Pediatric Brain Injury Research Articles

Increased in-hospital mortality following severe head injury in young children: results from a nationwide trauma registry.

BackgroundIn the current literature, the outcome of paediatric brain injury is controversially discussed. According to the majority of the studies, there seems to be a decreased mortality but worse recovery in paediatric, traumatic brain injury in comparison with adults. However, there is a lack of information concerning the differences in various stages of development in patients younger than 18 years. The aim of our study was to verify the in-hospital outcome of different paediatric age groups in comparison to adults with respect to the treatment strategy.MethodsWe performed a retrospective analysis of the TraumaRegister DGU® from 2002 to 2012. Inclusion criteria were an Abbreviated Injury Scale (AIS) head ≥3 points and an AIS ≤2 points of the remaining body regions. The collective was divided into different subgroups according to age (1–3, 4–6, 7–10, 11–14, 15–17) and an adult control group aged between 18 and 55 years. We descriptively analysed the endpoint rate of sepsis, multiple organ failure, and mortality. Additionally, the Glasgow Outcome Scale (GOS) at discharge was observed.ResultsOverall, 1110 children and 6491 adult control patients were included. Comparing the rate of intubation on-scene, the rate of cranial CT scans, the rate of craniotomies, and the rate and length of intensive care treatment, we could only identify minor differences between the age groups. The treatment after discharge from hospital was markedly different due to a very low rate of in-patient rehabilitation treatment in children. On one hand, the rate of systemic complications, such as sepsis and multiple organ failure increased with increasing age. On the other hand, we found a significantly increased mortality in children younger than 7 years after very (AIS head = 5) severe brain injury. The in-hospital functional outcome in survivors, according to the GOS, was beneficial for younger children in comparison to adolescents and adults.ConclusionsWe were unable to identify marked age-related differences in the therapeutic approach. Nevertheless, we were able to demonstrate marked differences of outcome. Children younger than 7 years significantly die more often due to direct impact of severe trauma. But if they survive, they seem to develop less systemic complications and profit from a better functional outcome.

Progesterone for neuroprotection in pediatric traumatic brain injury.

To provide an overview of the preclinical literature on progesterone for neuroprotection after traumatic brain injury and to describe unique features of developmental brain injury that should be considered when evaluating the therapeutic potential for progesterone treatment after pediatric traumatic brain injury. National Library of Medicine PubMed literature review. The mechanisms of neuroprotection by progesterone are reviewed, and the preclinical literature using progesterone treatment in adult animal models of traumatic brain injury is summarized. Unique features of the developing brain that could either enhance or limit the efficacy of neuroprotection by progesterone are discussed, and the limited preclinical literature using progesterone after acute injury to the developing brain is described. Finally, the current status of clinical trials of progesterone for adult traumatic brain injury is reviewed. Progesterone is a pleiotropic agent with beneficial effects on secondary injury cascades that occur after traumatic brain injury, including cerebral edema, neuroinflammation, oxidative stress, and excitotoxicity. More than 40 studies have used progesterone for treatment after traumatic brain injury in adult animal models, with results summarized in tabular form. However, very few studies have evaluated progesterone in pediatric animal models of brain injury. To date, two human phase II trials of progesterone for adult traumatic brain injury have been published, and two multicenter phase III trials are underway. The unique features of the developing brain from that of a mature adult brain make it necessary to independently study progesterone in clinically relevant, immature animal models of traumatic brain injury. Additional preclinical studies could lead to the development of a novel neuroprotective therapy that could reduce the long-term disability in head-injured children and could potentially provide benefit in other forms of pediatric brain injury (global ischemia, stroke, and statue epilepticus).

Clinical manifestations that predict abnormal brain computed tomography (CT) in children with minor head injury.

