Risk of Hypovitaminosis and Vitamin C Deficiency in Pediatric Patients Undergoing Cardiopulmonary Bypass.

Vitamin C levels are known rapidly decrease in adult critical illness. Vitamin C scavenges free radicals, provides critical protection of the endothelial barrier, and improves endothelial responsiveness to catecholamines. Children with congenital heart disease and undergoing cardiac surgery might be at increased risk for low circulating vitamin C levels. A prospective single-center observational study investigated perioperative changes in vitamin C levels in critically ill Children who underwent congenital heart surgery using CPB. Vitamin C serum levels were collected preoperatively and postoperatively (upon admission to the ICU, 24 and 72 h). Linear mixed-effect model was used to estimate mean circulating concentration of vitamin C and to estimate changes in concentration over time. Primary outcome was change in circulating levels of vitamin C before and after CPB. Secondary outcomes were hospital length of stay (LOS), acute kidney injury (AKI), and illness severity. Forty-one patients with a median age of 4.5 [interquartile range (IQR) 2.6-65.6] months at the time of surgery were consented and enrolled. Median CPB duration was 130 [90-175] minutes, and hospital LOS was 9.1 [5.2-19] days. Mean vitamin C levels (µmol/L) before CPB, at PICU admission, 24 h, and 72 h were 82.0 (95% CI 73.4-90.7), 53.4 (95% CI 44.6,62.0), 55.1 (95% CI 46.3,63.8), and 59.2 (95% CI 50.3,68.1), respectively. Upon postoperative admission to the PICU, vitamin C levels decreased by 28.7 (95% CI 20.6-36.8; p < 0.001) µmol/L, whereas levels at 24 and 72 h recovered and did not differ substantially from concentrations reported upon PICU admission (p > 0.15). Changes in vitamin C concentration were not associated with CPB time, STAT mortality category, age, or PIM3. Three patients had post-CPB hypovitaminosis C or vitamin C deficiency. Reduction in vitamin C levels was not associated with hospital LOS (p = 0.673). A 25 µmol/L decrease in vitamin C levels upon PICU admission was associated with developing AKI (aOR = 3.65; 95% CI 1.01-18.0, p = 0.049). Pediatric patients undergoing cardiac surgery with CPB showed decreased vitamin C levels during the immediate postoperative period. Effects of hypovitaminosis C and vitamin C deficiency in this population remain unclear.

Mahalanobis distance tractometry (MaD-Tract) - a framework for personalized white matter anomaly detection applied to TBI.

Imaging-based quantitative measures from diffusion-weighted MRI (dMRI) offer the ability to non-invasively extract microscopic information from human brain tissues. Group-level comparisons of such measures represent an important approach to investigate abnormal brain conditions. These types of analyses are especially useful when the regions of abnormality spatially coincide across subjects. When this is not true, approaches for individualized analyses are necessary. Here we present a framework for single-subject multidimensional analysis based on the Mahalanobis distance. This is conducted along specific white matter pathways represented by tractography-derived streamline bundles. A definition for abnormality was constructed from Wilk's criterion, which accounts for normative sample size, number of features used in the Mahalanobis distance, and multiple comparisons. One example of a condition exhibiting high heterogeneity across subjects is traumatic brain injury (TBI). Using the Mahalanobis distance computed from the three eigenvalues of the diffusion tensor along the cingulum, uncinate, and parcellated corpus callosum tractograms, 8 severe TBI patients were individually compared to a normative sample of 49 healthy controls. For all TBI patients, the analyses showed statistically significant deviations from the normative data at one or multiple locations along the analyzed bundles. The detected anomalies were widespread across the analyzed tracts, consistent with the expected heterogeneity that is hallmark of TBI. Each of the controls subjects was also compared to the remaining 48 subjects in the control group in a leave-one-out fashion. Only two segments were identified as abnormal out of the entire analysis in the control group, thus the method also demonstrated good specificity.

Novel Injury Scoring Tool for Assessing Brain Injury following Neonatal Hypoxia-Ischemia in Mice.

