Bruce P. Capehart

Brain Injuries from Blast

Traumatic brain injury (TBI) from blast produces a number of conundrums. This review focuses on five fundamental questions including: (1) What are the physical correlates for blast TBI in humans? (2) Why is there limited evidence of traditional pulmonary injury from blast in current military field epidemiology? (3) What are the primary blast brain injury mechanisms in humans? (4) If TBI can present with clinical symptoms similar to those of Post-Traumatic Stress Disorder (PTSD), how do we clinically differentiate blast TBI from PTSD and other psychiatric conditions? (5) How do we scale experimental animal models to human response? The preponderance of the evidence from a combination of clinical practice and experimental models suggests that blast TBI from direct blast exposure occurs on the modern battlefield. Progress has been made in establishing injury risk functions in terms of blast overpressure time histories, and there is strong experimental evidence in animal models that mild brain injuries occur at blast intensities that are similar to the pulmonary injury threshold. Enhanced thoracic protection from ballistic protective body armor likely plays a role in the occurrence of blast TBI by preventing lung injuries at blast intensities that could cause TBI. Principal areas of uncertainty include the need for a more comprehensive injury assessment for mild blast injuries in humans, an improved understanding of blast TBI pathophysiology of blast TBI in animal models and humans, the relationship between clinical manifestations of PTSD and mild TBI from blunt or blast trauma including possible synergistic effects, and scaling between animals models and human exposure to blasts in wartime and terrorist attacks. Experimental methodologies, including location of the animal model relative to the shock or blast source, should be carefully designed to provide a realistic blast experiment with conditions comparable to blasts on humans. If traditional blast scaling is appropriate between species, many reported rodent blast TBI experiments using air shock tubes have blast overpressure conditions that are similar to human long-duration nuclear blasts, not high explosive blasts.

Survival Risk Assessment for Primary Blast Exposures to the Head

Many soldiers returning from the current conflicts in Iraq and Afghanistan have had at least one exposure to an explosive event and a significant number have symptoms consistent with traumatic brain injury. Although blast injury risk functions have been determined and validated for pulmonary injury, there is little information on the blast levels necessary to cause blast brain injury. Anesthetized male New Zealand White rabbits were exposed to varying levels of shock tube blast exposure focused on the head, while their thoraces were protected. The specimens were euthanized and evaluated when the blast resulted in respiratory arrest that was non-responsive to resuscitation or at 4?h post-exposure. Injury was evaluated by gross examination and histological evaluation. The fatality data from brain injury were then analyzed using Fishers exact test to determine a brain fatality risk function. Greater blast intensity was associated with post-blast apnea and the need for mechanical ventilation. Gross examination revealed multifocal subdural hemorrhages, most often near the brainstem, at more intense levels of exposure. Histological evaluation revealed subdural and subarachnoid hemorrhages in the non-responsive respiratory-arrested specimens. A fatality risk function from blast exposure to the head was determined for the rabbit specimens with an LD(50) at a peak overpressure of 750?kPa. Scaling techniques were used to predict injury risk at other blast overpressure/duration combinations. The fatality risk function showed that the blast level needed to cause fatality from an overpressure wave exposure to the head was greater than the peak overpressure needed to cause fatality from pulmonary injury. This risk function can be used to guide future research for blast brain injury by providing a realistic fatality risk to guide the design of protection or to evaluate injury.

