Appendix J

Contemporary Methods for Assessing Behind-Armor Blunt Trauma in Live Animals

This appendix provides an overview of behind-armor blunt trauma (BABT) assessment methodologies.73 Several research groups from at least four nations have adopted a pig model for live-animal testing, and a fairly standard instrumentation package has evolved. This was agreed upon by a meeting in Koblenz in 1998 involving the principal countries involved in this work (Mayorga et al., 2010). The protocols for these studies require animals to be anesthetized and to have approval from animal care and welfare review boards.

Pigs weighing up to 60 kg are used because of their availability, thorax size that mimics human anatomy, and ease of instrumentation. Each pig is intubated and properly infused with supportive electrolytes. Respiration, blood pressure, electrocardiogram, blood oxygen saturation, and temperature are monitored. Most experiments used the North Atlantic Treaty Organization (NATO) 7.62 mm projectile fired at full charge from 10 meters at a velocity of approximately 820 m/sec. The pigs are shot over the eighth rib. The rib cage is instrumented with accelerometers and pressure sensors close to the impact point. (This is a major protocol defect because the placements of pressure transducers are affected by motion sensor saturation.) Each animal is examined by autopsy using a standard procedure including photography, with specific attention directed to the thoracic organs and the presence of trauma to the abdominal viscera.

This is the protocol followed by the NATO group and is not a protocol that will allow observations of pressure waves or measurement of pressure transmission and pathophysiology of organs such as brain, heart, and intestines. The protocol for most of the NATO experiments does not allow observing effects beyond the acute stage of 30 min. Thus, to answer the question of remote damage from blunt trauma a more extensive protocol is needed. Essential elements of such a protocol are shown in Figure J-1.

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73The committee is grateful to Miriam D. Budinger and Robert Smith of Lawrence Berkley National Laboratory, who provided information for the preparation of this appendix.



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PREPUBLICATION DRAFT—SUBJECT TO EDITORIAL CORRECTION Appendix J Contemporary Methods for Assessing Behind-Armor Blunt Trauma in Live Animals This appendix provides an overview of behind-armor blunt trauma (BABT) assessment methodologies.73 Several research groups from at least four nations have adopted a pig model for live-animal testing, and a fairly standard instrumentation package has evolved. This was agreed upon by a meeting in Koblenz in 1998 involving the principal countries involved in this work (Mayorga et al., 2010). The protocols for these studies require animals to be anesthetized and to have approval from animal care and welfare review boards. Pigs weighing up to 60 kg are used because of their availability, thorax size that mimics human anatomy, and ease of instrumentation. Each pig is intubated and properly infused with supportive electrolytes. Respiration, blood pressure, electrocardiogram, blood oxygen saturation, and temperature are monitored. Most experiments used the North Atlantic Treaty Organization (NATO) 7.62 mm projectile fired at full charge from 10 meters at a velocity of approximately 820 m/sec. The pigs are shot over the eighth rib. The rib cage is instrumented with accelerometers and pressure sensors close to the impact point. (This is a major protocol defect because the placements of pressure transducers are affected by motion sensor saturation.) Each animal is examined by autopsy using a standard procedure including photography, with specific attention directed to the thoracic organs and the presence of trauma to the abdominal viscera. This is the protocol followed by the NATO group and is not a protocol that will allow observations of pressure waves or measurement of pressure transmission and pathophysiology of organs such as brain, heart, and intestines. The protocol for most of the NATO experiments does not allow observing effects beyond the acute stage of 30 min. Thus, to answer the question of remote damage from blunt trauma a more extensive protocol is needed. Essential elements of such a protocol are shown in Figure J-1. 73 The committee is grateful to Miriam D. Budinger and Robert Smith of Lawrence Berkley National Laboratory, who provided information for the preparation of this appendix. -305-