The variability of severity in hypoxia-ischemia (HI)-induced brain injury among research subjects is a major challenge in developmental brain injury research. Our laboratory developed a novel injury scoring tool based on our gross pathological observations during hippocampal extraction. The hippocampi received scores of 0-6 with 0 being no injury and 6 being severe injury post-HI. The hippocampi exposed to sham surgery were grouped as having no injury. We have validated the injury scoring tool with T2-weighted MRI analysis of percent hippocampal/hemispheric tissue loss and cell survival/death markers after exposing the neonatal mice to Vannucci's rodent model of neonatal HI. In addition, we have isolated hippocampal nuclei and quantified the percent good quality nuclei to provide an example of utilization of our novel injury scoring tool. Our novel injury scores correlated significantly with percent hippocampal and hemispheric tissue loss, cell survival/death markers, and percent good quality nuclei. Caspase-3 and Poly (ADP-ribose) polymerase-1 (PARP1) have been implicated in different cell death pathways in response to neonatal HI. Another gene, sirtuin1 (SIRT1), has been demonstrated to have neuroprotective and anti-apoptotic properties. To assess the correlation between the severity of injury and genes involved in cell survival/death, we analyzed caspase-3, PARP1, and SIRT1 mRNA expressions in hippocampi 3 days post-HI and sham surgery, using quantitative reverse transcription polymerase chain reaction. The ipsilateral (IL) hippocampal caspase-3 and SIRT1 mRNA expressions post-HI were significantly higher than sham IL hippocampi and positively correlated with the novel injury scores in both males and females. We detected a statistically significant sex difference in IL hippocampal caspase-3 mRNA expression with comparable injury scores between males and females with higher expression in females.

The Utilization of Critical Care Resources in Pediatric Neurocritical Care Patients.

OBJECTIVES: To define the prevalence of neurologic diagnoses and evaluate the utilization of critical care and neurocritical care (NCC) resources among children admitted to the PICU. DESIGN: Retrospective cohort analysis. SETTING: Data submitted to the Virtual Pediatric Systems (VPS) database. PATIENTS: All children entered in VPS during 2016 (January 1, 2016, to December 31, 2016). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 128,688 patients entered into VPS and were comprised of 24.3% NCC admissions and 75.7% general PICU admissions. The NCC cohort was older, represented more scheduled admissions, and was more frequently admitted from the operating room. The NCC cohort also experienced a greater decline in prehospitalization to posthospitalization functional status and required more frequent use of endotracheal intubation, arterial lines, and foley catheters but had an overall shorter duration of PICU and hospital length of stay with a higher mortality rate. One thousand seven hundred fifteen patients at 12 participating institutions were entered into a novel, pilot NCC module evaluating sources of secondary neurologic injury. Four hundred forty-eight patients were manually excluded by the data entrant, leaving 1,267 patients in the module. Of the patients in the module, 75.8% of patients had a NCC diagnosis as their primary diagnosis; they experienced a high prevalence of pathophysiologic events associated with secondary neurologic insult (ranging from hyperglycemia at 10.5% to hyperthermia at 36.8%). CONCLUSIONS: In children admitted to a VPS-contributing PICU, a diagnosis of acute neurologic disease was associated with greater use of resources. We have identified the most common etiologies of acute neurologic disease in the 2016 VPS cohort, and such admissions were associated with significant decrease in functional status, as well as an increase in mortality.

Anticholinergics and serious adverse events in pediatric procedural sedation: A report of the pediatric sedation research consortiums.

BACKGROUND: Pediatric sedation is a clinical activity with potential for serious but rare airway adverse events, particularly laryngospasm. Anticholinergic drugs, atropine and glycopyrrolate, are frequently used with the intention to improve sedation safety by virtue of their antisialagogue effects. AIMS: The objective of this study is to describe the current practice of anticholinergic use in pediatric sedation and to compare the frequency of serious sedation-related adverse events in patients who received anticholinergics to those who did not. METHODS: We examined prospectively collected data from the Pediatric Sedation Research Consortium database. Patient characteristics, procedure type, sedation provider, sedatives, location of sedation, anticholinergic administered, adverse events, and airway interventions were reported. Propensity score matching and multivariable logistic regression were used to test whether any association exists between anticholinergic use and serious sedation-related adverse events. RESULTS: Anticholinergics were administered in 7.1% (n = 18 707) of all cases (n = 263 883) reported between November 2011 and October 2017. When anticholinergics were used, atropine was used in 22% (n = 4111) and glycopyrrolate in 78.1% (n = 14 601) of sedations. Use of anticholinergics was more common in patients with well-described risk factors for airway adverse events: active/history of upper respiratory infection, history of reactive airway disease/asthma, and exposure to smoke. However, infants and ASA 3 patients were not associated with higher rate of anticholinergic use. Anticholinergic use was independently associated with an increase in the odds of serious adverse events, OR 1.8 (95% CI 1.6-2.1), especially airway adverse events. CONCLUSIONS: In this large Pediatric Sedation Research Consortium study, we found the use of anticholinergic adjuvants independently associated with greater odds of serious adverse events, especially airway adverse events, after adjusting for well-known sedation risk factors using propensity score matching and multivariate analysis.

