrictions were used. Papers studying inflammatory and imaging biomarkers were excluded. The risk of bias, strengths, and limitations of the study were reported. Study was registered in PROSPERO ID: CRD42021258385. RESULTS: A total of 1449 articles were retrieved, and 27 were included. Eight neurological biomarkers were examined. Outcomes assessed included prognosis of poor neurological outcome, mortality, readmission, and diagnosis of brain injury. Results from these studies support that significant perioperative elevations in brain injury biomarkers in cerebrospinal fluid and serum, including S100B, GFAP, NSE, and activin A, may be diagnostic of real-time brain injury and serve as an independent predictor of adverse neurological outcomes in patients with CHD undergoing cardiopulmonary bypass. CONCLUSIONS: There are limited homogeneous data in the field, limiting the generalizability and comparability of the results. Further large-scale longitudinal studies addressing neurological biomarkers in children undergoing CHD corrective surgery are required to support the routine use of neuronal biomarkers in this population.

The First Hybrid International Educational Comprehensive Cleft Care Workshop.

OBJECTIVE: Describe the first hybrid global simulation-based comprehensive cleft care workshop, evaluate impact on participants, and compare experiences based on in-person versus virtual attendance. DESIGN: Cross-sectional survey-based evaluation. SETTING: International comprehensive cleft care workshop. PARTICIPANTS: Total of 489 participants. INTERVENTIONS: Three-day simulation-based hybrid comprehensive cleft care workshop. MAIN OUTCOME MEASURES: Participant demographic data, perceived barriers and interventions needed for global comprehensive cleft care delivery, participant workshop satisfaction, and perceived short-term impact on practice stratified by in-person versus virtual attendance. RESULTS: The workshop included 489 participants from 5 continents. The response rate was 39.9%. Participants perceived financial factors (30.3%) the most significant barrier and improvement in training (39.8%) as the most important intervention to overcome barriers facing cleft care delivery in low to middle-income countries. All participants reported a high level of satisfaction with the workshop and a strong positive perceived short-term impact on their practice. Importantly, while this was true for both in-person and virtual attendees, in-person attendees reported a significantly higher satisfaction with the workshop (28.63 ± 3.08 vs 27.63 ± 3.93; P = .04) and perceived impact on their clinical practice (22.37 ± 3.42 vs 21.02 ± 3.45 P = .01). CONCLUSION: Hybrid simulation-based educational comprehensive cleft care workshops are overall well received by participants and have a positive perceived impact on their clinical practices. In-person attendance is associated with significantly higher satisfaction and perceived impact on practice. Considering that financial and health constraints may limit live meeting attendance, future efforts will focus on making in-person and virtual attendance more comparable.

Mechanisms to expedite pediatric clinical trial site activation: The DOSE trial experience.

BACKGROUND: Timely trial start-up is a key determinant of trial success; however, delays during start-up are common and costly. Moreover, data on start-up metrics in pediatric clinical trials are sparse. To expedite trial start-up, the Trial Innovation Network piloted three novel mechanisms in the trial titled Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multi-site, randomized, double-blind, placebo-controlled trial in the pediatric intensive care setting. METHODS: The three novel start-up mechanisms included: 1) competitive activation; 2) use of trial start-up experts, called site navigators; and 3) supplemental funds earned for achieving pre-determined milestones. After sites were activated, they received a web-based survey to report perceptions of the DOSE start-up process. In addition to perceptions, metrics analyzed included milestones met, time to start-up, and subsequent enrollment of subjects. RESULTS: Twenty sites were selected for participation, with 19 sites being fully activated. Across activated sites, the median (quartile 1, quartile 3) time from receipt of regulatory documents to site activation was 82 days (68, 113). Sites reported that of the three novel mechanisms, the most motivating factor for expeditious activation was additional funding available for achieving start-up milestones, followed by site navigator assistance and then competitive site activation. CONCLUSION: Study start-up is a critical time for the success of clinical trials, and innovative methods to minimize delays during start-up are needed. Milestone-based funds and site navigators were preferred mechanisms by sites participating in the DOSE study and may have contributed to the expeditious start-up timeline achieved. CLINICALTRIALS: gov #: NCT03938857.