Pharmacotherapy for posttraumatic stress disorder: Review with clinical applications

Posttraumatic stress disorder (PTSD) is a prevalent psychiatric diagnosis among veterans and has high comorbidity with other medical and psychiatric conditions. This article reviews the pharmacotherapy recommendations from the 2010 revised Department of Veterans Affairs/Department of Defense Clinical Practice Guideline (CPG) for PTSD and provides practical PTSD treatment recommendations for clinicians. While evidence-based, trauma-focused psychotherapy is the preferred treatment for PTSD, pharmacotherapy is also an important treatment option. First-line pharmacotherapy agents include selective serotonin reuptake inhibitors and the selective serotonin-norepinephrine reuptake inhibitor venlafaxine. Second-line agents have less evidence for their usefulness in PTSD and carry a potentially greater side effect burden. They include nefazodone, mirtazapine, tricyclic antidepressants, and monoamine oxidase inhibitors. Prazosin is beneficial for nightmares. Benzodiazepines and antipsychotics, either as monotherapy or used adjunctively, are not recommended in the treatment of PTSD. Treating co-occurring disorders, such as major depressive disorder, substance use disorders, and traumatic brain injury, is essential in maximizing treatment outcomes in PTSD. The CPG provides evidence-based treatment recommendations for treating PTSD with and without such co-occurring disorders.

Porcine Head Response to Blast

Recent studies have shown an increase in the frequency of traumatic brain injuries related to blast exposure. However, the mechanisms that cause blast neurotrauma are unknown. Blast neurotrauma research using computational models has been one method to elucidate that response of the brain in blast, and to identify possible mechanical correlates of injury. However, model validation against experimental data is required to ensure that the model output is representative of in vivo biomechanical response. This study exposes porcine subjects to primary blast overpressures generated using a compressed-gas shock tube. Shock tube blasts were directed to the unprotected head of each animal while the lungs and thorax were protected using ballistic protective vests similar to those employed in theater. The test conditions ranged from 110 to 740 kPa peak incident overpressure with scaled durations from 1.3 to 6.9 ms and correspond approximately with a 50% injury risk for brain bleeding and apnea in a ferret model scaled to porcine exposure. Instrumentation was placed on the porcine head to measure bulk acceleration, pressure at the surface of the head, and pressure inside the cranial cavity. Immediately after the blast, 5 of the 20 animals tested were apneic. Three subjects recovered without intervention within 30 s and the remaining two recovered within 8 min following respiratory assistance and administration of the respiratory stimulant doxapram. Gross examination of the brain revealed no indication of bleeding. Intracranial pressures ranged from 80 to 390 kPa as a result of the blast and were notably lower than the shock tube reflected pressures of 300–2830 kPa, indicating pressure attenuation by the skull up to a factor of 8.4. Peak head accelerations were measured from 385 to 3845 G’s and were well correlated with peak incident overpressure (R2 = 0.90). One SD corridors for the surface pressure, intracranial pressure (ICP), and head acceleration are presented to provide experimental data for computer model validation.

Brain Injury Risk from Primary Blast

BACKGROUND Military service members are often exposed to at least one explosive event, and many blast-exposed veterans present with symptoms of traumatic brain injury. However, there is little information on the intensity and duration of blast necessary to cause brain injury. METHODS Varying intensity shock tube blasts were focused on the head of anesthetized ferrets, whose thorax and abdomen were protected. Injury evaluations included physiologic consequences, gross necropsy, and histologic diagnosis. The resulting apnea, meningeal bleeding, and fatality were analyzed using logistic regressions to determine injury risk functions. RESULTS Increasing severity of blast exposure demonstrated increasing apnea immediately after the blast. Gross necropsy revealed hemorrhages, frequently near the brain stem, at the highest blast intensities. Apnea, bleeding, and fatality risk functions from blast exposure to the head were determined for peak overpressure and positive-phase duration. The 50% risk of apnea and moderate hemorrhage were similar, whereas the 50% risk of mild hemorrhage was independent of duration and required lower overpressures (144 kPa). Another fatality risk function was determined with existing data for scaled positive-phase durations from 1 millisecond to 20 milliseconds. CONCLUSION The first primary blast brain injury risk assessments for mild and moderate/severe injuries in a gyrencephalic animal model were determined. The blast level needed to cause a mild/moderate brain injury may be similar to or less than that needed for pulmonary injury. The risk functions can be used in future research for blast brain injury by providing realistic injury risks to guide the design of protection or evaluate injury. (J Trauma Acute Care Surg. 2012;73: 895–901. Copyright

