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.

A systematic correlation between finite element models (FEMs) and histopathology is needed to define deformation thresholds associated with traumatic brain injury (TBI). In this study, a FEM of a transected piglet brain was used to reverse engineer the range of optimal shear moduli for infant (5-day-old, 553-658 Pa) and 4-week old toddler piglet brain, (692-811 Pa) from comparisons with measured in situ tissue strains. The more mature brain modulus was found to have significant strain and strain rate dependencies not observed with the infant brain. Age-appropriate FEMs were then used to simulate experimental TBI in infant (n=36) and pre-adolescent (n=17) piglets undergoing a range of rotational head loads. The experimental animals were evaluated for the presence of clinically significant traumatic axonal injury (TAI), which was then correlated with FEM-calculated measures of overall and white matter tract-oriented tissue deformations, and used to identify the metric with the highest sensitivity and specificity for detecting TAI. The best predictors of TAI were the tract-oriented strain (6–7%), strain rate (38–40 s−1), and strain times strain rate (1.3–1.8 s−1) values exceeded by 90% of the brain. These tract-oriented strain and strain rate thresholds for TAI were comparable to those found in isolated axonal stretch studies. Furthermore, we proposed that the higher degree of agreement between tissue distortion aligned with white matter tracts and TAI may be the underlying mechanism responsible for more severe TAI after horizontal and sagittal head rotations in our porcine model of nonimpact TAI than coronal plane rotations.

OBJECTIVES To evaluate the effect of emergency department (ED) interventions on clinical, utilization, and care experience outcomes for older adults. DESIGN A conceptual model informed, protocol‐based systematic review. SETTING Emergency Department (ED). PARTICIPANTS Older adults 65 years of age and older. METHODS AND MEASUREMENT Medline, Embase, CINAHL, and PsycINFO were searched for English‐language studies published through December 2017. Studies evaluating the use of one or more eligible intervention strategies (discharge planning, case management, medication safety or management, and geriatric EDs including those that cited the 2014 Geriatric ED Guidelines) with adults 65 years of age and older were included. Studies were classified by the number of intervention strategies used (ie, single strategy or multi‐strategy) and key intervention components present (ie, assessment, referral plus follow‐up, and contact both before and after ED discharge [“bridge”]). The effect of ED interventions on clinical (functional status, quality of life [QOL]), patient experience, and utilization (hospitalization, ED return visit) outcomes was evaluated. RESULTS A total of 2000 citations were identified; 17 articles describing 15 unique studies (9 randomized and 6 nonrandomized) met eligibility criteria and were included in analyses. ED interventions showed a mixed pattern of effects. Overall, there was a small positive effect of ED interventions on functional status but no effects on QOL, patient experience, hospitalization at or after the initial ED index visit, or ED return visit. CONCLUSION Studies using two or more intervention strategies may be associated with the greatest effects on clinical and utilization outcomes. More comprehensive interventions, defined as those with all three key intervention components present, may be associated with some positive outcomes.

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.

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.

We sought to extract additional physiological information from the time-dependent left ventricular (LV) pressure contour and thereby gain new insights into ventricular function. We used phase plane analysis to characterize high-fidelity pressure data in selected subjects undergoing elective cardiac catheterization. The standard hemodynamic indexes of LV systolic and diastolic function derived from the time-dependent LV pressure contour could be easily obtained using the phase plane method. Additional novel attributes of the phase plane pressure loop, such as phase plane pressure loop area, graphical representation of the isovolumic relaxation time constant, and quantitative measures of beat-to-beat systolic-diastolic coupling were characterized. The asymmetry between the pressures at which maximum isovolumic pressure rise and pressure fall occur, as well as their load dependence, were also easily quantitated. These results indicate that the phase plane method provides a novel window for physiological discovery and has theoretical and applied advantages in quantitative ventricular function characterization.

Ischemic stroke is a leading cause of morbidity and mortality in the US; however, there currently exists only one effective acute pharmacological therapeutic intervention. Purinergic signaling has been shown to regulate vascular function and pathological processes, including inflammation and arterial myogenic reactivity, and plays a role in ischemic stroke outcome. Purinergic signaling requires extracellular purines; however, the mechanism of purine release from cells is unclear. Pannexin1 (Panx1) channels are potentially novel purine release channels expressed throughout the vascular tree that couples regulated purine release with purinergic signaling. Therefore, we examined the role of smooth muscle and endothelial cell Panx1, using conditional cell type-specific transgenic mice, in cerebral ischemia/reperfusion injury outcomes. Deletion of endothelial cell Panx1, but not smooth muscle cell Panx1, significantly reduced cerebral infarct volume after ischemia/reperfusion. Infiltration of leukocytes into brain tissue and development of cerebral myogenic tone were both significantly reduced when mice lacked endothelial Panx1. Panx1 regulation of myogenic tone was unique to the cerebral circulation, as mesenteric myogenic reactivity and blood pressure were independent of endothelial Panx1. Overall, deletion of endothelial Panx1 mitigated cerebral ischemic injury by reducing inflammation and myogenic tone development, indicating that endothelial Panx1 is a possible novel target for therapeutic intervention of ischemic stroke.

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 randomized 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 (PbtO2) probe, and cerebral microdialysis probe placed in the frontal lobe and data collected for 6 h following injury. RESULTS Injured animals had sustained elevations in intracranial pressure and lactate-pyruvate ratio (LPR), and decreased PbtO2 compared to 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 to sham at 6 hours post-injury. 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 non-terminal secondary markers in our injury model for neuropathology, and as evaluation metrics for novel interventions and therapeutics in the acute post-injury 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.