Background:Computed tomography (CT) used in pediatric pediatrics brain injury (TBI) to ascertain neurological manifestations. Nevertheless, this practice is associated with adverse effects. Reports in the literature suggest incidents of morbidity and mortality in children due to exposure to radiation. Hence, it is found imperative to search for a reliable alternative.Objectives:The aim of this study is to find a reliable clinical alternative to detect an intracranial injury without resorting to the CT.Materials and Methods:Retrospective cross-sectional study was undertaken in patients (1-14 years) with blunt head injury and having a Glasgow Coma Scale (GCS) of 13-15 who had CT performed on them. Using statistical analysis, the correlation between clinical examination and positive CT manifestation is analyzed for different age-groups and various mechanisms of injury.Results:No statistically significant association between parameteres such as Loss of Consciousness, ‘fall’ as mechanism of injury, motor vehicle accidents (MVA), more than two discrete episodes of vomiting and the CT finding of intracranial injury could be noted. Analyzed data have led to believe that GCS of 13 at presentation is the only important clinical predictor of intracranial injury.Conclusion:Retrospective data, small sample size and limited number of factors for assessing clinical manifestation might present constraints on the predictive rule that was derived from this review. Such limitations notwithstanding, the decision to determine which patients should undergo neuroimaging is encouraged to be based on clinical judgments. Further analysis with higher sample sizes may be required to authenticate and validate findings.

The development of lasting impairments: A mild pediatric brain injury alters gene expression, dendritic morphology, and synaptic connectivity in the prefrontal cortex of rats

Apart from therapeutic discovery, the study of mild traumatic brain injury (mTBI) has been focused on two challenges: why do a majority of individuals recover with little concern, while a considerable proportion suffer with persistent and often debilitating symptomology; and, how do mild injuries significantly increase risk for an early-onset neurodegeneration? Owing to a lack of observable damage following mTBI, this study was designed to determine if there were changes in neuronal morphology, synaptic connectivity, and epigenetic patterning that could contribute to the manifestation of persistent neurological dysfunction. Prefrontal cortex tissue from male and female rats was used for Golgi-Cox analysis along with the profiling of changes in gene expression (BDNF, DNMT1, FGF2, IGF1, Nogo-A, OXYR, and TERT) and telomere length (TL), following a single mTBI or sham injury in the juvenile period. Golgi-Cox analysis of dendritic branch order, dendritic length, and spine density demonstrate that an early mTBI increases complexity of pyramidal neurons in the mPFC. Furthermore, there are also substantial changes in the expression levels of the seven genes of interest and TL following a single mild injury in this brain region. The results from the neuroanatomical measures and changes in gene expression indicate that the mTBI disrupts normal pruning processes that are typically underway at this point in development. In addition, there are significant interactions between the social environment and epigenetic processes that work in concert to perpetuate neurological dysfunction.

Validation of a clinical prediction rule for pediatric abusive head trauma.

To reduce missed cases of pediatric abusive head trauma (AHT), Pediatric Brain Injury Research Network investigators derived a 4-variable AHT clinical prediction rule (CPR) with sensitivity of .96. Our objective was to validate the screening performance of this AHT CPR in a new, equivalent patient population. We conducted a prospective, multicenter, observational, cross-sectional study. Applying the same inclusion criteria, definitional criteria for AHT, and methods used in the completed derivation study, Pediatric Brain Injury Research Network investigators captured complete clinical, historical, and radiologic data on 291 acutely head-injured children <3 years of age admitted to PICUs at 14 participating sites, sorted them into comparison groups of abusive and nonabusive head trauma, and measured the screening performance of the AHT CPR. In this new patient population, the 4-variable AHT CPR demonstrated sensitivity of .96, specificity of .46, positive predictive value of .55, negative predictive value of .93, positive likelihood ratio of 1.67, and negative likelihood ratio of 0.09. Secondary analysis revealed that the AHT CPR identified 98% of study patients who were ultimately diagnosed with AHT. Four readily available variables (acute respiratory compromise before admission; bruising of the torso, ears, or neck; bilateral or interhemispheric subdural hemorrhages or collections; and any skull fractures other than an isolated, unilateral, nondiastatic, linear, parietal fracture) identify AHT with high sensitivity in young, acutely head-injured children admitted to the PICU.

Interleukin-1 receptor blockade in perinatal brain injury.