Sex differences in Hippocampal Memory and Learning following Neonatal Brain Injury: Is There a Role for Estrogen Receptor-α?

Neonatal encephalopathy due to hypoxia-ischemia (HI) leads to severe, life-long morbidities in thousands of neonates born in the USA and worldwide each year. Varying capacities of long-term episodic memory, verbal working memory, and learning can present without cerebral palsy and have been associated with the severity of neonatal encephalopathy sustained at birth. Among children who sustain a moderate degree of HI at birth, girls have larger hippocampal volumes compared to boys. Clinical studies indicate that female neonatal brains are more resistant to the effects of neonatal HI, resulting in better long-term cognitive outcomes compared to males with comparable brain injury. Our most recent mechanistic studies have addressed the origins and cellular basis of sex differences in hippocampal neuroprotection following neonatal HI-related brain injury and implicate estrogen receptor-α (ERα) in the neurotrophin receptor-mediated hippocampal neuroprotection in female mice. This review summarizes the recent findings on ERα-dependent, neurotrophin-mediated hippocampal neuroprotection and weighs the evidence that this mechanism plays an important role in preservation of long-term memory and learning following HI in females.

TrkB-mediated neuroprotection in female hippocampal neurons is autonomous, estrogen receptor alpha-dependent, and eliminated by testosterone: a proposed model for sex differences in neonatal hippocampal neuronal injury.

BACKGROUND: Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of learning disabilities and memory deficits in children. In both human and animal studies, female neonate brains are less susceptible to HI than male brains. Phosphorylation of the nerve growth factor receptor TrkB has been shown to provide sex-specific neuroprotection following in vivo HI in female mice in an estrogen receptor alpha (ERα)-dependent manner. However, the molecular and cellular mechanisms conferring sex-specific neonatal neuroprotection remain incompletely understood. Here, we test whether female neonatal hippocampal neurons express autonomous neuroprotective properties and assess the ability of testosterone (T) to alter this phenotype. METHODS: We cultured sexed hippocampal neurons from ERα+/+ and ERα-/- mice and subjected them to 4 h oxygen glucose deprivation and 24 h reoxygenation (4-OGD/24-REOX). Sexed hippocampal neurons were treated either with vehicle control (VC) or the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) following in vitro ischemia. End points at 24 h REOX were TrkB phosphorylation (p-TrkB) and neuronal survival assessed by immunohistochemistry. In addition, in vitro ischemia-mediated ERα gene expression in hippocampal neurons were investigated following testosterone (T) pre-treatment and TrkB antagonist therapy via q-RTPCR. Multifactorial analysis of variance was conducted to test for significant differences between experimental conditions. RESULTS: Under normoxic conditions, administration of 3 µM 7,8-DHF resulted an ERα-dependent increase in p-TrkB immunoexpression that was higher in female, as compared to male neurons. Following 4-OGD/24-REOX, p-TrkB expression increased 20% in both male and female ERα+/+ neurons. However, with 3 µM 7,8-DHF treatment p-TrkB expression increased further in female neurons by 2.81 ± 0.79-fold and was ERα dependent. 4-OGD/24-REOX resulted in a 56% increase in cell death, but only female cells were rescued with 3 µM 7,8-DHF, again in an ERα dependent manner. Following 4-OGD/3-REOX, ERα mRNA increased ~ 3 fold in female neurons. This increase was blocked with either the TrkB antagonist ANA-12 or pre-treatment with T. Pre-treatment with T also blocked the 7,8-DHF- dependent sex-specific neuronal survival in female neurons following 4-OGD/24-REOX. CONCLUSIONS: OGD/REOX results in sex-dependent TrkB phosphorylation in female neurons that increases further with 7,8-DHF treatment. TrkB phosphorylation by 7,8-DHF increased ERα mRNA expression and promoted cell survival preferentially in female hippocampal neurons. The sex-dependent neuroprotective actions of 7,8-DHF were blocked by either ANA-12 or by T pre-treatment. These results are consistent with a model for a female-specific neuroprotective pathway in hippocampal neurons in response to hypoxia. The pathway is activated by 7,8-DHF, mediated by TrkB phosphorylation, dependent on ERα and blocked by pre-exposure to T.

