45.1. INTRODUCTION

Explosions are physical phenomena that result in the sudden release of energy; they may be chemical, nuclear, or mechanical. This process results in a near-instantaneous pressure rise above atmospheric pressure. The positive pressure rise (“overpressure”) compresses the surrounding medium (air or water) and results in the propagation of a blast wave, which extends outward from the explosion in a radial fashion. As the front or leading edge of the blast wave expands, the positive phase is followed by a decrease in pressure and the development of a negative wave (“underpressure”) before subsequently returning to baseline. Figure 45.1 shows an idealized form of a shock wave (Friedländer wave) (Friedlander, 1955) generated by a spherical, uncased explosive in the air in free field conditions. The extent of damage from the blast wave mainly depends on five factors: (1) the peak of the initial positive-pressure wave (an overpressure of 690–1,724 kPa, for example, 100–250 psi, is considered potentially lethal) (Champion et al., 2009); (2) the duration of overpressure; (3) the medium of explosion; (4) the distance from the incident blast wave; and (5) the degree of focusing because of a confined area or walls. Intensity of an explosion pressure wave declines with the cubed root of the distance from the explosion. Thus, a person 3 m (10 ft) from an explosion experiences nine times more overpressure than a person 6 m (20 ft) away. Additionally, explosions near or within hard solid surfaces can be amplified two to nine times because of shock wave reflection (Rice and Heck, 2000). Indeed, it was observed that victims positioned between a blast and a building often suffer injuries two to three times the degree of the injury of a person in an open space. People exposed to explosion rarely experience the idealized pressure-wave form. Even in open-field conditions, the blast wave reflects from the ground, generating reflective waves that interact with the primary wave, thus changing its characteristics. In a closed environment (such as a building, an urban setting, or a vehicle), the blast wave interacts with the surrounding structures and creates multiple wave reflections, which, interacting with the primary wave and between each other, generate a complex wave (Ben-Dor et al., 2001; Mainiero and Sapko, 1996).

FIGURE 45.1

The Friedländer wave describing an ideal blast from a spherical source in an open environment. t₀ is the time at which the pressure began to rise above ambient pressure. Positive magnitude is the difference between peak pressure and ambient pressure. (more...)

Blast injuries are characterized by interwoven mechanisms of systemic, local, and cerebral responses to blast exposure (Cernak, 2010). When a blast generated by explosion strikes a living body, part of the shock wave is reflected and another fraction is absorbed becoming a tissue-transmitted shock wave. The transferred kinetic energy causes low-frequency stress waves that accelerate a medium from its resting state, leading to rapid physical movement, displacement, deformation, or rupture of the medium (Clemedson, 1956; Clemedson and Criborn, 1955). Thus, a militarily relevant blast injury model should be able to capture and measure these phenomena based on sufficient knowledge of shock wave physics, the characteristics of the injurious environment generated by an explosion, and the clinical manifestations and sequelae of the injuries. The purpose of this chapter is to outline the pathophysiology of blast-body/blast-brain interactions and to summarize the scientific evidence to date for the selection of appropriate experimental models for characterizing and understanding these interactions.

45.2. BLAST-BODY AND BLAST-BRAIN INTERACTIONS

Conceptually, explosive blast may have five distinct effects on the body (Figure 45.2): (1) primary blast effects causing injuries as sole consequences of the shock wave–body interaction; (2) secondary blast effects from the fragments of debris propelled by the explosion and connecting with the body, causing penetrating and/or blunt trauma; (3) tertiary blast effects from acceleration/deceleration of the body or part of the body (Richmond et al., 1961); (4) quaternary blast effects caused by the transient but intense heat of the explosion (flash burns) (Mellor, 1988); and (5) quinary blast effects caused by “post-detonation environmental contaminants,” such as bacteria and radiation from dirty bombs, and tissue reactions to fuel and metal residues, among others (Kluger et al., 2007). Often, especially in the case of moderate-to-severe blast injuries, the multiple blast effects interact with the body simultaneously. In some literature sources, such an injurious environment and related injuries are referred to as “blast plus” scenarios (Moss et al., 2009).

FIGURE 45.2

Complex injurious environment resulting from blast. Primary blast effects are caused by the blast wave itself (excludes penetrating and blunt force injury); secondary blast effects are caused by particles propelled by the blast (penetrating or blunt force (more...)

When a shock wave generated by detonating a high-energy explosive strikes a living body, several physical events take place: a fraction of the shock wave is reflected, whereas another fraction of the shock wave energy is absorbed and propagates through the body as a tissue-transmitted shock wave (Clemedson and Criborn, 1955). Different organ and body structures differ in their reaction. Nevertheless, tissues typically respond (1) either on the impulse of the shock wave—this response is of longer duration—or (2) on the pressure variations of the shock wave, and this response is in a form of oscillations or pressure deflections of shorter duration (Clemedson and Pettersson, 1956). For example, basic experiments showed that tissues in the abdomen and costal interspaces react with typical impulse response, whereas the rib and the hind leg responded with a more or less pure maximum pressure type curve (Clemedson and Granstom, 1950; Clemedson et al., 1956, 1969).

The energy of the primary blast shock wave is either absorbed or transformed into the kinetic energy of a medium, which could be solid, liquid, gas, or plasma, when the interaction between them occurs (Clemedson and Jonsson, 1961). The transferred kinetic energy, then, moves and accelerates elements of the medium from their resting state with a speed that depends on the density of the medium; this leads to the medium’s rapid physical movement, displacement, deformation, or rupture (Clemedson and Pettersson, 1956). As a result, the main physical mechanisms of the blast-body interaction and subsequent tissue damage include spalling, implosion, and inertia (Benzinger, 1950). Spallation occurs at the boundary between two media of different densities when a compression wave in the denser medium is reflected at the interface. Implosion happens in a liquid medium containing a dissolved gas. Because the shock wave penetrates such a medium, it compresses the gas bubbles, raising the pressure in the bubbles much higher than the initial shock pressure; after the pressure wave passes, the bubbles can rebound explosively and damage surrounding tissue. Inertial effects also occur at the interface of the different densities; the lighter object will be accelerated more than the heavier one, creating a large stress at the boundary (Sanborn et al., 2012)

Recent results suggest a frequency dependence of the primary blast effects. High-frequency (0.5–1.5 kHz) low-amplitude stress waves have been observed to target mostly organs that contain abrupt density changes from one medium to another (for example, the air–blood interface in the lungs or the blood–parenchyma interface in the brain). On the other hand, low-frequency (<0.5 kHz), high-amplitude shear waves show a tendency to disrupt a tissue by generating local motions that overcome natural tissue elasticity (for example, at the contact of gray and white brain matter) (Cooper et al., 1991; Gorbunov et al., 2004).

45.3. MODIFYING POTENTIAL OF SYSTEMIC CHANGES CAUSED BY BLAST

Because of the complexity of the injurious environment (i.e., multiple blast effects that may interact with the body in parallel), blast injuries involve interwoven mechanisms of systemic, local, and cerebral responses to blast exposure (Cernak et al., 1991, 1996b) (Figure 45.3). Even when the multiorgan responses are mild, systemic changes significantly extend the original organ damage and influence their severity and functional outcome. Air emboli, activation of the autonomous nervous system, vascular mechanisms, and systemic inflammation are among the most important deleterious systemic alterations that could modify the initial injuries due to blast.

FIGURE 45.3

Simultaneous activation of systemic, local, and cerebral responses to blast exposure and interactive mechanisms causing or contributing to the pathobiology of BINT. ANS, autonomous nervous system; BBB, blood–brain barrier; CBF, cerebral blood (more...)

45.3.3. Vascular Mechanisms

Bearing in mind the previously described mechanisms of blast effects, it becomes obvious that one of the most important media for the shock wave’s energy transfer is blood. Veins contain approximately 70% of total blood volume. From this, the splanchnic system receives approximately 25% of cardiac output (translating into approximately 20% of total blood volume) compared with 18% in arteries and only 3% in terminal arteries and arterioles (Gelman, 2008). In general, veins are 30 times more compliant than the arteries, and splanchnic and cutaneous veins represent the most compliant venous vessels of all. Thus, these venous systems form the largest blood volume reservoirs in the human body. Figure 45.4 shows a simplified schematic representation of the consequences of blast-induced pressure changes and their extremely complex interactions, which form several interconnected loops. The shock wave’s energy transferred to the body leads not only to a sudden increase in both abdominal and thoracic pressures (ThorP), but also causes increase in intramural central venous pressure (CVP). Hypoxia caused by alveolar damage and subsequently reduced surface area for gas exchange, impaired ventilation/perfusion caused by J-receptor activation, or decreased cardiac output from activation of Bezold–Jarish reflex, among others, increases pulmonary arterial resistance, which might also increase ThorP (Gelman, 2008). The elevated ThorP further amplifies the increase in central venous pressure.

FIGURE 45.4

Simplified overview of vascular mechanisms activated by shock wave propagation through the body leading to alterations in functions of multiple organs and organ systems, which significantly influence the brain’s response to blast. (Created by (more...)

Having a high density of α₁- and α₂-adrenergic receptors and hence high sensitivity to adrenergic stimulation, the venoconstriction and mobilization of blood volume mainly depend on splanchnic circulation (Pang, 2001; Rutlen et al., 1979). Thus, it is highly feasible that the initial sudden drop in systemic arterial pressure initiates a compensatory increase in sympathetic outflow through vagovagal reflexes with reduction in the inhibitory influences of the baroreceptors of the carotid sinus and aortic area on the vasomotor center. Consequently, the increased sympathetic stimuli induced by blast constrict venous smooth musculature and lead to mobilization of splanchnic blood toward the heart (Rutlen et al., 1979).

Cerebrovascular vasospasm has been found frequently in casualties with moderate or severe blast-induced traumatic brain injury (TBI), more often than in patients with TBI of other origins (i.e., impact, fall, or acceleration/deceleration) (Armonda et al., 2006; Ling et al., 2009). Vasospasm can develop early, often within 48 hours of injury, and can also manifest later, typically between 10–14 days postexposure. It is noteworthy that although cerebral vasospasm is usually prompted by subarachnoid hemorrhage, subarachnoid hemorrhage is not required for vasospasm in blast-induced TBI (Magnuson et al., 2012). A recent experimental study using theoretical and in vitro models demonstrated that a single rapid mechanical insult is capable of inducing vascular hypercontractility and remodeling, indicative of vasospasm initiation. Furthermore, the results implied that the prolonged hypercontraction is linked to switching of the vascular smooth muscle phenotype in tissues exposed to simulated blast (Alford et al., 2011). These findings suggest a hypothetical scenario that when the shock wave passes through the vasculature, it interacts with cellular elements of vascular wall such as endothelium and vascular smooth muscle. As a consequence of this interaction, various mediators and modulators are released, which cause hypercontraction and subsequent genetic switch that potentiates vascular remodeling and cerebral vasospasm (Hald and Alford, 2013).

45.4. REQUIREMENTS FOR BLAST-INDUCED INJURY MODELS

Regardless of the research questions to be addressed, clinically and militarily relevant blast injury models should satisfy all of the following four criteria: (1) the injurious component of the blast should be clearly identified and reproduced in controlled, reproducible, and quantifiable manner; (2) the inflicted injury should be reproducible, quantifiable, and mimic components of human blast injuries; (3) the injury outcome established, based on morphological, physiological, biochemical, and/or behavioral parameters, should be related to the chosen injurious component of the blast; and (4) the mechanical properties (intensity, complexity of blast signature, and/or its duration) of the injurious factor should predict the outcome severity (Cernak and Noble-Haeusslein, 2010). The mechanistic factors underlying blast injuries are extremely complex as compared with the injuries caused by an impact or acceleration/deceleration force. Hence, an appropriate and clinically relevant blast injury model should be based on sufficient knowledge of shock wave physics, the characteristics of the injurious environment generated by an explosion, and clinical manifestations of resultant injuries.

45.5. CHOICE OF MODELS

The purpose of experimental models of CNS damage such as TBI is to replicate certain pathological components or phases of clinical trauma in experimental animals, aiming to address pathology and/or treatment. The goal of research specifies the design and choice of the experimental model (Cernak, 2005; Risling and Davidsson, 2012). The extremely complex nature of blast injuries requires full understanding of blast physics, and a model reproducing multiple aspects of blast injuries should be defined with particular scientific fidelity to conditions observed in theater. Otherwise, a model will lack military and clinical relevance and the obtained results might be dangerously misleading. Because of the widely varying experimental conditions the currently existing models use, the results across studies are very difficult to compare or summarize (Panzer et al., 2012).

There are several decision-making steps in the process of choosing a model for blast research (Figure 45.5). Most importantly, the researcher should identify which of the blast effects should be reproduced. If the choice is primary blast, the experimenter should ensure the animals are restrained so that there will be no blast-induced acceleration of the body/head during the exposure. Namely, in a situation where the body/head is allowed to move, the injury mechanisms would involve both primary and tertiary blast effects; this would make the interpretation of the results difficult. Next, a decision should be made about the biological complexity of the research study. This factor will dictate the choice of the biological surrogate used to reproduce blast-induced pathologies seen in humans (e.g., cell culture, tissue, small or large experimental animals, nonhuman primates); positioning of the biological surrogates; means of generating a shock wave (open field, shock or blast tubes); and length of the experiment, among others. Thus, based on the research question and the scale of complexity, a choice is made between nonbiological models and biological models.

FIGURE 45.5

Factors influencing the choice of blast injury and BINT models. (Created by Ibolja Cernak for the Committee on Gulf War and Health: Long-Term Effects of Blast Exposures Institute of Medicine, U.S. National Academies, Copyright 2014.)

Nonbiological models such as in silico and surrogate physical models provide an experimental platform for analyzing interactions between blast loading and different types of materials; the obtained information then is extrapolated to biological materials at different levels of scaling. The biofidelic computer (i.e., in silico) models provide spatially and temporally resolved descriptions of stress, strain, and acceleration that blast generates; as such, they are helpful tools in characterizing the physics of the blast-induced mechanical changes in the brain tissue (Chafi et al., 2010; Nyein et al., 2010; Zhu et al., 2010). The physical surrogate models use a human surrogate torso or head, which are made from synthetic materials (such as glass/epoxy or polyurethane) with biofidelic properties and incorporate multiple displacement and pressure sensors molded into the organs’ material to record the biomechanical parameters such as linear/angular acceleration, velocity, displacement, force, torque, and pressure (Desmoulin and Dionne, 2009; Ganpule et al., 2012; Roberts et al., 2012).

The nonbiological models can be valuable in identifying blast-induced biomechanical alterations and suggest potential consequences in biological systems. Nevertheless, they are unable to give explanations for functional and physiological changes in a living system caused by blast exposure. Hence the need for biological (in vitro, ex vivo, and in vivo) models, which use biological systems of differing complexity. The in vitro models use cell cultures and can be helpful in characterizing the cell-response mechanisms to blast loading in a highly controlled experimental environment (Effgen et al., 2012; Panzer et al., 2012). The ex vivo models use an organ or a segment of a specific tissue such as brain or spinal cord, taken outside the organism into an artificial environment, which is more controlled than is possible with in vivo experiments. As for all blast injury models, applying operationally relevant loading histories is critical for the in vitro and ex vivo models. Namely, mechanisms of the energy transfer to the tissue and the resultant biological response can be reliably analyzed only when blast-loading conditions are realistic and would happen at the cellular or tissue level of an individual who had been exposed to and survived a militarily relevant blast environment (Effgen et al., 2012).

The success of a research study using biological models, especially at the whole-animal level, depends on rigorous selection of animal species used as experimental models. Rodents are the most frequently used experimental animals in trauma research. The relatively small size and low cost of rodents permit repetitive measurements of morphological, biochemical, cellular, and behavioral parameters that require relatively large numbers of animals; this, because of ethical, technical, and/or financial limitations, is less achievable in phylogenetically higher species (Cernak, 2005). Nevertheless, the anatomical and physiological differences between humans and rodents, especially in circulatory and nervous systems, limit the utilization of small experimental animals in blast-injury research.

Extensive studies conducted in Albuquerque, New Mexico, confirmed by German, Swedish, and British findings, demonstrated significant interspecies differences in blast tolerance among 15 mammals (Bowen et al., 1967; Richmond et al., 1967, 1968, 2005). The size-dependent differences in blast tolerance have been explained by reference to variation of interspecies lung densities and volumes. Namely, lung density in larger species, including man and monkey, cat, and dog, is only about half of the lung density of smaller species (e.g., rodents), whereas lung volumes normalized to body mass are three times bigger in large species than in smaller animals (White et al., 1965). Also, there are significant interspecies differences in body geometry that influence the blast-body blast-head interactions (Bass et al., 2012). The body position of the animal in the shock tube also has an important impact on blast injury severity. Animals facing the incoming shock wave front with their chest and abdomen (i.e., supine position) provide the best conditions for the shock wave’s energy transfer; consequently, they have the highest mortality rate and most severe injuries (Cernak et al., 2011). Furthermore, in blast injury modeling, especially when acceleration is included as one of the mechanistic factors, scaling laws should be taken into careful consideration (Bass et al., 2008, 2012). Taking a blast-head scenario as an example, for a given blast, when calculating the net loading scales for cross-sectional area of the skull, even if other parameters would be identical, a specimen 20-fold the size would experience 20-fold less acceleration for the same blast. Nevertheless, other anatomical differences between the human and animal heads, such as bone volume fraction, trabecular separation and number, and connectivity density, among others (Holzer et al., 2012; Pietschmann et al., 2010), should also be considered. Evolutionary and developmental changes in the structure and arrangement of blood vessels (Vries, 1904) are also important factors that should be taken into account when choosing models for reproducing blast injury. For example, the internal carotid artery is the main blood supply both in humans/nonhuman primates and rodents (rats and mice). Nevertheless, although in lower vertebrates the internal carotid artery directs the blood to the brain parenchyma through the posterior branch without contribution from the basilar artery, in higher vertebrates, there are the two posterior branches that stem from a single and central branch turning into the branch of the basilar artery (Casals et al., 2011). These anatomical differences could significantly influence the shock wave propagation through the cerebrovasculature.

Previously, it has been shown that the level of phylogenetic maturity has a decisive role in brain’s response to a high-pressure environment (Brauer et al., 1979), a factor that should be taken into account in planning blast-induced neurotrauma (BINT) experiments. Because basic molecular and gene injury-response mechanisms are conserved through evolution, phylogenetically lower species such as rodents can be used for studies studying blast-induced changes at cellular and subcellular levels. However, establishing the pathogenesis of impaired higher brain functions would require larger animals with a gyrencephalic brain.

45.6. Blast-Induced Neurotrauma

Blast can interact with the brain by means of a (1) direct interaction with the head via direct passage of the blast wave through the skull (primary blast), causing acceleration and/or rotation of the head (tertiary blast), or through impacting particles accelerated by the energy released during explosion (secondary blast) (Goldstein et al., 2012; Mellor, 1988), and (2) kinetic energy transfer of the primary blast wave to organs and organ systems, including fluid medium (blood) in large blood vessels in the abdomen and chest, and the CNS (Cernak and Noble-Haeusslein, 2010; Cernak et al., 2001b). Namely, during the interaction with the body surface, the shock wave compresses the abdomen and chest and transfers its kinetic energy to the body’s internal structures, including the blood as fluid medium. The resulting oscillating waves traverse the body at about the speed of sound in water and deliver the shock wave’s energy to the brain. Clemedson, based on his extensive experimental work on shock wave propagation through the body (Clemedson and Jonsson, 1961), was among the first scientists to suggest the possibility of shock wave transmission to the CNS (Clemedson, 1956). These two potential avenues of interaction do not exclude each other (Cernak and Noble-Haeusslein, 2010). Most recent experimental data suggest both the importance of the blast’s direct interaction with the head (Moss et al., 2009) and the role of shock wave–induced vascular load (Cernak, 2010) in the pathogenesis of BINT.

45.7. CONCLUSION

The problem of BINT and related long-term neurological deficits has been gradually increasing with the progress of military warfare and the pathological experience of returning veterans of Operation Enduring Freedom/Operation Iraqi Freedom. The long-term health problems manifesting in growing number of veterans have triggered intensified research efforts aiming to clarify the vital mechanisms underlying blast injuries and blast-induced brain damage. This is an extremely challenging task, which requires a unified front of physicists, military scientists, biomedical researchers, and clinicians applying out-of-the-box thinking and novel research approaches. Clear guidelines about experimental models that are acceptable for blast injury research should be established and strict adherence to those guidelines enforced. Without such consensus among blast researchers and close cooperation between the researchers and those with military operational experience, this research field will remain contradictory and misleading, and the soldiers with blast injuries and/or BINT left without improvement in their treatment.

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