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PREPUBLICATION DRAFT—SUBJECT TO EDITORIAL CORRECTION FIGURE J-1 Comprehensive protocol for live-animal live-fire tests. COMPREHENSIVE PROTOCOL FOR ASSESSING DAMAGE TO TISSUES REMOTE FROM THE SITE OF BLUNT TRAUMA It is important to maintain surveillance of animals for as long as feasible after the live-fire exposure. Previous studies under NATO protocols lasted for a little as 30 min. Other studies have observed animals up to 8 hr before termination. The humane guidance has been to terminate the animals before they recover from the anesthesia, and this is recommended if the animals have received substantial trauma. Under conditions that produce minimal trauma—for example, EKG, EEG, and respirations—and no hemoptisis, permission to observe the animals longer term should be pursued, as the resulting medical information would be crucial for development of personnel protective armor. Theory and model studies cannot predict long-term consequence for blunt trauma to live organisms. Pathology Conventional gross and microscopic histopathology studies should be routine at the termination of animal studies. Measurements of blood-brain barrier -306-

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PREPUBLICATION DRAFT—SUBJECT TO EDITORIAL CORRECTION or small vessel permeability changes are extremely important according to original studies by Suneson et al. (1987), wherein Evans blue dye injected before live-fire tests showed small vessel leakage at autopsy. Important additions to the study of the brain are the search for T-tau hyperphosphorylated protein as well as measurements of c-Fos and c-Myc expression and deposition of -APP (Blennow et al., 1995; Blennow et al., 2010; Säljö et al., 2002). Other important assays for nerve damage include glial fibrillar acidic protein and fibrillar light protein. The timing for these measurements after trauma is important as previous studies might have waited too long (e.g., 7 days) to see some chemical manifestation of nerve damage from spinal fluid samples. Detection of Brain Pathology from Transmitted Shock Pressures in Animals Perhaps of greatest importance is the need for a method that can detect one or more of the following subtle and often microscopic changes in vivo through noninvasive imaging for large animals.  Early epidural and subdural hematomas less than 5 mm wide at the cortical-skull boundary;  Early signs of edema, such as flattening of the sulci, changes in MR T1, changes in acoustic reflection (impedance), microwave reflective power (dielectric coefficient), or electrical activity (impedance, potential difference dynamics);  Axonal damage in the brain stem and corpus callosum with local edema and water diffusion changes;  Brain surface contusion before frank edema occurs;  Brain blood flow changes;  Local brain blood volume changes due to local vascular dilatation or vascular tears at the cortical-skull boundary (epidural and subdural hematomas less than 5 mm wide). Quantification of Pressure Wave Dispersion Two general categories for measurement are pressure wave dispersion imaging and pressure transducer implantation. The early imaging studies included the spark gap optical methods of Harvey and McMillen (1947) and cineradiography applied to ballistic trauma to the head (Butler et al., 1945) and to nerve and bone (Puckett et al., 1946). Modern instrumentation for cineradiography, while expensive to deploy in live-fire tests in live large animals, is an important approach. Quantification of pressure distribution does require more invasive instrumentation. While straightforward for low frequency measurements, instrumentation for very high frequency response is needed for these applications, and miniaturization is essential for minimizing trauma during implantation. In addition the pressure sensor must be insensitive to accelerations and temperature changes. Successful recordings of pressures in the brain have -307-