Multi-modal MRI of hippocampal morphometry and connectivity after pediatric severe TBI.

This investigation explores memory performance using the California Verbal Learning Test in relation to morphometric and connectivity measures of the memory network in severe traumatic brain injury. Twenty-two adolescents with severe traumatic brain injury were recruited for multimodal MRI scanning 1-2 years post-injury at 13 participating sites. Analyses included hippocampal volume derived from anatomical T1-weighted imaging, fornix white matter microstructure from diffusion tensor imaging, and hippocampal resting-state functional magnetic resonance imaging connectivity as well as diffusion-based structural connectivity. A typically developing control cohort of forty-nine age-matched children also underwent scanning and neurocognitive assessment. Results showed hippocampus volume was decreased in traumatic brain injury with respect to controls. Further, hippocampal volume loss was associated with worse performance on memory and learning in traumatic brain injury subjects. Similarly, hippocampal fornix fractional anisotropy was reduced in traumatic brain injury with respect to controls, while decreased fractional anisotropy in the hippocampal fornix also was associated with worse performance on memory and learning in traumatic brain injury subjects. Additionally, reduced structural connectivity of left hippocampus to thalamus and calcarine sulcus was associated with memory and learning in traumatic brain injury subjects. Functional connectivity in the left hippocampal network was also associated with memory and learning in traumatic brain injury subjects. These regional findings from a multi-modal neuroimaging approach should not only be useful for gaining valuable insight into traumatic brain injury induced memory and learning disfunction, but may also be informative for monitoring injury progression, recovery, and for developing rehabilitation as well as therapy strategies.

MRI and Clinical Variables for Prediction of Outcomes After Pediatric Severe Traumatic Brain Injury.

Importance: Traumatic brain injury (TBI) is a leading cause of death and disability in children, and predicting functional outcome after TBI is challenging. Magnetic resonance imaging (MRI) is frequently conducted after severe TBI; however, the predictive value of MRI remains uncertain. Objectives: To identify early MRI measures that predict long-term outcome after severe TBI in children and to assess the added predictive value of MRI measures over well-validated clinical predictors. Design, Setting, and Participants: This preplanned prognostic study used data from the Approaches and Decisions in Acute Pediatric TBI (ADAPT) prospective observational comparative effectiveness study. The ADAPT study enrolled 1000 consecutive children (aged <18 years) with severe TBI between February 1, 2014, and September 30, 2017. Participants had a Glasgow Coma Scale (GCS) score of 8 or less and received intracranial pressure monitoring. Magnetic resonance imaging scans performed as part of standard clinical care within 30 days of injury were collected at 24 participating sites in the US, UK, and Australia. Summary imaging measures were correlated with the Glasgow Outcome Scale-Extended for Pediatrics (GOSE-Peds), and the predictive value of MRI measures was compared with the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) core clinical predictors. Data collection, image analysis, and data analyses were completed in July 2023. Exposures: Pediatric severe TBI with an MRI scan performed as part of clinical care. Main Outcomes and Measures: All measures were selected a priori. Magnetic resonance imaging measures included contusion, ischemia, diffuse axonal injury, intracerebral hemorrhage, and brainstem injury. Clinical predictors included the IMPACT core measures (GCS motor score and pupil reactivity). All models adjusted for age and sex. Outcome measures included the GOSE-Peds score obtained at 3, 6, and 12 months after injury. Results: This study included 233 children with severe TBI who were enrolled at participating sites and had an MRI scan and preselected clinical predictors available. Their median age was 6.9 (IQR, 3.0-13.3) years, and more than half of participants (134 [57.5%]) were male. In a multivariable model including MRI measures and IMPACT core clinical variables, contusion volume (odds ratio [OR], 1.13; 95% CI, 1.02-1.26), brain ischemia (OR, 2.11; 95% CI, 1.58-2.81), brainstem lesions (OR, 5.40; 95% CI, 1.90-15.35), and pupil reactivity were each independently associated with GOSE-Peds score. Adding MRI measures to the IMPACT clinical predictors significantly improved model fit and discrimination between favorable and unfavorable outcomes compared with IMPACT predictors alone (area under the receiver operating characteristic curve, 0.77; 95% CI, 0.72-0.85 vs 0.67; 95% CI, 0.61-0.76 for GOSE-Peds score >3 at 6 months after injury). Conclusions and Relevance: In this prognostic study of children with severe TBI, the addition of MRI measures significantly improved outcome prediction over well-established and validated clinical predictors. Magnetic resonance imaging should be considered in children with severe TBI to inform prognosis and may also promote stratification of patients in future clinical trials.

