Abusive Head Trauma and Mortality-An Analysis From an International Comparative Effectiveness Study of Children With Severe Traumatic Brain Injury.

OBJECTIVES: Small series have suggested that outcomes after abusive head trauma are less favorable than after other injury mechanisms. We sought to determine the impact of abusive head trauma on mortality and identify factors that differentiate children with abusive head trauma from those with traumatic brain injury from other mechanisms. DESIGN: First 200 subjects from the Approaches and Decisions in Acute Pediatric Traumatic Brain Injury Trial-a comparative effectiveness study using an observational, cohort study design. SETTING: PICUs in tertiary children's hospitals in United States and abroad. PATIENTS: Consecutive children (age < 18 yr) with severe traumatic brain injury (Glasgow Coma Scale ≤ 8; intracranial pressure monitoring). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, injury-related scores, prehospital, and resuscitation events were analyzed. Children were dichotomized based on likelihood of abusive head trauma. A total of 190 children were included (n = 35 with abusive head trauma). Abusive head trauma subjects were younger (1.87 ± 0.32 vs 9.23 ± 0.39 yr; p < 0.001) and a greater proportion were female (54.3% vs 34.8%; p = 0.032). Abusive head trauma were more likely to 1) be transported from home (60.0% vs 33.5%; p < 0.001), 2) have apnea (34.3% vs 12.3%; p = 0.002), and 3) have seizures (28.6% vs 7.7%; p < 0.001) during prehospital care. Abusive head trauma had a higher prevalence of seizures during resuscitation (31.4 vs 9.7%; p = 0.002). After adjusting for covariates, there was no difference in mortality (abusive head trauma, 25.7% vs nonabusive head trauma, 18.7%; hazard ratio, 1.758; p = 0.60). A similar proportion died due to refractory intracranial hypertension in each group (abusive head trauma, 66.7% vs nonabusive head trauma, 69.0%). CONCLUSIONS: In this large, multicenter series, children with abusive head trauma had differences in prehospital and in-hospital secondary injuries which could have therapeutic implications. Unlike other traumatic brain injury populations in children, female predominance was seen in abusive head trauma in our cohort. Similar mortality rates and refractory intracranial pressure deaths suggest that children with severe abusive head trauma may benefit from therapies including invasive monitoring and adherence to evidence-based guidelines.

Structure, Process, and Culture Differences of Pediatric Trauma Centers Participating in an International Comparative Effectiveness Study of Children with Severe Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) is an important worldwide cause of death and disability for children. The Approaches and Decisions for Acute Pediatric TBI (ADAPT) Trial is an observational, cohort study to compare the effectiveness of six aspects of TBI care. Understanding the differences between clinical sites-including their structure, clinical processes, and culture differences-will be necessary to assess differences in outcome from the study and can inform the overall community regarding differences across academic centers. METHODS: We developed a survey and queried ADAPT site principal investigators with a focus on six domains: (i) hospital, (ii) pediatric intensive care unit (PICU), (iii) medical staff characteristics, (iv) quality of care, (v) medication safety, and (vi) safety culture. Summary statistics were used to describe differences between centers. RESULTS: ADAPT clinical sites that enrolled a subject within the first year (32 US-based, 11 international) were studied. A wide variation in site characteristics was observed in hospital and ICU characteristics, including an almost sevenfold range in ICU size (8-55 beds) and more than fivefold range of overall ICU admissions (537-2623). Nursing staffing (predominantly 1:1 or 1:2) and the presence of pharmacists within the ICU (79 %) were less variable, and most sites "strongly agreed" or "agreed" that Neurosurgery and Critical Care teams worked well together (81.4 %). However, a minority of sites (46 %) used an explicit protocol for treatment of children with severe TBI care. CONCLUSIONS: We found a variety of inter-center structure, process, and culture differences. These intrinsic differences between sites may begin to explain why interventional studies have failed to prove efficacy of experimental therapies. Understanding these differences may be an important factor in analyzing future ADAPT trial results and in determining best practices for pediatric severe TBI.