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PREPUBLICATION DRAFT—SUBJECT TO EDITORIAL CORRECTION been reported in small animals by Chavko et al. (2007), who used a miniature fiberoptic transducer implanted in the brain and invented by Pinet et al. (2005). The probe is an order of magnitude smaller than conventional piezoelectric sensors and is able to withstand harsh environments (Pinet et al., 2005). Electrical Pathophysiology Electroencephalography and electrical impedance tomography are two techniques that might be used to assess central nervous system integrity through measurement of electrical properties both during the acute phase of ballistic trauma and during posttrauma intervals up to months. Both approaches require sensitive instruments and are plagued by electrode coupling noise. However, in previously successful large- and small-animal experiments, EEG measurements and impedance measurements (Drobin et al., 2007; Cooper, 1996; Olsson et al., 2006; Klein and Krop-Van Gastel, 1993) have shown the kinetics of brain physiologic response to blunt trauma to the chest. MRI Imaging Of the four methods that have known efficacy in the examination of the brain in vivo (EEG, X-ray CT, PET, and MRI), MRI is the one that can provide noninvasive information specific to most of the relevant pathologies. MRI can provide a wealth of information regarding organ changes associated with ballistic trauma to the body, as has already been shown in studies of blast-injured veterans (Van Boven et al., 2009). Specific capabilities for noninvasive measurements are as follows.  Brain contusion. Edema is an expected early sign of contusion. It will appear as a bright signal on T2-weighted or fluid attenuation inversion recovery MRI. T1-weighted protocols might give as sensitive a diagnosis as other protocols.  Brain edema. Edema resulting from vascular compromise (i.e., air emboli from lung damage), pressure impulse transmitted from the periphery to the brain, or ischemic damage from other causes can be detected by MRI diffusion weighted imaging sequences by fluid attenuation inversion recovery, and possibly by T1-weighted protocols.  Hemorrhage. Early signs of hemorrhage usually occur due to tears in the tributary surface veins that bridge the brain surface to the dural venous sinus. T2-weighted MRI can show the accumulation of blood as a bright signal initially, with an evolution to a dark signal in 2 to 3 days and back again to a bright signal within the first 2 weeks (Taber et al., 2003).  Neuronal disruption. Neural axon injury might be the most subtle yet the most important pathology that requires early imaging for diagnosis -308-

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PREPUBLICATION DRAFT—SUBJECT TO EDITORIAL CORRECTION (Mayorga, 1997). Experience has shown that this pathology might be seen in the corpus callosum and brain stem. Diffusion weighted imaging and T1-weighted protocols might be of extreme importance in this diagnosis (Huisman, 2010). But the choice of MR protocol is important here as it has been shown that susceptibility-weighted MRI depicts significantly more small hemorrhagic lesions than does conventional gradient echo MRI and therefore has the potential to improve the diagnosis of diffuse axonal injury (Tong et al., 2003). The MRI system should be able to perform the above imaging studies in addition to standard structural sequences, including gradient echo as well as spin echo approaches to achieve the desired physiologic contrast signals. Instrumentation availability and costs vary widely from a permanent magnet system for small animals at less than $0.5 million to elaborate systems that combine magnetic resonance with PET at over $2 million. Most studies can be enabled through collaboration with medical studies. PET and SPECT Imaging Metabolic and quantitative flow imaging using positron emission tomography or single photon tomography can provide sensitive metrics of pathological changes in most of the body organs of medium to large animals. The methods are noninvasive and can be repeated over the course of hours or days. Whereas PET and SPECT are readily available in medical centers, not all experimentalists will have these instruments and the required radioisotopes available, particularly for small animal studies. The spatial resolution in instruments designed for animal studies can be 2 mm or less. Normally the spatial resolution for large animals and human subjects is 5 to 6 mm. The tracers available allow studies of blood flow, glucose uptake (commonly interpreted as cerebral metabolism), dopamine transporters and receptors, muscarinic system activity, and blood-brain permeability. Recent human studies in boxers showed patterns of hypometabolism using as a marker the accumulation of F-18 deoxyglucose, but one must be careful not to interpret hypometabolism when the reason for less apparent tracer uptake is tissue atrophy rather than a decrease in the metabolic uptake mechanism (Provenzano et al., 2010). Thus, metabolic and neurochemical studies should be accompanied by MR anatomical studies and, in some cases, by flow studies since compromised flow will lead to an apparent decrease in uptake, particularly when studying the neurochemical systems. PET and SPECT instrumentation for small animal studies is available from a number of vendors. Large animal studies can be accomplished through collaborators at medical institutions where the requisite approvals for use of radionuclides are already in place. -309-

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PREPUBLICATION DRAFT—SUBJECT TO EDITORIAL CORRECTION Ultrasound Brain Blood Flow Measurements Measurements of blood flow in the brain basal arteries and the carotids by transcranial Doppler are surrogates for estimating cerebral vascular resistance and are effective methods for detection of vasospasm associated with abnormally high velocities (Jaffres et al., 2005; Visocchi et al., 2002). These measurements rely on some skill of the operator. Vascular spasm can occur late after brain injury and this will result in a change in the flow characteristics with eventual change in electrical impedance (Armonda et al., 2006; Kochanowicz et al., 2006; Oertel et al., 2005; Fritz et al., 2005; Harting et al., 2010). Ultrasound instrumentation is generally more available than the other radiological imaging systems for human studies. Specialized small animal systems are now available to the researcher. Short- and Long-Term Cardiac Responses During the first hour after blunt trauma to the chest, temporary cardiac arrhythmias have been observed in previous live-fire tests on animals protected by vests. The longer term as well as short term changes in heart contractions are unknown but will be important to determine for current and future protective vest designs. Thus in some experiments direct and continuous measurements of intrathoracic cardiac and aortic pressures and dimensions are recommended using radiotelemetry. These techniques are well known and can be reliably implemented in unrestrained animals. GLOSSARY Acoustic impedance. A material property that relates to its resistance to the propagation of sound pressure. It is the square root of the product of the tissue modulus of elasticity and the tissue density. The equivalent definition is impedance equals the product of tissue density and the speed of sound in that tissue (e.g., 1,480 m/sec for solid tissue and water, 5,900 m/sec in steel, 9,900 m/sec in alumina). Atmospheric pressure. The pressure exerted at sea level from atmospheric gases is measured as 14.7 pounds per square inch or, in SI units, as about 100 kilopascals (kPa). Backface deformation (BFD). The extent to which the back material of the body armor is displaced by low- or high-velocity ballistic impacts. Behind-armor blunt trauma (BABT). When body armor is impacted by a high- velocity bullet but not perforated, some of the energy of the bullet will enter the body. The interaction of this energy with the thoracic region of the human body may or may not cause an injury. If injury is caused, it is referred to as behind- armor blunt trauma (BABT). In the past, it was considered as trauma to the ribs and lungs but now includes trauma anywhere in the body. -310-

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PREPUBLICATION DRAFT—SUBJECT TO EDITORIAL CORRECTION Cineradiography. Method for acquiring x-rays at very rapid rate so that the dynamics of a process can be recorded when tissue opaqueness does not allow rapid light photography. Decibel. A measure of the amount of some physical parameter relative to a reference base. For blast pressure it is force per area (newtons/m2), and the ratio of the measured pressure to the base value for human perception of sound is so great that the decibel is reported as 20 times the logarithm of the ratio. Sound intensity is power per area (watts/m2) and the decibel is 10 times the logarithm of the ratio. Conversion of decibel sound pressure level, dB(SPL), to pascal, (Pa) units is (Pa) = 2 × 10-5 × 10 dB/20 where the factor 2 × 10-5 is the minimum pressure for human sound detection in newtons/m2, or pascals. Thus the pressure for normal conversation at 60 dB is 0.02 Pa and for a passing truck at 100 dB is 2 Pa. Pressures from behind armor are in the range of 500 kPa, or 208 dB. Kinetic energy. The energy associated with the velocity and mass of a body (projectile). It is ½ mass × (velocity)2. The unit is the joule (J). Projectiles deliver 033 to 13 kJ depending on the bullet used. Magnetic resonance imaging (MRI). An imaging method that shows tissue anatomy based on water content and local environment characteristics. Diffusion- weighted imaging (DWI) and diffusion tensor imaging (DTI) are forms of MRI that allow definition of structural properties of tissue based on water diffusion directional preferences. National Institute of Justice (NIJ) Standard. The NIJ 0101.04 standard stipulates the maximum deformation a soft armor vest can undergo without penetration is 44 mm as measured in a clay substrate after a live fire test of the armor. Overpressure. The blast pressure from a bomb, artillery discharge, bazooka, or other explosion. Overpressure is defined as the pressure from the blast over atmospheric pressure; it is usually followed by an underpressure. Pascal. Unit for pressure equivalent to 1 newton/m2 (1 pascal is 0.0001 atmospheric pressure). A gigapascal (GPa) is a unit of pressure equal to a billion pascals. A kilopascal (kPa) is a unit of pressure equal to a 1,000 pascals (100 kPa is 1 atmosphere of pressure). Positron emission tomography (PET). An imaging method that provides quantative information on metabolism, flow, and neurochemical receptors using radionuclides usually obtained from a cyclotron. The method is useful for imaging metabolism and function in the brain, lungs, and other organs. Power. Energy per time. Unit is the watt, which is 1 Joule/sec. Pressure. Force per area (newton /m2 = pascal). Single photon emission tomography (SPECT). This is an imaging method similar to PET; however, it uses radionuclides generally obtainable without the need for a cyclotron. The method is useful for imaging metabolism and function in brain, lungs, and other organs. -311-

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PREPUBLICATION DRAFT—SUBJECT TO EDITORIAL CORRECTION Strain. The relative change in dimension ∆L/L in response to a stress, where L= is a length measure. Stress. The force per area applied to a material. Units are newton/m2 and are usually reported as pascals. Stress waves. Compression waves in a material due to an impulse or sudden load change. Underpressure. The negative pressure relative to atmospheric pressure experienced by personnel following the blast pressure from an explosion. Young’s modulus. A measure of the stiffness of elastic material, it is defined as the ratio of the uniaxial stress or force per area over the strain or the fractional length change in the direction of the stress. The dimension is given as pascals or pounds per square inch (psi). For example, steel has a Young’s modulus of 200 GPa, Kevlar of about 100 GPa, and polyethylene of 3 GPa. 7.62 mm x 51 mm bullet. A rifle bullet similar to the .30-06 bullet in dimensions and performance. Another model is the 7.62 mm × 61 mm bullet. REFERENCES Armonda, R., R. Bell, A. Vo, G. Ling, T. DeGraba, B. Crandall, J. Ecklund, and W. Campbell. 2006. Wartime traumatic cerebral vasospasm: Recent review of combat casualties. Neurosurgery 59(6):1215-1225. Blennow, K., M. Johnson, N. Andreasen, L. Rosengren, A. Wallin, P. Hellström, and H. Zetterrberg. 2010. No neurochemical evidence for brain injury after blast overpressure by repeated explosions or firing heavy weapons. Acta Neurologica Scandinavica. Available online . Last accessed January 24, 2011. Blennow, K., K. Walllin, H. Agren, C. Spenger, J. Siegfied, and E. Vanmechelen. 1995. Tau protein in cerebrospinal fluid: A biochemical marker for axonal degeneration in Alzheimer’s disease? Molecular and Chemical Neuropathology 26(3):231-245. Butler, E., W. Puckett, E. Harvey, and J. McMillen. 1945. Experiments on head wounding by high velocity missiles. Journal of Neurosurgery 2(4):358-363. Chavko, M., W. Koller, W. Prusaczyk, and R. McCarron. 2007. Measurement of blast wave by a miniature fiber optic pressure transducer in the rat brain. Journal of Neuroscience Methods 159(2):277-281. Cooper, G. 1996. Protection of the lung from blast overpressure by thoracic stress wave decouplers. The Journal of Trauma: Injury, Infection, and Critical Care 40(3S):105S-110S. -312-

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PREPUBLICATION DRAFT—SUBJECT TO EDITORIAL CORRECTION Visocchi, M., A. Chiaretti, D. Cabezza, and M. Meglio. 2002. Hypoflow and hyperflow in diffuse axonal injury. Prognostic and therapeutic implications of transcranial Doppler sonography evaluation. Journal of Neurosurgical Sciences 46(1):10-17. -315-