Stephanie A. Eucker

Diffuse optical monitoring of hemodynamic changes in piglet brain with closed head injury.

We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R=0.89, p<0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.

Physiological and histopathological responses following closed rotational head injury depend on direction of head motion

Rotational inertial forces are thought to be the underlying mechanism for most severe brain injuries. However, little is known about the effect of head rotation direction on injury outcomes, particularly in the pediatric population. Neonatal piglets were subjected to a single non-impact head rotation in the horizontal, coronal, or sagittal direction, and physiological and histopathological responses were observed. Sagittal rotation produced the longest duration of unconsciousness, highest incidence of apnea, and largest intracranial pressure increase, while coronal rotation produced little change, and horizontal rotation produced intermediate and variable derangements. Significant cerebral blood flow reductions were observed following sagittal but not coronal or horizontal injury compared to sham. Subarachnoid hemorrhage, ischemia, and brainstem pathology were observed in the sagittal and horizontal groups but not in a single coronal animal. Significant axonal injury occurred following both horizontal and sagittal rotations. For both groups, the distribution of injury was greater in the frontal and parietotemporal lobes than in the occipital lobes, frequently occurred in the absence of ischemia, and did not correlate with regional cerebral blood flow reductions. We postulate that these direction-dependent differences in injury outcomes are due to differences in tissue mechanical loading produced during head rotation.

Finite Element Model Predictions of Intracranial Hemorrhage from Non-Impact, Rapid Head Rotations in the Piglet

Clinicians are charged with the significant task of distinguishing between accidental and inflicted head trauma. Oftentimes this distinction is straightforward, but many times probabilities of injuries from accidental scenarios are unknown making the differential diagnosis difficult. For example, it is unknown whether intracranial hemorrhage (IH) can occur at a location other than a focal contact site following a low height fall. To create a foundation for predicting regional IH in infants, we sought to identify the biomechanical response and injury threshold best able to predict IH in 3–5 day old piglets. First, finite element (FE) model simulations of in situ animal studies were performed to ascertain the optimal representation of the pia‐arachnoid complex, cerebrospinal fluid and cortical vasculature (PCC) for predicting brain strain and brain/skull displacement. Second, rapid head rotations resulting in various degrees of IH were simulated (n = 24) to determine the biomechanical predictor and injury threshold most closely correlated with IH. FE models representing the PCC with either spring connectors or solid elements between the brain and skull resulted in peak brain strain and brain/skull displacement similar to measured values in situ. However, when predicting IH, the spring connector representation of the PCC had the best predictive capability for IH with a sensitivity of 80% and a specificity of 85% when ≥1% of all spring connectors had at least a peak strain of 0.31 mm/mm. These findings and reported methodology will be used in the development of a human infant FE model to simulate real‐world falls and identify injury thresholds for predicting IH in infants.

Neurocritical Care Monitoring Correlates with Neuropathology in a Swine Model of Pediatric Traumatic Brain Injury

BACKGROUND Small-animal models have been used in traumatic brain injury (TBI) research to investigate the basic mechanisms and pathology of TBI. Unfortunately, successful TBI investigations in small-animal models have not resulted in marked improvements in clinical outcomes of TBI patients. OBJECTIVE To develop a clinically relevant immature large-animal model of pediatric neurocritical care following TBI. METHODS Eleven 4-week-old piglets were randomly assigned to either rapid axial head rotation without impact (n = 6) or instrumented sham (n = 5). All animals had an intracranial pressure monitor, brain tissue oxygen tension (Pbto2) probe, and cerebral microdialysis probe placed in the frontal lobe and data collected for 6 hours following injury. RESULTS Injured animals had sustained elevations in intracranial pressure and lactate-pyruvate ratio (LPR), and decreased Pbto2 compared with sham. Pbto2 and LPR from separate frontal lobes had strong linear correlation in both sham and injured animals. Neuropathologic examination demonstrated significant axonal injury and infarct volumes in injured animals compared with sham at 6 hours postinjury. Averaged over time, Pbto2 in both injured and sham animals had a strong inverse correlation with total injury volume. Average LPR had a strong correlation with total injury volume. CONCLUSION LPR and Pbto2 can be utilized as serial nonterminal secondary markers in our injury model for neuropathology, and as evaluation metrics for novel interventions and therapeutics in the acute postinjury period. This translational model bridges a vital gap in knowledge between TBI studies in small-animal models and clinical trials in the pediatric TBI population. ABBREVIATIONS ANOVA: analysis of variance &bgr;-APP: &bgr;-amyloid precursor protein CPP: cerebral perfusion pressure H&E: hematoxylin and eosin ICP: intracranial pressure LPR: lactate-pyruvate ratio Pbto2: brain tissue oxygen tension TBI: traumatic brain injury

Development of a fluorescent microsphere technique for rapid histological determination of cerebral blood flow.