A research definition and framework for acute paediatric critical illness across resource-variable settings: a modified Delphi consensus.

The true global burden of paediatric critical illness remains unknown. Studies on children with life-threatening conditions are hindered by the absence of a common definition for acute paediatric critical illness (DEFCRIT) that outlines components and attributes of critical illness and does not depend on local capacity to provide critical care. We present an evidence-informed consensus definition and framework for acute paediatric critical illness. DEFCRIT was developed following a scoping review of 29 studies and key concepts identified by an interdisciplinary, international core expert panel (n=24). A modified Delphi process was then done with a panel of multidisciplinary health-care global experts (n=109) until consensus was reached on eight essential attributes and 28 statements as the basis of DEFCRIT. Consensus was reached in two Delphi rounds with an expert retention rate of 89%. The final consensus definition for acute paediatric critical illness is: an infant, child, or adolescent with an illness, injury, or post-operative state that increases the risk for or results in acute physiological instability (abnormal physiological parameters or vital organ dysfunction or failure) or a clinical support requirement (such as frequent or continuous monitoring or time-sensitive interventions) to prevent further deterioration or death. The proposed definition and framework provide the conceptual clarity needed for a unified approach for global research across resource-variable settings. Future work will centre on validating DEFCRIT and determining high priority measures and guidelines for data collection and analysis that will promote its use in research.

Development of a Deep Learning Model for Retinal Hemorrhage Detection on Head Computed Tomography in Young Children.

Importance: Abusive head trauma (AHT) in children is often missed in medical encounters, and retinal hemorrhage (RH) is considered strong evidence for AHT. Although head computed tomography (CT) is obtained routinely, all but exceptionally large RHs are undetectable on CT images in children. Objective: To examine whether deep learning-based image analysis can detect RH on pediatric head CT. Design, Setting, and Participants: This diagnostic study included 301 patients diagnosed with AHT who underwent head CT and dilated fundoscopic examinations at a quaternary care children's hospital. The study assessed a deep learning model using axial slices from 218 segmented globes with RH and 384 globes without RH between May 1, 2007, and March 31, 2021. Two additional light gradient boosting machine (GBM) models were assessed: one that used demographic characteristics and common brain findings in AHT and another that combined the deep learning model's risk prediction plus the same demographic characteristics and brain findings. Main Outcomes and Measures: Sensitivity (recall), specificity, precision, accuracy, F1 score, and area under the curve (AUC) for each model predicting the presence or absence of RH in globes were assessed. Globe regions that influenced the deep learning model predictions were visualized in saliency maps. The contributions of demographic and standard CT features were assessed by Shapley additive explanation. Results: The final study population included 301 patients (187 [62.1%] male; median [range] age, 4.6 [0.1-35.8] months). A total of 120 patients (39.9%) had RH on fundoscopic examinations. The deep learning model performed as follows: sensitivity, 79.6%; specificity, 79.2%; positive predictive value (precision), 68.6%; negative predictive value, 87.1%; accuracy, 79.3%; F1 score, 73.7%; and AUC, 0.83 (95% CI, 0.75-0.91). The AUCs were 0.80 (95% CI, 0.69-0.91) for the general light GBM model and 0.86 (95% CI, 0.79-0.93) for the combined light GBM model. Sensitivities of all models were similar, whereas the specificities of the deep learning and combined light GBM models were higher than those of the light GBM model. Conclusions and Relevance: The findings of this diagnostic study indicate that a deep learning-based image analysis of globes on pediatric head CTs can predict the presence of RH. After prospective external validation, a deep learning model incorporated into CT image analysis software could calibrate clinical suspicion for AHT and provide decision support for which patients urgently need fundoscopic examinations.

Features derived from blood pressure and intracranial pressure predict elevated intracranial pressure events in critically ill children.