TrkB-mediated sustained neuroprotection is sex-specific and Erα-dependent in adult mice following neonatal hypoxia ischemia.

BACKGROUND: Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of life-long neurological morbidities that result in learning and memory impairments. Evidence suggests that male neonates are more susceptible to the detrimental effects of HI, yet the mechanisms mediating these sex-specific responses to neural injury in neonates remain poorly understood. We previously tested the effects of treatment with a small molecule agonist of the tyrosine kinase B receptor (TrkB), 7,8-dihydroxyflavone (DHF) following neonatal HI and determined that females, but not males exhibit increased phosphorylation of TrkB and reduced apoptosis in their hippocampi. Moreover, these female-specific effects of the TrkB agonist were found to be dependent upon the expression of Erα. These findings demonstrated that TrkB activation in the presence of Erα comprises one pathway by which neuroprotection may be conferred in a female-specific manner. The goal of this study was to determine the role of Erα-dependent TrkB-mediated neuroprotection in memory and anxiety in young adult mice exposed to HI during the neonatal period. METHODS: In this study, we used a unilateral hypoxic ischemic (HI) mouse model. Erα+/+ or Erα-/- mice were subjected to HI on postnatal day (P) 9 and mice were treated with either vehicle control or the TrkB agonist, DHF, for 7 days following HI. When mice reached young adulthood, we used the novel object recognition, novel object location and open field tests to assess long-term memory and anxiety-like behavior. The brains were then assessed for tissue damage using immunohistochemistry. RESULTS: Neonatal DHF treatment prevented HI-induced decrements in recognition and location memory in adulthood in females, but not in males. This protective effect was absent in female mice lacking Erα. The female-specific improved recognition and location memory outcomes in adulthood conferred by DHF therapy after neonatal HI tended to be or were Erα-dependent, respectively. Interestingly, DHF triggered anxiety-like behavior in both sexes only in the mice that lacked Erα. When we assessed the severity of injury, we found that DHF therapy did not decrease the percent tissue loss in proportion to functional recovery. We additionally observed that the presence of Erα significantly reduced overall HI-associated mortality in both sexes. CONCLUSIONS: These observations provide evidence for a therapeutic role for DHF in which TrkB-mediated sustained recovery of recognition and location memories in females are Erα-associated and dependent, respectively. However, the beneficial effects of DHF therapy did not include reduction of gross tissue loss but may be derived from the enhanced functioning of residual tissues in a cell-specific manner.

Periods of low oxygen delivery and blood flow to the brains of newborns are known to cause life-long impairments to their cognitive ability as adults. Interestingly, male newborns are more susceptible to this injury than females. The mechanisms causing this sex difference are poorly understood. Here we test the role of the nerve growth factor receptor tyrosine kinase B (TrkB) in providing long-term neuroprotection following neonatal hypoxia­ischemia (HI) in mice. We have previously shown that when mice are treated with the TrkB agonist 7,8-dihydroxyflavone (DHF) in the days following neonatal HI, the result is short-term neuroprotection only in females and this protection is dependent on the presence of the estrogen receptor alpha receptor ([Formula: see text]). In this study, we extend these observations by subjecting mice either with or without [Formula: see text] to HI. Some of the mice were then treated with DHF immediately after HI. As adults, we performed tests to assess the mice's memory and anxiety-like behavior. At the end of these tests, we assessed the brains for tissue loss. Our results show that as adults the DHF treatment following HI in neonatal mice preserved memory only in females and this effect was dependent on the presence of [Formula: see text]. In addition, DHF therapy triggered anxiety-like behavior in mice lacking [Formula: see text]. We also show that this neuroprotection is not dependent on preservation of brain tissue following the injury. These results provide insight into the mechanisms behind the female resistance to hypoxic ischemic episodes as newborns.

Post-discharge outcomes of hospitalized children diagnosed with acute SARS-CoV-2 or MIS-C.