The purpose of this study was to develop a more efficient fluorescent microsphere method to facilitate the rapid use of the histological technique and to enable its use in large tissue regions. Using fluorescent plate/slide imaging technology and automated detection and analysis software, we were able to rapidly image, detect, and count 3 separate microsphere colors in 200 microm thick tissue sections from piglet brain. In resting newborn piglets (n=6) on isoflurane anesthesia, we measured a median total cerebral blood flow (CBF) of 105 ml/min/100g (range 27-206 ml/min/100 g). Compared with other FM analysis methods, our method reduces the time required to determine blood flow, improves accuracy in lipid-rich tissues and large tissue regions and, unlike the radiolabeled microsphere method, can be combined with histological analysis.

In situ deformations in the immature brain during rapid rotations.

Head trauma is the leading cause of death and debilitating injury in children. Computational models are important tools used to understand head injury mechanisms but they must be validated with experimental data. In this communication we present in situ measurements of brain deformation during rapid, nonimpact head rotation in juvenile pigs of different ages. These data will be used to validate computational models identifying age-dependent thresholds of axonal injury. Fresh 5 days (n=3) and 4 weeks (n=2) old piglet heads were transected horizontally and secured in a container. The cut surface of each brain was marked and covered with a transparent, lubricated plate that allowed the brain to move freely in the plane of rotation. For each brain, a rapid (20-28 ms) 65 deg rotation was applied sequentially at 50 rad/s, 75 rad/s, and 75 rad/s. Each rotation was digitally captured at 2500 frames/s (480x320 pixels) and mark locations were tracked and used to compute strain using an in-house program in MATLAB. Peak values of principal strain (E(peak)) were significantly larger during deceleration than during acceleration of the head rotation (p<0.05), and doubled with a 50% increase in velocity. E(peak) was also significantly higher during the second 75 rad/s rotation than during the first 75 rad/s rotation (p<0.0001), suggesting structural alteration at 75 rad/s and the possibility that similar changes may have occurred at 50 rad/s. Analyzing only lower velocity (50 rad/s) rotations, E(peak) significantly increased with age (16.5% versus 12.4%, p<0.003), which was likely due to the larger brain mass and smaller viscoelastic modulus of the 4 weeks old pig brain compared with those of the 5 days old. Strain measurement error for the overall methodology was estimated to be 1%. Brain tissue strain during rapid, nonimpact head rotation in the juvenile pig varies significantly with age. The empirical data presented will be used to validate computational model predictions of brain motion under similar loading conditions and to assist in the development of age-specific thresholds for axonal injury. Future studies will examine the brain-skull displacement and will be used to validate brain-skull interactions in computational models.

Quality of the Development of Traumatic Brain Injury Clinical Practice Guidelines: A Systematic Review

Traumatic brain injury (TBI) is a leading cause of death worldwide and is increasing exponentially particularly in low and middle income countries (LMIC). To inform the development of a standard Clinical Practice Guideline (CPG) for the acute management of TBI that can be implemented specifically for limited resource settings, we conducted a systematic review to identify and assess the quality of all currently available CPGs on acute TBI using the AGREE II instrument. In accordance with PRISMA guidelines, from April 2013 to December 2015 we searched MEDLINE, EMBASE, Google Scholar and the Duke University Medical Center Library Guidelines for peer-reviewed published Clinical Practice Guidelines on the acute management of TBI (less than 24 hours), for any level of traumatic brain injury in both high and low income settings. A comprehensive reference and citation analysis was performed. CPGs found were assessed using the AGREE II instrument by five independent reviewers and scores were aggregated and reported in percentage of total possible score. An initial 2742 articles were evaluated with an additional 98 articles from the citation and reference analysis, yielding 273 full texts examined. A total of 24 final CPGs were included, of which 23 were from high income countries (HIC) and 1 from LMIC. Based on the AGREE II instrument, the best score on overall assessment was 100.0 for the CPG from the National Institute for Health and Clinical Excellence (NIHCE, 2007), followed by the New Zealand Guidelines Group (NZ, 2006) and the National Clinical Guideline (SIGN, 2009) both with a score of 96.7. The CPG from a LMIC had lower scores than CPGs from higher income settings. Our study identified and evaluated 24 CPGs with the highest scores in clarity and presentation, scope and purpose, and rigor of development. Most of these CPGs were developed in HICs, with limited applicability or utility for resource limited settings. Stakeholder involvement, Applicability, and Editorial independence remain weak and insufficiently described specifically with piloting, addressing potential costs and implementation barriers, and auditing for quality improvement.