Clinicians frequently observe hemodynamic changes preceding elevated intracranial pressure events. We employed a machine learning approach to identify novel and differentially expressed features associated with elevated intracranial pressure events in children with severe brain injuries. Statistical features from physiologic data streams were derived from non-overlapping 30-min analysis windows prior to 21 elevated intracranial pressure events; 200 records without elevated intracranial pressure events were used as controls. Ten Monte Carlo simulations with training/testing splits provided performance benchmarks for 4 machine learning approaches. XGBoost yielded the best performing predictive models. Shapley Additive Explanations analyses demonstrated that a majority of the top 20 contributing features consistently derived from blood pressure data streams up to 240 min prior to elevated intracranial events. The best performing prediction model was using the 30-60 min analysis window; for this model, the area under the receiver operating characteristic window using XGBoost was 0.82 (95% CI 0.81-0.83); the area under the precision-recall curve was 0.24 (95% CI 0.23-0.25), above the expected baseline of 0.1. We conclude that physiomarkers discernable by machine learning are concentrated within blood pressure and intracranial pressure data up to 4 h prior to elevated intracranial pressure events.

Respiratory Syncytial Virus Bronchiolitis Complicated by Necrotizing Enterocolitis: A Case Series.

In rare instances, severe respiratory syncytial virus (RSV) infections of the lower respiratory tract can cause life-threatening extrapulmonary complications. In this report, we describe 4 previously healthy, term and late-preterm infants admitted to the PICU with respiratory failure due to RSV bronchiolitis who developed necrotizing enterocolitis shortly after admission. All infants exhibited progressive abdominal distention, had typical radiographic findings, and developed simple or complex ascites. In addition to being managed with broad-spectrum antibiotics and bowel rest, 1 infant was treated with colon resection and ileostomy, 2 had peritoneal drainage procedures for ascites, and one of those later developed small bowel strictures treated with delayed resection and anastomosis. Three were discharged from the hospital without further complications; 1 died of septic shock. In this case series, we describe development of necrotizing enterocolitis in otherwise healthy neonates with severe RSV disease in the absence of traditional risk factors. We hypothesize that a dysregulated proinflammatory response associated with severe RSV disease may alter intestinal blood flow and compromise barriers to bacterial translocation. Enteral feeding intolerance, septic ileus, and/or complex ascites may represent important clinical corollaries in these patients.

Evidence Limitations in Determining Sexually Dimorphic Outcomes in Pediatric Post-Traumatic Hypopituitarism and the Path Forward.

Neuroendocrine dysfunction can occur as a consequence of traumatic brain injury (TBI), and disruptions to the hypothalamic-pituitary axis can be especially consequential to children. The purpose of our review is to summarize current literature relevant to studying sex differences in pediatric post-traumatic hypopituitarism (PTHP). Our understanding of incidence, time course, and impact is constrained by studies which are primarily small, are disadvantaged by significant methodological challenges, and have investigated limited temporal windows. Because hormonal changes underpin the basis of growth and development, the timing of injury and PTHP testing with respect to pubertal stage gains particular importance. Reciprocal relationships among neuroendocrine function, TBI, adverse childhood events, and physiological, psychological and cognitive sequelae are underconsidered influencers of sexually dimorphic outcomes. In light of the tremendous heterogeneity in this body of literature, we conclude with the common path upon which we must collectively arrive in order to make progress in understanding PTHP.

Use of magnetic resonance imaging in severe pediatric traumatic brain injury: assessment of current practice.