Introduction: Hospitalized children diagnosed with SARS-CoV-2-related conditions are at risk for new or persistent symptoms and functional impairments. Our objective was to analyze post-hospital symptoms, healthcare utilization, and outcomes of children previously hospitalized and diagnosed with acute SARS-CoV-2 infection or Multisystem Inflammatory Syndrome in Children (MIS-C). Methods: Prospective, multicenter electronic survey of parents of children <18 years of age surviving hospitalization from 12 U.S. centers between January 2020 and July 2021. The primary outcome was a parent report of child recovery status at the time of the survey (recovered vs. not recovered). Secondary outcomes included new or persistent symptoms, readmissions, and health-related quality of life. Multivariable backward stepwise logistic regression was performed for the association of patient, disease, laboratory, and treatment variables with recovered status. Results: The children [n = 79; 30 (38.0%) female] with acute SARS-CoV-2 (75.7%) or MIS-C (24.3%) had a median age of 6.5 years (interquartile range 2.0-13.0) and 51 (64.6%) had a preexisting condition. Fifty children (63.3%) required critical care. One-third [23/79 (29.1%)] were not recovered at follow-up [43 (31, 54) months post-discharge]. Admission C-reactive protein levels were higher in children not recovered vs. recovered [5.7 (1.3, 25.1) vs. 1.3 (0.4, 6.3) mg/dl, p = 0.02]. At follow-up, 67% overall had new or persistent symptoms. The most common symptoms were fatigue (37%), weakness (25%), and headache (24%), all with frequencies higher in children not recovered. Forty percent had at least one return emergency visit and 24% had a hospital readmission. Recovered status was associated with better total HRQOL [87 (77, 95) vs. 77 (51, 83), p = 0.01]. In multivariable analysis, lower admission C-reactive protein [odds ratio 0.90 (95% confidence interval 0.82, 0.99)] and higher admission lymphocyte count [1.001 (1.0002, 1.002)] were associated with recovered status. Conclusions: Children considered recovered by their parents following hospitalization with SARS-CoV-2-related conditions had less symptom frequency and better HRQOL than those reported as not recovered. Increased inflammation and lower lymphocyte count on hospital admission may help to identify children needing longitudinal, multidisciplinary care. Clinical Trial Registration: ClinicalTrials.gov (NCT04379089).

Corrigendum: Post-discharge outcomes of hospitalized children diagnosed with acute SARS-CoV-2 or MIS-C.

[This corrects the article DOI: 10.3389/fped.2024.1340385.].

Severe Pediatric Neurological Manifestations With SARS-CoV-2 or MIS-C Hospitalization and New Morbidity.

Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition. Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.

Diffusion tensor MRI of spinal decompression sickness.

In order to develop more sensitive imaging tools for clinical use and basic research of spinal decompression sickness (DCS), we used diffusion tensor MRI (DTI) validated by histology to assess DCS-related tissue injury in sheep spinal cords. DTI is based on the measurement of water diffusion indices, including fractional anisotropy (FA) and mean diffusion (MD) to detect tissue microstructural abnormalities. In this study, we measured FA and MD in white and gray matter spinal cord regions in samples taken from sheep following hyperbaric exposure to 60-132 fsw and 0-180 minutes of oxygen pre-breathing treatment before rapid decompression. The main finding of the study was that decompression from >60 fsw resulted in reduced FA that was associated with cell death and disrupted tissue microstructure in spinal cord white matter tracts. Additionally, animals exposed to prolonged oxygen pre-breathing prior to decompression demonstrated reduced MD in spinal cord gray matter regions regardless of dive depth. To our knowledge, this is the first study to demonstrate the utility of DTI for the investigation of DCS-related injury and to define DTI biomarkers of spinal DCS.

Selectively compromised inner retina function following hypoxic-ischemic encephalopathy in mice: A noninvasive measure of severity of the injury.

The intricate system of connections between the eye and the brain implies that there are common pathways for the eye and brain that get activated following injury. Hypoxia-ischemia (HI) related encephalopathy is a consequence of brain injury caused by oxygen and blood flow deprivation that may result in visual disturbances and neurodevelopmental disorders in surviving neonates. We have previously shown that the tyrosine receptor kinase B (TrkB) agonist/modulator improves neuronal survival and long-term neuroprotection in a sexually differential way. In this study, we tested the hypotheses that; 1) TrkB agonist therapy improves the visual function in a sexually differential way; 2) Visual function detected by electroretinogram (ERG) correlates with severity of brain injury detected by magnetic resonance (MRI) imaging following neonatal HI in mice. To test our hypotheses, we used C57/BL6 mice at postnatal day (P) 9 and subjected them to either Vannucci's rodent model of neonatal HI or sham surgery. ERG was performed at P 30, 60, and 90. MRI was performed following the completion of the ERG. ERG in these mice showed that the a-wave is normal, but the b-wave amplitude is severely abnormal, reducing the b/a wave amplitude ratio. Inner retina function was found to be perturbed as we detected severely attenuated oscillatory potential after HI. No sex differences were detected in the injury and severity pattern to the retina as well as in response to 7,8-DHF therapy. Strong correlations were detected between the percent change in b/a ratio and percent hemispheric/hippocampal tissue loss obtained by MRI, suggesting that ERG is a valuable noninvasive tool that can predict the long-term severity of brain injury.