Interleukin-1 (IL-1) is a potent inflammatory cytokine that can be produced by a variety of cell types throughout the body. While IL-1 is a central mediator of inflammation and response to infection, the role of IL-1 signaling in adult and pediatric brain injury is becoming increasingly clear. Although the mechanisms of IL-1 expression are largely understood, the downstream effects and contributions to excitotoxicity and oxidative stress are poorly defined. Here, we present a review of mechanisms of IL-1 signaling with a focus on the role of IL-1 in perinatal brain injury. We highlight research models of perinatal brain injury and the use of interleukin-1 receptor antagonist (IL-1RA) as an agent of therapeutic potential in preventing perinatal brain injury due to exposure to inflammation.

Vomiting Alone May Not Indicate Serious Pediatric Brain Injury

Vomiting Alone May Not Indicate Serious Pediatric Brain Injury

Emergence to the Conscious State During Inpatient Rehabilitation After Traumatic Brain Injury in Children and Young Adults

To describe clinical patterns related to emergence to the conscious state (CS) in children and young adults with traumatic brain injury receiving acute inpatient rehabilitation. One academically affiliated pediatric brain injury rehabilitation unit. Fourteen consecutive patients aged 1 to 20 years with traumatic brain injury and disorders of consciousness. Retrospective case series. The primary outcome was emergence to CS during the inpatient rehabilitation admission. Factors evaluated for relationship to emergence to CS included age at injury, admission level of consciousness, admission Rappaport Coma/Near-Coma Scale score, and admission Cognitive and Linguistic Scale responsiveness item score. Ten of 14 patients emerged to CS during the inpatient rehabilitation admission. Those who emerged to CS had higher levels of responsiveness at admission to rehabilitation. There was a trend toward older age in those who emerged to CS. In this limited cohort, the majority of patients with disorders of consciousness after traumatic brain injury emerged to CS during acute inpatient rehabilitation, underscoring the presence of functional goals for inpatient rehabilitation in this population. Larger cohorts are needed to further explore clinical variables associated with emergence to CS.

Prevalence of respiratory colonisations and related antibiotic resistances among paediatric tracheostomised patients of a long-term rehabilitation centre in Italy.

Patients with brain injury are prone to bacterial colonisations because of mechanical ventilation during intensive care and the long-term retention of tracheostomical tubes during rehabilitation. Reduced levels of isolation, typical of rehabilitation, could also contribute to propagate colonisations. We evaluated the presence of bacteria through different stages of healthcare, their antibiotic resistances and their clinical impact in a rehabilitation setting. This retrospective study included all tracheostomised patients referred to the paediatric brain injury unit of the Scientific Institute IRCCS E. Medea (Italy) over a six-year period. Data were collected from antibiograms regarding the presence of bacterial species and antibiotic resistances; clinical data were collected from medical records. Antibiograms revealed bacteria and antibiotic resistances typical of intensive care, while prevalence patterns were characteristic for each species (P. aeruginosa and S. aureus prevailing in the acute setting, K. pneumoniae, A. baumannii and others in rehabilitation). Despite very frequent antibiotic resistances, consistent with Italian averages, we observed a limited clinical impact for these colonisations. We analysed risk factors correlating to the development of respiratory symptoms and found a role for the acute clinical course after brain injury (having undergone neurosurgery; duration of intensive care stay) as well as for rehabilitation (duration of coma). Our data suggest that, in a long-term perspective, an appropriate balance is yet to be found between patient isolation and social interactions, to control respiratory colonisations and antibiotic resistances without compromising rehabilitation. They also suggest that regular containment measures should be complemented by thorough training to non-medic personnel and parents alike.

Sociosexual and communication deficits after traumatic injury to the developing murine brain.