Inflammasomes as biomarkers and therapeutic targets in traumatic brain injury and related-neurodegenerative diseases: A comprehensive overview.

Given the ambiguity surrounding traumatic brain injury (TBI) pathophysiology and the lack of any Food and Drug Administration (FDA)-approved neurotherapeutic drugs, there is an increasing need to better understand the mechanisms of TBI. Recently, the roles of inflammasomes have been highlighted as both potential therapeutic targets and diagnostic markers in different neurodegenerative disorders. Indeed, inflammasome activation plays a pivotal function in the central nervous system (CNS) response to many neurological conditions, as well as to several neurodegenerative disorders, specifically, TBI. This comprehensive review summarizes and critically discusses the mechanisms that govern the activation and assembly of inflammasome complexes and the major methods used to study inflammasome activation in TBI and its implication for other neurodegenerative disorders. Also, we will review how inflammasome activation is critical in CNS homeostasis and pathogenesis, and how it can impact chronic TBI sequalae and increase the risk of developing neurodegenerative diseases. Additionally, we discuss the recent updates on inflammasome-related biomarkers and the potential to utilize inflammasomes as putative therapeutic targets that hold the potential to better diagnose and treat subjects with TBI.

A Virtual Community of Practice: An International Educational Series in Pediatric Neurocritical Care.

Pediatric neurocritical care (PNCC) is a rapidly growing field. Challenges posed by the COVID-19 pandemic on trainee exposure to educational opportunities involving direct patient care led to the creative solutions for virtual education supported by guiding organizations such as the Pediatric Neurocritical Care Research Group (PNCRG). Our objective is to describe the creation of an international, peer-reviewed, online PNCC educational series targeting medical trainees and faculty. More than 1600 members of departments such as pediatrics, pediatric critical care, and child neurology hailing from 75 countries across six continents have participated in this series over a 10-month period. We created an online educational channel in PNCC with over 2500 views to date and over 130 followers. This framework could serve as a roadmap for other institutions and specialties seeking to address the ongoing problems of textbook obsolescence relating to the rapid acceleration in knowledge acquisition, as well as those seeking to create new educational content that offers opportunities for an interactive, global audience. Through the creation of a virtual community of practice, we have created an international forum for pediatric healthcare providers to share and learn specialized expertise and best practices to advance global pediatric health.

Biomarkers in Moderate to Severe Pediatric Traumatic Brain Injury: A Review of the Literature.

BACKGROUND: Despite decades of research, outcomes in pediatric traumatic brain injury (pTBI) remain highly variable. Brain biofluid-specific biomarkers from pTBI patients may allow us to diagnose and prognosticate earlier and with a greater degree of accuracy than conventional methods. This manuscript reviews the evidence surrounding current brain-specific biomarkers in pTBI and assesses the temporal relationship between the natural history of the traumatic brain injury (TBI) and measured biomarker levels. METHODS: A literature search was conducted in the Ovid, PubMed, MEDLINE, and Cochrane databases seeking relevant publications. The study selection and screening process were documented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. Extraction forms included developmental stages of patients, type and biofluid source of biomarkers, brain injury type, and other relevant data. RESULTS: The search strategy identified 443 articles, of which 150 examining the biomarkers of our interest were included. The references retrieved were examined thoroughly and discussed at length with a pediatric neurocritical care intensivist specializing in pTBI and a Ph.D. scientist with a high degree of involvement in TBI biomarker research, authoring a vast amount of literature in this field. CONCLUSIONS: TBI biomarkers might serve as valuable tools in the diagnosis and prognosis of pTBI. However, while each biomarker has its advantages, they are not without limitations, and therefore, further research is critical in pTBI biomarkers.

Simulation Use in Outreach Setting: A Novel Approach to Building Sustainability.

SUMMARY STATEMENT: Simulation is a well-studied teaching tool for multidisciplinary teamwork, crisis resource management, and communication skills. These attributes are essential for successful international medical missions, which include healthcare providers with different familiarities with the outreach environment and each team member's role. However, immersive simulation remains underused in similar settings. Our team designed a simulation-based curriculum that focuses on multidisciplinary teamwork and crisis resource management skills. In this commentary, we describe its implementation during high-risk cleft care outreach missions conducted by the Global Smile Foundation. We discuss the importance of a simple, feasible, and flexible platform to successfully overcome the limitations of time and resources inherent to outreach mission work while addressing the clinical and geographic needs specific to each site. We highlight challenges, including unpredictability of the outreach environment, a language barrier, and the short duration of missions. Finally, we offer a roadmap for groups involved in similar global health efforts.

Blood-based traumatic brain injury biomarkers - Clinical utilities and regulatory pathways in the United States, Europe and Canada.

INTRODUCTION: Traumatic brain injury (TBI) is a major global health issue, resulting in debilitating consequences to families, communities, and health-care systems. Prior research has found that biomarkers aid in the pathophysiological characterization and diagnosis of TBI. Significantly, the FDA has recently cleared both a bench-top assay and a rapid point-of-care assays of tandem biomarker (UCH-L1/GFAP)-based blood test to aid in the diagnosis mTBI patients. With the global necessity of TBI biomarkers research, several major consortium multicenter observational studies with biosample collection and biomarker analysis have been created in the USA, Europe, and Canada. As each geographical region regulates its data and findings, the International Initiative for Traumatic Brain Injury Research (InTBIR) was formed to facilitate data integration and dissemination across these consortia. AREAS COVERED: This paper covers heavily investigated TBI biomarkers and emerging non-protein markers. Finally, we analyze the regulatory pathways for converting promising TBI biomarkers into approved in-vitro diagnostic tests in the United States, European Union, and Canada. EXPERT OPINION: TBI biomarker research has significantly advanced in the last decade. The recent approval of an iSTAT point of care test to detect mild TBI has paved the way for future biomarker clearance and appropriate clinical use across the globe.

Risk Factors for Seizures and Epilepsy in Children With Congenital Heart Disease.

OBJECTIVES: To identify potential risk factors for pre- and postoperative seizures and epilepsy in children with congenital heart disease. METHODS: Retrospective cohort study of neonates and infants <3 months of age with congenital heart disease who underwent cardiopulmonary bypass from November 24, 2006, until June 1, 2015. Children with seizures were classified based on time of occurrence into early preoperative, early postoperative, and late postoperative. Children with recurring seizures 30 days after cardiac surgery met criteria for epilepsy. RESULTS: 247 patients completed follow-up; 2.4% had seizures early preoperation and 1.6% early postoperation. Late postoperative epilepsy occurred in 5.3% of the cohort. The majority of seizures in the late postoperative epilepsy group started after 1 year of age (mean 1.53 years, range = 0.18-4.7 years). One of the 13 patients with epilepsy had a seizure during their intensive care unit hospitalization. Potential risk factors for seizures included brain injury (P < .001), high-risk surgery (Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery score ≥3, P = .024), and low birth weight (P < .04). Infants with stroke were more likely to develop epilepsy (P = .04). Presence of seizures was associated with increased length of stay (P < .001). CONCLUSIONS: Our study suggests an association between children with congenital heart disease diagnosed with stroke in the neonatal/infancy period and the development of epilepsy. These children may not have prior early pre- and postoperative seizures. Risk factors for seizures include brain injury, high-risk surgery, and lower birth weight. Seizures were associated with an increased length of stay but did not necessarily lead to subsequent epilepsy.

An Evaluation of Risperidone Dosing for Pediatric Delirium in Children Less Than or Equal to 2 Years of Age.

Background: Risperidone dosing and safety data are limited in patients ≤2 years of age. Objective: To describe the dosing strategies, safety, and tolerability of risperidone in infants ≤2 years of age. Methods: An institutional review board-approved retrospective study was conducted in a 24-bed pediatric intensive care unit at an academic medical center in patients ≤2 years of age receiving risperidone for the management of ICU delirium. The primary outcome was mean initial daily dose of risperidone. Secondary outcomes included mean daily dose, dosing frequency, treatment duration, and adverse effects. Results: Seventeen patients who received at least 1 dose of risperidone were included in the study. The initial daily dose ranged from 0.1 to 0.25 mg (0.01-0.04 mg/kg), with a mean of 0.17 mg (0.02 mg/kg). Most patients were initiated on once-daily dosing (76.5%) versus twice-daily dosing (17.6%). More than 80% of patients required a dose increase during therapy. Median daily doses of fentanyl, morphine, ketamine, and midazolam were decreased following initiation of risperidone. No adverse events that led to discontinuation of risperidone were reported. Conclusion and Relevance: Risperidone was found to be safe and well tolerated at daily doses of risperidone of 0.1 to 0.25 mg in 1 or 2 doses per day in patients ≤2 years old for the management of ICU delirium. To our knowledge, these results provide the largest cohort describing dosing recommendations specific for risperidone in this age group. Further investigation on the effect of antipsychotic administration on other sedation and analgesic regimens is necessary.

Assessing Nursing and Pediatric Resident Understanding of Delirium in the Pediatric Intensive Care Unit.

Delirium is a common disease process in the pediatric critical care unit, yet practices for screening and prevention vary drastically between institutions. The authors hypothesized that surveying pediatric residents and nurses who care for patients in the intensive care setting would expose misunderstandings about delirium. They brought to light common incorrect beliefs that benzodiazepines are appropriate therapy for delirium and that children who are delirious will not have memories of the experience. Many nurses and residents listed that they were not comfortable or were extremely uncomfortable identifying delirious patients. Findings demonstrate an opportunity to improve on nursing and resident knowledge.

Development of a Model of Hemispheric Hypodensity ("Big Black Brain").

Subdural hematoma (SDH) is the most common finding after abusive head trauma (AHT). Hemispheric hypodensity (HH) is a radiological indicator of severe brain damage that encompasses multiple vascular territories, and may develop in the hemisphere(s) underlying the SDH. In some instances where the SDH is predominantly unilateral, the widespread damage is unilateral underlying the SDH. To date, no animal model has successfully replicated this pattern of injury. We combined escalating severities of the injuries and insults commonly associated with HH including SDH, impact, mass effect, seizures, apnea, and hypoventilation to create an experimental model of HH in piglets aged 1 week (comparable to human infants) to 1 month (comparable to human toddlers). Unilateral HH evolved over 24 h when kainic acid was applied ipsilateral to the SDH to induce seizures. Pathological examination revealed a hypoxic-ischemic injury-type pattern with vasogenic edema through much of the cortical ribbon with relative sparing of deep gray matter. The percentage of the hemisphere that was damaged was greater on the ipsilateral versus contralateral side and was positively correlated with SDH area and estimated seizure duration. Further studies are needed to parse out the pathophysiology of this injury and to determine if multiple injuries and insults act synergistically to induce a metabolic mismatch or if the mechanism of trauma induces severe seizures that drive this distinctive pattern of injury.

Sustainable Cleft Care Through Education: The First Simulation-Based Comprehensive Workshop in the Middle East and North Africa Region.

OBJECTIVE: To describe the conduct of the first multidisciplinary simulation-based workshop in the Middle East/North Africa region and evaluate participant satisfaction. DESIGN: Cross-sectional survey-based evaluation. SETTING: Educational comprehensive multidisciplinary simulation-based cleft care workshop. PARTICIPANTS: Total of 93 workshop participants from over 20 countries. INTERVENTIONS: Three-day educational comprehensive multidisciplinary simulation-based cleft care workshop. MAIN OUTCOME MEASURES: Number of workshop participants, number of participants stratified by specialty, satisfaction with workshop, number of workshop staff, and number of workshop staff stratified by specialty. RESULTS: The workshop included 93 participants from over 20 countries. The response rate was 47.3%, and participants reported high satisfaction with all aspects of the workshop. All participants reported they would recommend it to colleagues (100.0%) and participate again (100.0%). No significant difference was detected based on participant specialty or years of experience. The majority were unaware of other cleft practitioners in their countries (68.2%). CONCLUSION: Multidisciplinary simulation-based cleft care workshops are well received by cleft practitioners in developing countries, serve as a platform for intellectual exchange, and are only possible through strong collaborations. Advocates of international cleft surgery education should translate these successes from the regional to the global arena in order to contribute to sustainable cleft care through education.