Computational head models are essential tools for predicting the risk of mild traumatic brain injury (mTBI). However, computational models vary in the level of anatomical details, most notably the cortical folds. This study aims to determine the effect of modeling cortical folds on mTBI risk assessment. We compared gyrencephalic (with cortical folds) and lissencephalic (without cortical folds) finite element (FE) head models of 18 subjects aged 9–18 years, subjected to a rotational head acceleration of 10 krad/s ^2 (10 ms duration) about each principal head axis. We analyzed the effect of cortical folds on different tissue-level mTBI injury metrics, including maximum principal strain (MPS95), maximum principal strain rate (MPSR95), and cumulative strain damage measure (CSDM15). The inclusion of cortical folds consistently yielded higher injury metrics across all individuals and rotational directions, with a bias (mean ± std. dev. relative to maximum lissencephalic values) of 21.7 ± 9.1 % in MPS95, 17.1± 7.6% in MPSR95, and 14.4± 11.3% in CSDM15. Differences in the spatial strain distribution were also found between the models, with the DICE similarity coefficient ranging between 0.07-0.43 and 0.42-0.70 for the peak MPS and CSDM15, respectively. Increases in peak injury metrics (up to ∼ 50

Hypoxia-ischemia (HI)-related brain injury impacts millions of neonates worldwide. Male neonates are two times more susceptible to developing HI. We have previously reported that the administration of the neurotrophin receptor tyrosine kinase B (TrkB) agonist 7,8-dihydroxyflavone (DHF) following neonatal HI increases hippocampal TrkB phosphorylation and improves hippocampal-dependent learning and memory in early adult life only in females. We hypothesize that sex differences in HI outcomes are due to alterations in neonatal hippocampal steroid content, mainly the neural testosterone. At postnatal day 9, C57BL/6J mice underwent sham and Vannucci's HI surgeries and were treated either with DHF or vehicle control. Hippocampi and plasma were collected on days 1 and 3 post-HI and liquid chromatography tandem mass spectrometry was used to determine the testosterone (T), estradiol (E2), progesterone (P4), and corticosterone (CORT) contents in these samples. All hippocampal steroid contents were at least 10-fold higher than in plasma, suggesting neural synthesis. Males had higher hippocampal T content than females at 3 days post-HI. Treatment with DHF reduced T in the female hippocampi at 3 days post-HI, but not in males. These findings suggest that the neuroprotective effect of DHF in females may be mediated, at least in part, through the reduction in hippocampal T following HI.

Purpose: Repeated heading of soccer balls has raised concerns of potential long-term neurological effects. Consequently, numerous studies have estimated head kinematics and brain deformation due to soccer headers across different cohorts and play scenarios to identify higher risk conditions. However, heterogeneity in study design, data collection, and analysis has produced inconsistent findings, and injury risk is infrequently reported. Therefore, a meta-analysis of the existing literature was conducted to identify knowledge gaps and inform future studies assessing injury risk in soccer. Methods: We synthesized data from studies reporting head kinematics or brain deformation from soccer headers on human subjects. The data from these studies were analyzed to obtain the risk of mild traumatic brain injury (mTBI) based on applicable injury metrics and risk curves. Results: The meta-analysis revealed specific trends, indicating that match scenarios, corner and goal-kicks, top and oblique impacts, and older age cohorts were associated with higher head kinematics, while sex-based trends were inconclusive. The choice of sensor system affected the estimated head kinematics, with headband sensors consistently measuring higher kinematics than mouthpiece sensors. The data showed large variability stemming from heterogeneous study designs, limiting the applicability of the observed trends. These factors also influenced injury risk predictions, with estimated concussion risks generally below 20