Despite the life-long implications of social and communication dysfunction after pediatric traumatic brain injury, there is a poor understanding of these deficits in terms of their developmental trajectory and underlying mechanisms. In a well-characterized murine model of pediatric brain injury, we recently demonstrated that pronounced deficits in social interactions emerge across maturation to adulthood after injury at postnatal day (p) 21, approximating a toddler-aged child. Extending these findings, we here hypothesized that these social deficits are dependent upon brain maturation at the time of injury, and coincide with abnormal sociosexual behaviors and communication. Age-dependent vulnerability of the developing brain to social deficits was addressed by comparing behavioral and neuroanatomical outcomes in mice injured at either a pediatric age (p21) or during adolescence (p35). Sociosexual behaviors including social investigation and mounting were evaluated in a resident-intruder paradigm at adulthood. These outcomes were complemented by assays of urine scent marking and ultrasonic vocalizations as indices of social communication. We provide evidence of sociosexual deficits after brain injury at p21, which manifest as reduced mounting behavior and scent marking towards an unfamiliar female at adulthood. In contrast, with the exception of the loss of social recognition in a three-chamber social approach task, mice that received TBI at adolescence were remarkably resilient to social deficits at adulthood. Increased emission of ultrasonic vocalizations (USVs) as well as preferential emission of high frequency USVs after injury was dependent upon both the stimulus and prior social experience. Contrary to the hypothesis that changes in white matter volume may underlie social dysfunction, injury at both p21 and p35 resulted in a similar degree of atrophy of the corpus callosum by adulthood. However, loss of hippocampal tissue was greater after p21 compared to p35 injury, suggesting that a longer period of lesion progression or differences in the kinetics of secondary pathogenesis after p21 injury may contribute to observed behavioral differences. Together, these findings indicate vulnerability of the developing brain to social dysfunction, and suggest that a younger age-at-insult results in poorer social and sociosexual outcomes.

Application of advanced neuroimaging modalities in pediatric traumatic brain injury.

Neuroimaging is commonly used for the assessment of children with traumatic brain injury and has greatly advanced how children are acutely evaluated. More recently, emphasis has focused on how advanced magnetic resonance imaging methods can detect subtler injuries that could relate to the structural underpinnings of the neuropsychological and behavioral alterations that frequently occur. We examine several methods used for the assessment of pediatric brain injury. Susceptibility-weighted imaging is a sensitive 3-dimensional high-resolution technique in detecting hemorrhagic lesions associated with diffuse axonal injury. Magnetic resonance spectroscopy acquires metabolite information, which serves as a proxy for neuronal (and glial, lipid, etc) structural integrity and provides sensitive assessment of neurochemical alterations. Diffusion-weighted imaging is useful for the early detection of ischemic and shearing injury. Diffusion tensor imaging allows better structural evaluation of white matter tracts. These methods are more sensitive than conventional imaging in demonstrating subtle injury that underlies a child's clinical symptoms. There also is an increasing desire to develop computational methods to fuse imaging data to provide a more integrated analysis of the extent to which components of the neurovascular unit are affected. The future of traumatic brain injury neuroimaging research is promising and will lead to novel approaches to predict and improve outcomes.

Assessment of an Experimental Rodent Model of Pediatric Mild Traumatic Brain Injury

Childhood is one the highest risk periods for experiencing a mild traumatic brain injury (mTBI) from sports-related concussions, motor vehicle accidents, and falls. In addition, many children experience lingering symptomology (post-concussion syndrome) from these closed head injuries. Although the negative sequel of mTBI has been described, a clinically reliable animal model of mild pediatric brain injury has not. The purpose of this study was to examine the validity of a modified weight-drop technique as a model for the induction of mTBI/concussion in juvenile rats following a single impact. Male and female rats (P30) were exposed to a single mTBI or a sham injury followed by a behavioral test battery. Juvenile rats who experienced a single mTBI displayed significant motor/balance impairments when tested on the beam walking task and in the open field, as well as deficits of executive functioning as measured with the novel context mismatch task and the probe trial of the Morris water task. In addition, both male and female rats showed depression-like behavior in the forced swim task, with male rats also exhibiting decreased anxiety-related behaviors in the elevated plus maze. The results from this study suggest that the modified weight-drop technique induces a clinically relevant behavioral phenotype in juvenile rats, and may provide researchers with a reliable animal model of mTBI/concussion from which clinical therapeutic strategies could be developed.