Are Two Drugs Better Than One For Acute Agitation? A Discussion On Black Box Warnings, Waiver of Informed Consent, and the Ethics of Enrolling Impaired Subjects in Clinical Trials

D Editor’s Note: You are reading the 31st installment of Annals of Emergency Medicine Journal Club. This Journal Club refers to the Chan et al article published in this edition. This bimonthly feature seeks to improve the critical appraisal skills of emergency physicians and other interested readers through a guided critique of actual Annals of Emergency Medicine articles. Each Journal Club will pose questions that encourage readers—be they clinicians, academics, residents, or medical students—to critically appraise the literature. During a 2to 3-year cycle, we plan to ask questions that cover the main topics in research methodology and critical appraisal of the literature. To do this, we will select articles that use a variety of study designs and analytic techniques. These may or may not be the most clinically important articles in a specific issue, but they are articles that serve the mission of covering the clinical epidemiology curriculum. Journal Club entries are published in 2 phases. In the first phase, a list of questions about the article is published in the issue in which the article appears. Questions are rated “novice,” ( ) “intermediate,” ( ), and “advanced” ( ) so that individuals planning a journal club can assign the right question to the right student. The answers to this journal club will be published in the June 2013 issue. US residency directors will have immediate access to the answers through the Council of Emergency Medicine Residency Directors Share Point Web site. International residency directors can gain access to the questions by going to http://www.emergencymedicine.ucla. edu/annalsjc/ and following the directions. Thus, if a program conducts its journal club within 5 months of the publication of the questions, no one will have access to the published answers except the residency director. The purpose of delaying the publication of the answers is to promote

Are Nonpharmacologic Pain Interventions Effective at Reducing Pain in Adult Patients Visiting the Emergency Department? A Systematic Review and Meta‐analysis

OBJECTIVES Pain is a common complaint in the emergency department (ED). Its management currently depends heavily on pharmacologic treatment, but evidence suggests that nonpharmacologic interventions may be beneficial. The purpose of this systematic review and meta-analysis was to assess whether nonpharmacologic interventions in the ED are effective in reducing pain. METHODS We conducted a systematic review of the literature on all types of nonpharmacologic interventions in the ED with pain reduction as an outcome. We performed a qualitative summary of all studies meeting inclusion criteria and meta-analysis of randomized controlled studies measuring postintervention changes in pain. Interventions were divided by type into five categories for more focused subanalyses. RESULTS Fifty-six studies met inclusion criteria for summary analysis. The most studied interventions were acupuncture (10 studies) and physical therapy (six studies). The type of pain most studied was musculoskeletal pain (34 studies). Most (42 studies) reported at least one improved outcome after intervention. Of these, 23 studies reported significantly reduced pain compared to control, 24 studies showed no difference, and nine studies had no control group. Meta-analysis included 22 qualifying randomized controlled trials and had a global standardized mean difference of -0.46 (95% confidence interval = -0.66 to -0.27) in favor of nonpharmacologic interventions for reducing pain. CONCLUSION Nonpharmacologic interventions are often effective in reducing pain in the ED. However, most existing studies are small, warranting further investigation into their use for optimizing ED pain management.

FEM-predicted regional tissue strains aligned with the white matter tracts predict axonal injury

Finite element modeling (FEM) is frequently used to study the biomechanical effects of traumatic brain injury (TBI). Utility of these models in predicting tissue injury depends on close correspondence between calculated mechanical response parameters and those actually occurring in tissue, as well as the establishment of accurate thresholds of tissue injury for each of these parameters. We developed a three-dimensional FEM of the neonatal piglet brain and used it to predict the spatial distributions of tissue strains during horizontal, coronal and sagittal rotations of the head in order to evaluate our hypothesis that the spatial pattern of axonal injury is attributed to differences in regional tissue strains. The maximum principal strains and the white matter tract (WMT) oriented strains were compared. Diffusion tensor imaging (DTI) was used to obtain the directions of the axonal fibers in the white matter tracts. While both maximum principal strains and the white matter tract oriented strains are correlated with regional axonal injury, WMT-oriented strain had a higher predictive power (WMT strain Receiver Operating Characteristic (ROC) area under curve = 0.848; Max Principal Strain ROC area under curve=0.807). The strain thresholds predicting axonal injury were 4.7% for WMT strain and 39.9% for Max Principal Strain.