OBJECTIVE: There is no consensus on the optimal timing and specific brain MRI sequences in the evaluation and management of severe pediatric traumatic brain injury (TBI), and information on current practices is lacking. The authors performed a survey of MRI practices among sites participating in a multicenter study of severe pediatric TBI to provide information for designing future clinical trials using MRI to assess brain injury after severe pediatric TBI. METHODS: Information on current imaging practices and resources was collected from 27 institutions participating in the Approaches and Decisions after Pediatric TBI Trial. Multiple-choice questions addressed the percentage of patients with TBI who have MRI studies, timing of MRI, MRI sequences used to investigate TBI, as well as the magnetic field strength of MR scanners used at the participating institutions and use of standardized MRI protocols for imaging after severe pediatric TBI. RESULTS: Overall, the reported use of MRI in pediatric patients with severe TBI at participating sites was high, with 40% of sites indicating that they obtain MRI studies in > 95% of this patient population. Differences were observed in the frequency of MRI use between US and international sites, with the US sites obtaining MRI in a higher proportion of their pediatric patients with severe TBI (94% of US vs 44% of international sites reported MRI in at least 70% of patients with severe TBI). The reported timing and composition of MRI studies was highly variable across sites. Sixty percent of sites reported typically obtaining an MRI study within the first 7 days postinjury, with the remainder of responses distributed throughout the first 30-day postinjury period. Responses indicated that MRI sequences sensitive for diffuse axonal injury and ischemia are frequently obtained in patients with TBI, whereas perfusion imaging and spectroscopy techniques are less common. CONCLUSIONS: Results from this survey suggest that despite the lack of consensus or guidelines, MRI is commonly obtained during the acute clinical setting after severe pediatric TBI. The variation in MRI practices highlights the need for additional studies to determine the utility, optimal timing, and composition of clinical MRI studies after TBI. The information in this survey describes current clinical MRI practices in children with severe TBI and identifies important challenges and objectives that should be considered when designing future studies.

Erythropoietin potentiates EDHF-mediated dilations in rat middle cerebral arteries.

The neuroprotective effects of exogenous erythropoietin (EPO) in animals and humans after brain injury may be afforded, in part, by the influence of EPO on cerebral arteries. We tested (1) if EPO itself is vasoactive and (2) if EPO enhances endothelium-mediated dilations, specifically those mediated by endothelium-derived hyperpolarizing factor (EDHF). Immunoblotting and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to detect EPO receptor. Rat middle cerebral arteries (MCAs) were isolated, pressurized, and perfused in vitro. EPO was directly applied to MCAs to test its vasoactivity. Endothelium-mediated dilations were elicited by UTP, whereas EDHF-mediated dilations were elicited by UTP after inhibition of endothelial nitric oxide synthase and cyclooxygenase. mRNA and protein for EPO receptor was found in rat MCA. Abluminal application of 0.001-10 U/mL EPO, which is selective for vascular smooth muscle, did not alter vessel diameter. In contrast, luminal application of EPO, which is selective for endothelium, resulted in concentration-dependent dilations of up to 39 +/- 16% at 10 U/mL (p = 0.0018), though responses were variable. A single dose of EPO (1,000 U/kg) administered to rats 24 h prior to examining vascular function potentiated dilations to UTP 2.6-fold (p < 0.0001). EDHF-mediated dilations were potentiated 2.1-fold following in vivo EPO treatment (p = 0.0034). This study demonstrates that EPO can directly dilate rat MCAs via the endothelium, though not all vessels are responsive. Additionally, pre-treatment with EPO for 24 h in vivo potentiates endothelium-mediated dilations, specifically those mediated by EDHF. Thus, enhanced endothelium-mediated dilations may partially underlie the neuroprotective effects of EPO after brain injury.

Inspiratory muscle conditioning exercise and diaphragm gene therapy in Pompe disease: Clinical evidence of respiratory plasticity.