An open-source toolbox for automated phenotyping of mice in behavioral tasks

Classifying behavior patterns in mouse models of neurological, psychiatric and neurodevelopmental disorders is critical for understanding disease causality and treatment. However, complete characterization of behavior is time-intensive, prone to subjective scoring, and often requires specialized equipment. Although several reports describe automated home-cage monitoring and individual task scoring methods, we report the first open source, comprehensive toolbox for automating the scoring of several common behavior tasks used by the neuroscience community. We show this new toolbox is robust and achieves equal or better consistency when compared to manual scoring methods. We use this toolbox to study the alterations in behavior that occur following blast-induced traumatic brain injury (bTBI), and study if these behavior patterns are altered following genetic deletion of the transcription factor Ets-like kinase 1 (Elk-1). Due to the role of Elk-1 in neuronal survival and proposed role in synaptic plasticity, we hypothesized that Elk-1 deletion would improve some neurobehavioral deficits, while impairing others, following blast exposure. In Elk-1 knockout (KO) animals, deficits in open field, spatial object recognition (SOR) and elevated zero maze performance after blast exposure disappeared, while new significant deficits appeared in spatial and associative memory. These are the first data suggesting a molecular mediator of anxiety deficits following bTBI, and represent the utility of the broad screening tool we developed. More broadly, we envision this open-source toolbox will provide a more consistent and rapid analysis of behavior across many neurological diseases, promoting the rapid discovery of novel pathways mediating disease progression and treatment.

Primary Blast Survival and Injury Risk Assessment for Repeated Blast Exposures

Background: The widespread use of explosives by modern insurgents and terrorists has increased the potential frequency of blast exposure in soldiers and civilians. This growing threat highlights the importance of understanding and evaluating blast injury risk and the increase of injury risk from exposure to repeated blast effects. Methods: Data from more than 3,250 large animal experiments were collected from studies focusing on the effects of blast exposure. The current study uses 2,349 experiments from the data collection for analysis of the primary blast injury and survival risk for both long- and short-duration blasts, including the effects from repeated exposures. A piecewise linear logistic regression was performed on the data to develop survival and injury risk assessment curves. Results: New injury risk assessment curves uniting long- and short-duration blasts were developed for incident and reflected pressure measures and were used to evaluate the risk of injury based on blast overpressure, positive-phase duration, and the number of repeated exposures. The risk assessments were derived for three levels of injury severity: nonauditory, pulmonary, and fatality. The analysis showed a marked initial decrease in injury tolerance with each subsequent blast exposure. This effect decreases with increasing number of blast exposures. Conclusions: The new injury risk functions showed good agreement with the existing experimental data and provided a simplified model for primary blast injury risk. This model can be used to predict blast injury or fatality risk for single exposure and repeated exposure cases and has application in modern combat scenarios or in setting occupational health limits.

Valuing the work performed by anesthesiology residents and the financial impact on teaching hospitals in the United States of a reduced anesthesia residency program size

We performed a financial analysis at a large university tertiary care hospital to determine the incremental cost of replacing its anesthesiology residents with alternative dependent providers (i.e., certified registered nurse anesthetists in the operating room, advanced practice nurses and physician assistants outside the operating room). The annual average net cost of an anesthesiology resident during a 3-yr residency is approximately

Attenuation of blast pressure behind ballistic protective vests

38,000, and residents performed an average of

A pilot randomized placebo-controlled trial of adjunctive aripiprazole for chronic PTSD in US military Veterans resistant to antidepressant treatment.

89,000 of essential clinical work annually based on replacement costs. The incremental cost (replacement labor cost minus net resident cost) to replace all essential clinical duties performed by an anesthesiology resident at Duke University Medical Center and affiliated hospitals is approximately