Introduction7,8-Dihydroxyflavone (7,8-DHF) is a promising translational therapy in several brain injury models, including the neonatal hypoxia-ischemia (HI) model in mice. However, the neuroprotective effect of 7,8-DHF was only observed in female, but not male, neonatal mice with HI brain injury. It is unknown whether HI-induced physiological changes affect brain distribution of 7,8-DHF differently for male versus female mice. We aimed to evaluate the impact of sex on the pharmacokinetics of 7,8-DHF in plasma and brain neonatal mice following experimentally induced HI brain injury.MethodsLeft-sided HI brain injury was induced in postnatal day 9 (P9) mice, followed by a 5 mg/kg intraperitoneal injection of 7,8-DHF. A liquid chromatography-tandem mass spectrometry method was developed to quantitate the drug concentration in plasma samples, as well as in samples from the left and right brain hemispheres. A nonlinear mixed-effects model was used to analyze the plasma and brain concentration-time data. A semi-quantitative approach was used to evaluate the concentrations of two active O-methylated metabolites of 7,8-DHF (8H7M-flavone and 7H8M-flavone) in both plasma and brain samples.ResultsOur PK analyses show that plasma 7,8-DHF concentrations followed a two-compartment PK model, with more than 95% eliminated by 3 h after the IP injection. Sex was not significantly associated with the PK of 7,8-DHF; however, HI brain injury was associated with a 21% reduction in clearance (p < 0.01). The distribution of 7,8-DHF to the brain was rapid; however, the extent of brain distribution was low with the right and left brain-to-plasma partition coefficients being 8.6% and 9.9%, respectively. Additionally, both O-methylated metabolites of 7,8-DHF were detected in the plasma and brain.ConclusionThe plasma and brain PK of 7,8-DHF in neonatal mice were similar between males and females. The low extent of 7,8-DHF brain distribution and the potential effects of the active metabolites should be considered in future studies evaluating the therapeutic effects of 7,8-DHF.

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. CONCLUSION 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.

IntroductionHospitalized 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).MethodsProspective, 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.ResultsThe 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.ConclusionsChildren 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 RegistrationClinicalTrials.gov (NCT04379089).

Following in vitro ischemia, the nerve growth factor receptor TrkB is activated in the presence of the TrkB agonist 7,8-DHF only in female and not in male cultured hippocampal neurons, leading to increased neuronal survival. Expression of ERα is increased following in vitro ischemia in female but not male hippocampal neurons. The female hippocampal neuronal specific responses to in vitro ischemia are blocked by pre-treatment with testosterone. The data support a model for a female-specific a neuroprotective pathway in hippocampal neurons. The pathway is activated by a TrkB agonist, dependent on ERα and blocked by testosterone. 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. 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. 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

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.

Abstract 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 $$\text{ER}\alpha$$ ER α . These findings demonstrated that TrkB activation in the presence of $$\text{ER}\alpha$$ ER α 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 $$\text{ER}\alpha$$ ER α -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. $$\text{ER}\alpha$$ ER α +/+ or $$\text{ER}\alpha$$ ER α −/− 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 $$\text{ER}\alpha$$ ER α . The female-specific improved recognition and location memory outcomes in adulthood conferred by DHF therapy after neonatal HI tended to be or were $$\text{ER}\alpha$$ ER α -dependent, respectively. Interestingly, DHF triggered anxiety-like behavior in both sexes only in the mice that lacked $$\text{ER}\alpha$$ ER α . 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 $$\text{ER}\alpha$$ ER α 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 $$\text{ER}\alpha$$ ER α -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.

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

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.

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.

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.

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.

Key Points Question How commonly are hyperosmolar therapies used in the management of severe traumatic brain injury in children, and which agent—mannitol or hypertonic saline solution—is associated with greater decreases in intracranial pressure (ICP) and/or increases in cerebral perfusion pressure (CPP)? Findings In this comparative effectiveness research study of 1000 consecutive children with traumatic brain injury, more than 77% of the study population received hyperosmolar therapies during the ICP treatment phase of their care, and almost 2500 bolus administrations of 3% hypertonic saline and mannitol were analyzed. Hypertonic saline was associated with decreased ICP, whereas hypertonic saline and mannitol had similar observed effectiveness for CPP. Meaning This study of children with severe traumatic brain injury found that bolus administration of hypertonic saline was associated with superior ICP and CPP outcomes.

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.

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.

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.