Pompe disease is an inherited disorder due to a mutation in the gene that encodes acid α-glucosidase (GAA). Children with infantile-onset Pompe disease develop progressive hypotonic weakness and cardiopulmonary insufficiency that may eventually require mechanical ventilation (MV). Our team conducted a first in human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory neural dysfunction in infantile-onset Pompe. Subjects (aged 2-15years, full-time MV: n=5, partial/no MV: n=4) underwent a period of preoperative inspiratory muscle conditioning exercise. The change in respiratory function after exercise alone was compared to the change in function after intramuscular delivery of AAV1-CMV-GAA to the diaphragm with continued exercise. Since AAV-mediated gene therapy can reach phrenic motoneurons via retrograde transduction, we hypothesized that AAV1-CMV-GAA would improve dynamic respiratory motor function to a greater degree than exercise alone. Dependent measures were maximal inspiratory pressure (MIP), respiratory responses to inspiratory threshold loads (load compensation: LC), and physical evidence of diaphragm activity (descent on MRI, EMG activity). Exercise alone did not change function. After AAV1-CMV-GAA, MIP was unchanged. Flow and volume LC responses increased after dosing (p<0.05 to p<0.005), but only in the subjects with partial/no MV use. Changes in LC tended to occur on or after 180days. At Day 180, the four subjects with MRI evidence of diaphragm descent had greater maximal voluntary ventilation (p<0.05) and tended to be younger, stronger, and use fewer hours of daily MV. In conclusion, combined AAV1-CMV-GAA and exercise training conferred benefits to dynamic motor function of the diaphragm. Children with a higher baseline neuromuscular function may have greater potential for functional gains.

Endothelial influences on cerebrovascular tone.

The cerebrovascular endothelium exerts a profound influence on cerebral vessels and cerebral blood flow. This review summarizes current knowledge of various dilator and constrictor mechanisms intrinsic to the cerebrovascular endothelium. The endothelium contributes to the resting tone of cerebral arteries and arterioles by tonically releasing nitric oxide (NO*). Dilations can occur by stimulated release of NO*, endothelium-derived hyperpolarization factor, or prostanoids. During pathological conditions, the dilator influence of the endothelium can turn to that of constriction by a variety of mechanisms, including decreased NO* bioavailability and release of endothelin-1. The endothelium may participate in neurovascular coupling by conducting local dilations to upstream arteries. Further study of the cerebrovascular endothelium is critical for understanding the pathogenesis of a number of pathological conditions, including stroke, traumatic brain injury, and subarachnoid hemorrhage.

Considering the use of induced hypothermia in a pediatric patient with traumatic brain injury: a critical appraisal of two meta-analyses.

OBJECTIVE: To review whether induced hypothermia after traumatic brain injury affects morbidity and mortality based on the results of two meta-analyses. DESIGN: Critical appraisals of McIntyre et al: Prolonged therapeutic hypothermia after traumatic brain injury in adults: A systematic review. JAMA 2003; 289:2992-2999, and Henderson et al: Hypothermia in the management of traumatic brain injury: A systematic review and meta-analysis. Intensive Care Med 2003; 29:1637-1644. FINDINGS: Both meta-analyses included trials of adult patients with severe traumatic brain injury randomized to induced hypothermia or normothermia and evaluated risk of death and poor neurologic outcomes. McIntyre et al. found the overall relative risk of mortality with induced hypothermia to be 0.81 (95% confidence interval 0.69-0.96). By designing a priori analyses, these authors also found that the relative risk of death was reduced in patients cooled for >48 hrs, and the risk of poor neurologic outcome was reduced with all durations of cooling, cooling to 32-33 degrees C, and rewarming in <24 hrs. In contrast, Henderson et al. found that induced hypothermia did not change the odds of death after traumatic brain injury (odds ratio 0.81; 95% confidence interval 0.59-1.13) and that normothermic controls had an odds ratio of 0.42 (95% confidence interval 0.25-0.70) for developing intercurrent pneumonia. Both analyses found trials to be heterogeneous with respect to neurologic outcome. CONCLUSIONS: The discrepancies in the results of these contemporaneous meta-analyses may stem, in part, from differences in their trial selection strategies as well as from sources of trial heterogeneity. Nevertheless, McIntyre et al. uncovered the equivalent of a dose-dependent reduction in the risk of death with induced hypothermia, supporting further study of this neuroprotective strategy. Although these meta-analyses included trials containing adult patients, a phase II trial of induced hypothermia in pediatric traumatic brain injury has established its feasibility and safety in infants and children. As in adult patients, induced hypothermia for traumatic brain injury in children can be considered an optional therapy for refractory intracranial hypertension but should not be regarded as standard of care.

Retrograde gene delivery to hypoglossal motoneurons using adeno-associated virus serotype 9.

Retrograde viral transport (i.e., muscle to motoneuron) enables targeted gene delivery to specific motor pools. Recombinant adeno-associated virus serotype 9 (AAV9) robustly infects motoneurons, but the retrograde transport capabilities of AAV9 have not been systematically evaluated. Accordingly, we evaluated the retrograde transduction efficiency of AAV9 after direct tongue injection in 129SVE mice as well as a mouse model that displays neuromuscular pathology (Gaa(-/-)). Hypoglossal (XII) motoneurons were histologically evaluated 8 weeks after tongue injection with AAV9 encoding green fluorescent protein (GFP) with expression driven by the chicken ß-actin promoter (1 × 10(11) vector genomes). On average, GFP expression was detected in 234 ± 43 XII motoneurons 8 weeks after AAV9-GFP tongue injection. In contrast, tongue injection with a highly efficient retrograde anatomical tracer (cholera toxin ß subunit, CT-ß) resulted in infection of 818 ± 88 XII motoneurons per mouse. The retrograde transduction efficiency of AAV9 was similar between the 129SVE mice and those with neuromuscular disease (Gaa(-/-)). Routine hematoxylin and eosin staining and cluster of differentiation (CD) immunostaining for T cells (CD3) indicated no persistent inflammation within the tongue or XII nucleus after AAV9 injection. Additional experiments indicated no adverse effects of AAV9 on the pattern of breathing. We conclude that AAV9 can retrogradely infect a significant portion of a given motoneuron pool in normal and dystrophic mice, and that its transduction efficiency is approximately 30% of what can be achieved with CT-ß.

Effects of carbon monoxide and heme oxygenase inhibitors in cerebral vessels of rats and mice.

Carbon monoxide (CO) has been postulated to be a signaling molecule in many tissues, including the vasculature. We examined vasomotor responses of adult rat and mouse cerebral arteries to both exogenously applied and endogenously produced CO. The diameter of isolated, pressurized, and perfused rat middle cerebral arteries (MCAs) was not altered by authentic CO (10(-6) to 10(-4) M). Mouse MCAs, however, dilated by 21 +/- 10% at 10(-4) M CO. Authentic nitric oxide (NO., 10(-10) to 10(-7) M) dilated both rat and mouse MCAs. At 10(-8) M NO., rat vessels dilated by 84 +/- 4%, and at 10(-7) M NO., mouse vessels dilated by 59 +/- 9%. Stimulation of endogenous CO production through heme oxygenase (HO) with the heme precursor delta-aminolevulinic acid (10(-10) to 10(-4) M) did not dilate the MCAs of either species. The metalloporphyrin HO inhibitor chromium mesoporphyrin IX (CrMP) caused profound constriction of the rat MCA (44 +/- 2% at 3 x 10(-5) M). Importantly, this constriction was unaltered by exogenous CO (10(-4) M) or CO plus 10(-5) M biliverdine (both HO products). In contrast, exogenous CO (10(-4) M) reversed CrMP-induced constriction in rat gracilis arterioles. Control mouse MCAs constricted by only 3 +/- 1% in response to 10(-5) M CrMP. Magnesium protoporphyrin IX (10(-5) M), a weak HO inhibitor used to control for nonspecific effects of metalloporphyrins, also constricted the rat MCA to a similar extent as CrMP. We conclude that, at physiological concentrations, CO is not a dilator of adult rodent cerebral arteries and that metalloporphyrin HO inhibitors have nonspecific constrictor effects in rat cerebral arteries.