A Survey of Neuromonitoring Practices in North American Pediatric Intensive Care Units.

BACKGROUND: Neuromonitoring is the use of continuous measures of brain physiology to detect clinically important events in real-time. Neuromonitoring devices can be invasive or non-invasive and are typically used on patients with acute brain injury or at high risk for brain injury. The goal of this study was to characterize neuromonitoring infrastructure and practices in North American pediatric intensive care units (PICUs). METHODS: An electronic, web-based survey was distributed to 70 North American institutions participating in the Pediatric Neurocritical Care Research Group. Questions related to the clinical use of neuromonitoring devices, integrative multimodality neuromonitoring capabilities, and neuromonitoring infrastructure were included. Survey results were presented using descriptive statistics. RESULTS: The survey was completed by faculty at 74% (52 of 70) of institutions. All 52 institutions measure intracranial pressure and have electroencephalography capability, whereas 87% (45 of 52) use near-infrared spectroscopy and 40% (21/52) use transcranial Doppler. Individual patient monitoring decisions were driven by institutional protocols and collaboration between critical care, neurology, and neurosurgery attendings. Reported device utilization varied by brain injury etiology. Only 15% (eight of 52) of institutions utilized a multimodality neuromonitoring platform to integrate and synchronize data from multiple devices. A database of neuromonitoring patients was maintained at 35% (18 of 52) of institutions. Funding for neuromonitoring programs was variable with contributions from hospitals (19%, 10 of 52), private donations (12%, six of 52), and research funds (12%, six of 52), although 73% (40 of 52) have no dedicated funds. CONCLUSIONS: Neuromonitoring indications, devices, and infrastructure vary by institution in North American pediatric critical care units. Noninvasive modalities were utilized more liberally, although not uniformly, than invasive monitoring. Further studies are needed to standardize the acquisition, interpretation, and reporting of clinical neuromonitoring data, and to determine whether neuromonitoring systems impact neurological outcomes.

Magnetic Resonance Imaging Findings in Infants with Severe Traumatic Brain Injury and Associations with Abusive Head Trauma.

Young children with severe traumatic brain injury (TBI) have frequently been excluded from studies due to age and/or mechanism of injury. Magnetic resonance imaging (MRI) is now frequently being utilized to detect parenchymal injuries and early cerebral edema. We sought to assess MRI findings in infants with severe TBI, and to determine the association between specific MRI findings and mechanisms of injury, including abusive head trauma (AHT). MRI scans performed within the first 30 days after injury were collected and coded according to NIH/NINDS Common Data Elements (CDEs) for Neuroimaging in subjects age < 2 years old with severe TBI enrolled in the Approaches and Decisions in Acute Pediatric Traumatic Brain Injury Trial. Demographics and injury characteristics were analyzed. A total of 81 children were included from ADAPT sites with MRI scans. Median age was 0.77 years and 57% were male. Most common MRI finding was ischemia, present in 57/81 subjects (70%), in a median of 7 brain regions per subject. Contusion 46/81 (57%) and diffuse axonal injury (DAI) 36/81 (44.4%) subjects followed. Children were dichotomized based on likelihood of AHT with 43/81 subjects classified as AHT. Ischemia was found to be significantly associated with AHT (p = 0.001) and "inflicted" injury mechanism (p = 0.0003). In conclusion, the most common intracerebral injury seen on MRI of infants with severe TBI was ischemia, followed by contusion and DAI. Ischemia was associated with AHT, and ischemia affecting > 4 brain regions was predictive of AHT.

Comparison of Intracranial Pressure Measurements Before and After Hypertonic Saline or Mannitol Treatment in Children With Severe Traumatic Brain Injury.

