Matthew B. Panzer

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.

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.

A Multiscale Approach to Blast Neurotrauma Modeling: Part II: Methodology for Inducing Blast Injury to in vitro Models

Due to the prominent role of improvised explosive devices (IEDs) in wounding patterns of U.S. war-fighters in Iraq and Afghanistan, blast injury has risen to a new level of importance and is recognized to be a major cause of injuries to the brain. However, an injury risk-function for microscopic, macroscopic, behavioral, and neurological deficits has yet to be defined. While operational blast injuries can be very complex and thus difficult to analyze, a simplified blast injury model would facilitate studies correlating biological outcomes with blast biomechanics to define tolerance criteria. Blast-induced traumatic brain injury (bTBI) results from the translation of a shock wave in-air, such as that produced by an IED, into a pressure wave within the skull–brain complex. Our blast injury methodology recapitulates this phenomenon in vitro, allowing for control of the injury biomechanics via a compressed-gas shock tube used in conjunction with a custom-designed, fluid-filled receiver that contains the living culture. The receiver converts the air shock wave into a fast-rising pressure transient with minimal reflections, mimicking the intracranial pressure history in blast. We have developed an organotypic hippocampal slice culture model that exhibits cell death when exposed to a 530 ± 17.7-kPa peak overpressure with a 1.026 ± 0.017-ms duration and 190 ± 10.7 kPa-ms impulse in-air. We have also injured a simplified in vitro model of the blood–brain barrier, which exhibits disrupted integrity immediately following exposure to 581 ± 10.0 kPa peak overpressure with a 1.067 ± 0.006-ms duration and 222 ± 6.9 kPa-ms impulse in-air. To better prevent and treat bTBI, both the initiating biomechanics and the ensuing pathobiology must be understood in greater detail. A well-characterized, in vitro model of bTBI, in conjunction with animal models, will be a powerful tool for developing strategies to mitigate the risks of bTBI.

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

Blood-Brain Barrier Dysfunction after Primary Blast Injury in vitro

The incidence of blast-induced traumatic brain injury (bTBI) has increased substantially in recent military conflicts. However, the consequences of bTBI on the blood-brain barrier (BBB), a specialized cerebrovascular structure essential for brain homeostasis, remain unknown. In this study, we utilized a shock tube driven by compressed gas to generate operationally relevant, ideal pressure profiles consistent with improvised explosive devices (IEDs). By multiple measures, the barrier function of an in vitro BBB model was disrupted following exposure to a range of controlled blast loading conditions. Trans-endothelial electrical resistance (TEER) decreased acutely in a dose-dependent manner that was most strongly correlated with impulse, as opposed to peak overpressure or duration. Significantly increased hydraulic conductivity and solute permeability post-injury further confirmed acute alterations in barrier function. Compromised ZO-1 immunostaining identified a structural basis for BBB breakdown. After blast exposure, TEER remained significantly depressed 2 days post-injury, followed by spontaneous recovery to pre-injury control levels at day 3. This study is the first to report immediate disruption of an in vitro BBB model following primary blast exposure, which may be important for the development of novel helmet designs to help mitigate the effects of blast on the BBB.

A Multiscale Approach to Blast Neurotrauma Modeling: Part I – Development of Novel Test Devices for in vivo and in vitro Blast Injury Models

The loading conditions used in some current in vivo and in vitro blast-induced neurotrauma models may not be representative of real-world blast conditions. To address these limitations, we developed a compressed-gas driven shock tube with different driven lengths that can generate Friedlander-type blasts. The shock tube can generate overpressures up to 650 kPa with durations between 0.3 and 1.1 ms using compressed helium driver gas, and peak overpressures up to 450 kPa with durations between 0.6 and 3 ms using compressed nitrogen. This device is used for short-duration blast overpressure loading for small animal in vivo injury models, and contrasts the more frequently used long duration/high impulse blast overpressures in the literature. We also developed a new apparatus that is used with the shock tube to recreate the in vivo intracranial overpressure response for loading in vitro culture preparations. The receiver device surrounds the culture with materials of similar impedance to facilitate the propagation of a single overpressure pulse through the tissue. This method prevents pressure waves reflecting off the tissue that can cause unrealistic deformation and injury. The receiver performance was characterized using the longest helium-driven shock tube, and produced in-fluid overpressures up to 1500 kPa at the location where a culture would be placed. This response was well correlated with the overpressure conditions from the shock tube (R2 = 0.97). Finite element models of the shock tube and receiver were developed and validated to better elucidate the mechanics of this methodology. A demonstration exposing a culture to the loading conditions created by this system suggest tissue strains less than 5% for all pressure levels simulated, which was well below functional deficit thresholds for strain rates less than 50 s−1. This novel system is not limited to a specific type of culture model and can be modified to reproduce more complex pressure pulses.

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.

Scaling in neurotrauma: how do we apply animal experiments to people?

Scaling is an essential component for translating the clinical outcomes of a neurotrauma model to the human equivalent. This article reviews the principles of biomechanical scaling for traumatic brain injuries, and a number of different approaches to scaling the dose (inputs) and response (outputs) of an animal model to humans are highlighted. A particular focus on blast injury scaling is given as an ongoing area of research, and discussion on the implications of scaling on the current blast TBI literature is provided. The risk of using neurotrauma models without considering an appropriate scaling method is that injuries may be induced with non-realistic loading conditions, and the injury mechanisms produced in the laboratory may not be consistent with those in the clinical setting.

Pulmonary injury risk assessment for long-duration blasts: a meta-analysis

BACKGROUND Long-duration blasts are an increasing threat with the expanded use of thermobaric and other novel explosives. Other potential long-duration threats include large explosions from improvised explosive devices, weapons caches, and other explosives including nuclear explosives. However, there are very few long-duration pulmonary blast injury assessments, and use of short-duration exposure injury metrics is inappropriate as the injury mechanism for long-duration exposures is likely different from that of short-duration exposures. METHODS This study develops an injury model for long-duration (>10 milliseconds positive overpressure phase) blasts with sharp rising overpressures. For this study, data on more than 2,730 large animal experiments were collected from more than 55 experimental studies on blast. From this dataset, nearly 850 large animal experiments were selected with positive phase overpressure durations of 10 milliseconds or more. Various models were evaluated to determine the best fit of injury risk as a function of pressure and duration. A linear logistic regression was performed on the experimental data for threshold injury and lethality in terms of pressure and duration. The effects of mass, pressure, and duration scaling were all evaluated, and two goodness-of-fit indicators were used to assess the different models. RESULTS AND CONCLUSIONS New injury risk assessment curves were determined for both incident and reflected pressure conditions for reflecting surface and free-field exposures. Position dependent injury risk curves were also determined. The resulting curves are an improvement to existing assessments, because they use actual data to demonstrate theoretical assumptions on the injury risk.