The Importance of Orientation in Evaluating Recovery in Pediatric Traumatic Brain Injury

Objective: Decisions about whether children who have sustained a traumatic brain injury are ready to transition from a medical facility to home and school life requires insight into their cognitive status. This study evaluates whether orientation to time, place, and self (Ox3) serves as sufficient indicator of general cognitive status to support such decisions. Design: Participants with and without TBI were administered the PTBI in one to three individual testing sessions. Performance on Ox3 items were compared between groups, as well as performance on subtests representing broader cognitive and linguistic skills. Setting: Pediatric brain injury in patient acute and rehab units. Participants: Twenty-eight children with TBI (18 male, 10 female) between the ages of 6 and 16 years of age served as participants. Of these, 12 were initially classified as severe, 6 moderate, and 10 mild on the Glasgow Coma Scale. Interventions: NA Main Outcome Measures: The Pediatric Test of Brain Injury (PTBI) is a criterion-referenced, standardized test designed to measure neurocognitive, language and literacy abilities in children recovering from brain injury. The entire test, including its Orientation subtest, was administered to participants during the acute phase of recovery (within 3 months of injury). Results: Despite no differences between the TBI and control group on the Orientation subtests, deficits occurred in other cognitive-linguistic domains that are relevant to functioning outside medical and rehabilitation environments. Furthermore, even neurologically-normal children sometimes failed some Ox3 items. Conclusion: The findings on Orientation items from the PTBI indicates that caution is warranted in applying the “Ox3” standard for evaluating cognitive status to a pediatric TBI population.

Anesthetic approach in pediatric brain injury

Traumatic brain injury (TBI) is defined as an insult to the brain resulting from external force, leading alteration in brain function, permanent or temporary impaired cognition, wide-spread impairments in motor and behavior function. TBI is not only a leading cause of death but it is a significant contributor to disability in pediatric age group. Its sequelae is an important health problem throughout the world. The patients face numerous difficulties to return to a productive life. Improvements in the prognosis continue with its elucidated pathophysiology, technological developments in its monitorization, and sustained scientific research. In 2003, the Society of Critical Care Medicine published the Guidelines for the Acute Medical Management of Severe Traumatic Brain Injury in Infants, Children, and Adolecents and updated the guidelines in 2012 with some significant changes. Pediatric anesthesiologists are frequently faced with the perioperative management of such patients. This article reviews pathophysiology, anesthetic management, hemodynamic support, management of intracranial hypertension of pediatric patients with TBI in the light of current evidence-based medicine. Informing the anesthetists confronting TBI patients in the intensive care unit, during preoperative and peri-operative periods, about important issues related to pathophysiology and treatment of TBI will contribute to the improvements in the prognosis of these patients.

Chapter Six - Pediatric Hypoglycemia

Hypoglycemia in the pediatric population is a common finding important to recognize and manage to prevent brain injury. Recent advances in molecular genetics have provided new insight into its biochemical and physiologic basis and have led to more appropriate and specific treatment. Although a major cause of brain injury in pediatrics, the ability to predict the long-term outcome in these patients remains difficult. Identification of these at-risk individuals is important. The physiologic adaptations associated with transition from fetal to neonatal life are now better understood thus allowing for improved surveillance and management. Despite these advances, analytical limitations of point-of-care testing instruments at low glucose concentration continue to persist, This review aims to address these questions and provide an overview of pediatric hypoglycemia and the molecular pathways involved.

A novel mouse model of pediatric cardiac arrest and cardiopulmonary resuscitation reveals age-dependent neuronal sensitivities to ischemic injury

BackgroundPediatric sudden cardiac arrest (CA) is an unfortunate and devastating condition, often leading to poor neurologic outcomes. However, little experimental data on the pathophysiology of pediatric CA is currently available due to the scarcity of animal models. New methodWe developed a novel experimental model of pediatric cardiac arrest and cardiopulmonary resuscitation (CA/CPR) using postnatal day 20–25 mice. Adult (8–12 weeks) and pediatric (P20-25) mice were subjected to 6min CA/CPR. Hippocampal CA1 and striatal neuronal injury were quantified 3 days after resuscitation by hematoxylin and eosin (H&E) and Fluoro-Jade B staining, respectively. ResultsPediatric mice exhibited less neuronal injury in both CA1 hippocampal and striatal neurons compared to adult mice. Increasing ischemia time to 8min CA/CPR resulted in an increase in hippocampal injury in pediatric mice, resulting in similar damage in adult and pediatric brains. In contrast, striatal injury in the pediatric brain following 6 or 8min CA/CPR remained extremely low. As observed in adult mice, cardiac arrest causes delayed neuronal death in pediatric mice, with hippocampal CA1 neuronal damage maturing at 72h after insult. Finally, mild therapeutic hypothermia reduced hippocampal CA1 neuronal injury after pediatric CA/CPR. Comparison with existing methodThis is the first report of a cardiac arrest and CPR model of global cerebral ischemia in mice. ConclusionsTherefore, the mouse pediatric CA/CPR model we developed is unique and will provide an important new tool to the research community for the study of pediatric brain injury.

Anesthetic management of common pediatric emergencies

To keep pediatric anesthesiologists up-to-date in their management of pediatric emergencies by identifying the key publications from 2012 that are relevant to the anesthetic management of common pediatric emergencies. Little has been published about specific pediatric emergencies. A large multi-institutional audit of tracheo-esophageal fistula demonstrated a wide range of anesthesia practice and a difficulty with ventilation on induction in 7% of cases. Large audits of bronchoscopy for foreign body have also demonstrated a variety of effective practices with a low complication rate. More generally, studies have increasingly demonstrated that postoperative pain may be substantial after many common procedures including some emergency surgery. The management of the full stomach remains controversial and the use of ultrasound to assess gastric volume is promising but unproven. Recent guidelines for resuscitation have been published. It is increasingly recognized that meticulous management of pediatric brain injury is vital, and although the evidence base is very weak, a more coherent anesthetic approach is emerging. Many areas of the management of pediatric emergencies remain controversial and based on little good evidence. In spite of this, the complication rate is low. Postoperative pain is an emerging problem while the optimal management of the full stomach is still unresolved.

The Potential for Bio-Mediators and Biomarkers in Pediatric Traumatic Brain Injury and Neurocritical Care

The use of biomarkers of brain injury in pediatric neurocritical care has been explored for at least 15 years. Two general lines of research on biomarkers in pediatric brain injury have been pursued: (1) studies of “bio-mediators” in cerebrospinal fluid (CSF) of children after traumatic brain injury (TBI) to explore the components of the secondary injury cascades in an attempt to identify potential therapeutic targets and (2) studies of the release of structural proteins into the CSF, serum, or urine in order to diagnose, monitor, and/or prognosticate in patients with TBI or other pediatric neurocritical care conditions. Unique age-related differences in brain biology, disease processes, and clinical applications mandate the development and testing of brain injury bio-mediators and biomarkers specifically in pediatric neurocritical care applications. Finally, although much of the early work on biomarkers of brain injury in pediatrics has focused on TBI, new applications are emerging across a wide range of conditions specifically for pediatric neurocritical care including abusive head trauma, cardiopulmonary arrest, septic shock, extracorporeal membrane oxygenation, hydrocephalus, and cardiac surgery. The potential scope of the utility of biomarkers in pediatric neurocritical care is thus also discussed.

Pediatric brain injury: can DTI scalars predict functional outcome?

Diffusion imaging has made significant inroads into the clinical diagnosis of a variety of diseases by inferring changes in microstructure, namely cell membranes, myelin sheath and other structures that inhibit water diffusion. This review discusses recent progress in the use of diffusion parameters in predicting functional outcome. Studies in the literature using only scalar parameters from diffusion measurements, such as apparent diffusion coefficient (ADC) and fractional anisotropy (FA), are summarized. Other more complex mathematical models and post-processing uses are also discussed briefly.

Evidence-Based Approaches To the Management of Cognitive and Behavioral Impairments Following Pediatric Brain Injury

Much is now known about the short- and long-term sequelae of pediatric acquired brain injury, with impairments found in general intellectual ability and in more specific domains, including attention, memory, executive functioning (e.g., planning and organization) and educational achievement (e.g., spelling and arithmetic). More recently, researchers have investigated behavioral, adaptive, social and mental health outcomes, and similarly, difficulties have been reported in these domains. While the availability of evidence-based treatments is currently limited, the need for the management of such sequelae has led to an emergence of research with a focus on the development and evaluation of management strategies and intervention programs in order to provide such treatment options.