Importance: Hyperosmolar agents are cornerstone therapies for pediatric severe traumatic brain injury. Guideline recommendations for 3% hypertonic saline (HTS) are based on limited numbers of patients, and no study to date has supported a recommendation for mannitol. Objectives: To characterize current use of hyperosmolar agents in pediatric severe traumatic brain injury and assess whether HTS or mannitol is associated with greater decreases in intracranial pressure (ICP) and/or increases in cerebral perfusion pressure (CPP). Design, Setting, and Participants: In this comparative effectiveness research study, 1018 children were screened and 18 were excluded; 787 children received some form of hyperosmolar therapy during the ICP-directed phase of care, with 521 receiving a bolus. Three of these children were excluded because they had received only bolus administration of both HTS and mannitol in the same hour, leaving 518 children (at 44 clinical sites in 8 countries) for analysis. The study was conducted from February 1, 2014, to September 31, 2017, with follow-up for 1 week after injury. Final analysis was performed July 20, 2021. Interventions: Boluses of HTS and mannitol were administered. Main Outcomes and Measures: Data on ICP and CPP were collected before and after medication administration. Statistical methods included linear mixed models and corrections for potential confounding variables to compare the 2 treatments. Results: A total of 518 children (mean [SD] age, 7.6 [5.4] years; 336 [64.9%] male; 274 [52.9%] White) were included. Participants' mean (SD) Glasgow Coma Scale score was 5.2 (1.8). Bolus HTS was observed to decrease ICP and increase CPP (mean [SD] ICP, 1.03 [6.77] mm Hg; P < .001; mean [SD] CPP, 1.25 [12.47] mm Hg; P < .001), whereas mannitol was observed to increase CPP (mean [SD] CPP, 1.20 [11.43] mm Hg; P = .009). In the primary outcome, HTS was associated with a greater reduction in ICP compared with mannitol (unadjusted ß, -0.85; 95% CI, -1.53 to -0.19), but no association was seen after adjustments (adjusted ß, -0.53; 95% CI, -1.32 to 0.25; P = .18). No differences in CPP were observed. When ICP was greater than 20 mm Hg, greater than 25 mm Hg, or greater than 30 mm Hg, HTS outperformed mannitol for each threshold in observed ICP reduction (>20 mm Hg: unadjusted ß, -2.51; 95% CI, -3.86 to -1.15, P < .001; >25 mm Hg: unadjusted ß, -3.88; 95% CI, -5.69 to -2.06, P < .001; >30 mm Hg: unadjusted ß, -4.07; 95% CI, -6.35 to -1.79, P < .001), with results remaining significant for ICP greater than 25 mm Hg in adjusted analysis. Conclusions and Relevance: In this comparative effectiveness research study, bolus HTS was associated with lower ICP and higher CPP, whereas mannitol was associated only with higher CPP. After adjustment for confounders, both therapies showed no association with ICP and CPP. During ICP crises, HTS was associated with better performance than mannitol.

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.

Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C.

BACKGROUND: Our objective was to characterize the frequency, early impact, and risk factors for neurological manifestations in hospitalized children with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or multisystem inflammatory syndrome in children (MIS-C). METHODS: Multicenter, cross-sectional study of neurological manifestations in children aged <18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020 and April 2021. Multivariable logistic regression to identify risk factors for neurological manifestations was performed. RESULTS: Of 1493 children, 1278 (86%) were diagnosed with acute SARS-CoV-2 and 215 (14%) with MIS-C. Overall, 44% of the cohort (40% acute SARS-CoV-2 and 66% MIS-C) had at least one neurological manifestation. The most common neurological findings in children with acute SARS-CoV-2 and MIS-C diagnosis were headache (16% and 47%) and acute encephalopathy (15% and 22%), both P < 0.05. Children with neurological manifestations were more likely to require intensive care unit (ICU) care (51% vs 22%), P < 0.001. In multivariable logistic regression, children with neurological manifestations were older (odds ratio [OR] 1.1 and 95% confidence interval [CI] 1.07 to 1.13) and more likely to have MIS-C versus acute SARS-CoV-2 (OR 2.16, 95% CI 1.45 to 3.24), pre-existing neurological and metabolic conditions (OR 3.48, 95% CI 2.37 to 5.15; and OR 1.65, 95% CI 1.04 to 2.66, respectively), and pharyngeal (OR 1.74, 95% CI 1.16 to 2.64) or abdominal pain (OR 1.43, 95% CI 1.03 to 2.00); all P < 0.05. CONCLUSIONS: In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurological manifestations, which were associated with ICU admission and pre-existing neurological condition. Posthospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed.