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					J R Army Med Corps 2003; 149: 5-14




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                            Penetrating Brain Injury In Military Conflict: Does It Merit
                            More Research?
                            W Sapsford

                            Introduction                                      environment. The established experimental
                            One of the primary goals of the military          models of TBI understandably focus on
                            scientist addressing the prevention of            severe blunt head injury; this is much more
                            trauma, is to develop new concepts for            frequent than PBI in a civilian setting.
                            attenuating energy transfer to the body from      Furthermore, PBI in a civilian environment
                            either penetrating, non-penetrating or blast      is different both in the characteristics of
                            impacts. Personal armours have deficiencies,      injury and outcome to that seen on the
                            both in the body coverage achievable              battlefield when helmets are frequently
                            without degrading military performance,           worn. Militarily relevant PBI is an under-
                            and in the inherent ability of the materials to   investigated field and receives little attention
                            attenuate high energy impacts, particularly       in research laboratories. Indeed, previous
                            from high energy bullets and anti-personnel       models of PBI involving the use of
                            fragments. Protection of the head from these      projectiles fired into the brain have
                            types of projectiles is a difficult task –        succumbed to political pressure following
                            personal armour materials are available to        animal rights activism (1).
                            stop very high energy projectiles (even up to     The aims of this article are to:
                            12.7 mm bullets), but the weight of these         • examine the nature and extent of the
                            technologies precludes them from use on             problem of PBI in the military
                            helmets. It is inevitable, therefore, that          environment;
                            practical military helmets cannot stop high       • identify the key clinical issues wherein the
                            energy penetrating projectile impacts; they         military scientist may profitably focus
                            are remarkably effective however, against the       research to result in more effective
                            principal threat in war – low energy anti-          treatment of the brain-injured casualty,
                            personnel fragments. The development of             particularly in the early stages of the
                            practical helmets capable of stopping high          injury;
                            energy bullets is constrained by the              • provide a clinical basis for new approaches
                            limitations of currently available materials.       to the protection of the head from high
                            Penetrating wounds to the brain continue to         energy penetrating projectiles; specifically,
                            be a feature of military conflict.                  recognising the current inability to stop
                                There are two types of traumatic brain          high energy projectiles and the merit in
                            injury (TBI), blunt and penetrating. The            transforming a high energy transfer
                            mechanisms are very different. Blunt injury         penetrating wound to the brain into a low
                            involves the coupling of linear and rotational      energy transfer wound using lightweight
                            acceleration and deceleration forces into the       materials.
                            brain tissue. The resultant impacts of brain
                            tissue within the skull, and the tortional        Ballistic Considerations
                            forces in particular, lead to primary brain       Penetrating brain injury generally results
                            injury, complicated by secondary damage as        from bullets, munition fragments and low
                            a result of subsequent pathological               velocity objects such as arrows and knives.
                            processes. Penetrating brain injury (PBI)         Penetration is a function of the available
                            involves local forces and stress waves that       energy of the projectile, and the retardation
                            radiate out from the injury track, especially     afforded by the tissues. The retardation
                            in the case of high available energy bullet       transfers energy into the tissues; the energy
                            and fragment injury.                              does work on the tissues resulting in
                                What is the status of research into the       damage. The retardation is a function of the
Sqn Ldr W Sapsford          medical management of brain trauma –              shape of the object (presented area), the
MA MB BChir FRCS            penetrating and non-penetrating, civil and        angle of approach and the properties of the
RAF                         military? Experimental research to enhance        tissues. Brain injury is further complicated
                            management (and indeed protection)                by the generation of secondary bone
Honorary Research           requires models – tools to develop                fragments and multiple metallic fragments
Fellow                      principles.There are several different models     from the disrupted casing of the bullet.
Biomedical Sciences,
Defence Science and
                            of TBI, both penetrating and blunt; using            Lower available energy projectiles, such as
Technology                  techniques such as fluid percussion, cortical     small anti-personnel fragments, arrows and
Laboratory,Porton,          contusion, single artery occlusion, forebrain     knives create a track of primary tissue
Salisbury, Wiltshire,       ischaemia and stab wounds, but few address        damage without substantial gross injury
SP4 0JQ.                    the issues relevant to PBI in the military        peripheral to the track. Higher available
6                                                                                 Penetrating Brain Injury


    energy projectiles, such as bullets, result in a   through” wounds).
    more complex wounding pattern. A low                  These ballistic factors explain the span of
    available energy bullet may transfer               injuries observed in tissue penetration by a
    sufficient energy to create a permanent track      projectile. With low energy transfer, tissue
    of tissue injury as it penetrates the brain,       destruction is primarily limited to the track
    crushing and lacerating the tissue in its path.    of the missile, whereas high energy transfer
    Additionally, the bullet will also produce a       rounds destroy much more tissue along and
    small temporary cavity, and stress (pressure)      peripheral to the injury track, especially in
    waves. High available energy projectiles such      relatively inelastic tissue, such as the brain.
    as rifle bullets will normally transfer large         In practice, high energy transfer wounds
    quantities of energy and produce large             to the brain are invariably fatal. However,
    temporary cavities, and stress waves of great      the division of missiles into high- and low-
    magnitude. The transfer of energy from the         energy classes is arbitrary; a broad spectrum
    bullet to the tissue occurs radially from the      of energy levels is delivered to the tissue by
    primary track, compressing the tissue              high- and low-energy fragments as well as
    tangentially. The temporary cavity rapidly         bullets, ricocheting bullets and the
    expands,      reducing     pressure      below     penetration of helmets by missiles.
    atmospheric and sucking debris into the
    wound; it then collapses.The cavity will then      The Nature and extent of PBI
    undergo several smaller expansions and             Penetrating Brain Injury can be defined as
    contractions of diminishing amplitude.             any injury where the dura is breached and
    Within an inelastic tissue like the brain, the     brain is damaged directly.This may be by the
    extent of injured tissue may be 10 to 20           passage of a missile or any other penetrating
    times the size of the projectile.                  object, or indirectly by the transfer of energy
      The clinical effect of the temporary cavity      or local shear caused by, for example, dural
    on tissues depends upon their mechanical           penetration by depressed skull fracture. PBI
    properties, and the function of the tissues. In    can be differentiated into the following
    the case of brain, a notable feature               categories:
    influencing the transfer of energy and the         • Penetrating - a foreign object penetrates
    mechanical (and functional) injury is the            skull and dura and remains lodged in the
    presence of the cranial vault and base. The          intracranial cavity;
    formation of a large temporary cavity may          • Tangential - a foreign object glances off the
    devastate the integrity of the vault. The            skull, frequently driving bone fragments
    cranial cavity may also reflect stress waves         through the dura into the brain;
    leading to complex and intense pressure            • Perforating - a ‘through-and-through’
    fluctuations and shear in the hemispheres            injury characterised by both entry and exit
    and medullary centres.                               wounds. Bone fragments and debris are
       Handguns generally fire projectiles at or         commonly present within the brain in this
    near sonic velocity and are regarded as low          class of injury.
    available energy weapons compared to rifles
    that produce projectiles at supersonic             The nature of civilian PBI. Civilian PBI
    velocities and have high available energy.         can occur as a result of accidents with
    Rifle bullets are also longer and more             firearms and other implements but more
    pointed than handgun rounds; the instability       often it is the result of intentional injury –
    of the bullet consequential to entering tissue     armed conflict or suicide. In this setting, PBI
    such as brain leads to tumbling (yaw). The         is caused predominantly by firearms. Suicide
    presented area of the bullet will increase         is the single most common cause of such
    during the yawing cycle, resulting in greater      wounds. A substantial proportion of deaths
    retardation, high energy transfer, and a large     occurs in the first few hours following injury.
    temporary cavity. Fragmentation and
    deformation of the projectile can enhance          The nature of military PBI. Military PBI
    further the energy imparted to the tissue.         results from armed conflict, however, civilian
    Fragmenting rounds create multiple injury          and military armed conflict are significantly
    tracks. Fragmentation potential is increased       different, resulting in dissimilar mechanisms
    by scoring the jacket of the bullet to promote     of injury and outcome, especially death. In
    deformation and break-up (Dum-Dums) or             this setting, and in unprotected troops,
    by filling the round with pellets (the Glaser      penetrating injuries are predominantly
    round). In order to reduce “superfluous            caused by shell and mortar fragments. The
    wounding”, military bullets are jacketed to        use of rifles discharging high energy rounds
    inhibit disruption of the projectile (The          on the battlefield leads to such damaging
    Hague Peace Conference 1899). For police           cerebral injury that the majority of those
    use, deformation may be enhanced by                suffering high energy transfer wounds to the
    hollowing the point of the bullet so that it       head presumably never reach medical care.
    expands on impact, creating a larger               The result is that in the military
    permanent wound track, increasing energy           environment, the surviving PBI population
    transfer and reducing the incidence of             is skewed towards those with lower energy
    perforation of the body (“through and              fragment wounds. This skewing is further
W Sapsford                                                                                                             7


             accentuated by such moribund severely                        injury at 42% but only 20% of this CNS
             brain injured casualties receiving a low                     injury was the result of craniocerebral
             priority for transport to rear echelon medical               penetration, the remainder being blunt
             care and the prolonged time for evacuation                   trauma. The overall mortality rate for PBI in
             to occur in these hostile environments                       this civilian study was therefore about 8%.
             compared to the civilian environment.                          Of the total of those who died of CNS
             Appropriate medical resources available                      injury a third (35%) died before reaching the
             within the first ‘golden hour’ are negligible.               hospital and of the two-thirds (65%) who
             Furthermore, compared to the civilian                        did reach the hospital and died
             setting, triage and resuscitation are more                   subsequently, almost half (42%) had
             difficult, the skill levels of first medical                 gunshot wounds to the head (18). About
             providers is different, the likelihood of                    16,500 people die of gunshot wounds to the
             wound contamination in battlefield PBI is                    brain each year in the USA (19,20),
             increased and early treatment facilities are                 approximately half of the total of 33,000
             more rudimentary. Additionally, the ability                  fatal shootings. In two series of civilian
             of surviving casualties to reach higher levels               patients with PBI that included patients
             of medical care is also compromised.                         found dead at the scene or on arrival at the
             However, PBI in the military setting does                    hospital, the mortality rate was 83% - 93%
             occur mainly in young men in excellent                       (12,21). Thus, in a civilian environment
             physical condition.                                          where handguns are commonplace (such as
                                                                          in the US) PBI is very often fatal and it
             Hospital mortality rates of military and                     accounts for 8% of all post-injury deaths.
             civilian PBI. Death rates from PBI are                         Computed tomography scans (CT)
             lower for those casualties reaching medical                  identifying the location of trauma in the
             care in the military setting compared to the                 brain of those sustaining PBI have enabled
             civilian setting; many military casualties will              an association to be made between the site of
             already have succumbed in the field. The                     PBI and mortality. Twenty three percent die
             percentage of patients with PBI in hospital                  following unilobar injury, 40% where the
             who subsequently die is presented in for                     mid-sagittal plane is breached, 53% if the
             various conflicts (Table1).                                  bullet crosses the mid-coronal plane and
                                                                          75% if both these mid-planes are crossed.
              Conflict     Mortality - percentage of            Source    Transventricular injuries are also associated
                           PBI casualties in hospital                     with a high mortality as is fragmentation of
              WWII                      10-13                    (2, 3)   the bullet (7,11,22,23). The majority (80%)
              Korea                       10                       (4)    of fatal neurotrauma is, however, blunt and
                                                                          accounts for 34% of all post-injury deaths.
              Vietnam                     30                       (5)
              Lebanon                     26                     (6, 7)   Military incidence of PBI mortality. It is
              Iran-Iraq                   16                       (8)    estimated that TBI, in all its forms, is one of
              The data for the Iran-Iraq war only includes casualties     the leading causes of combat injury
              reaching a tertiary referral centre, a mean of 49 hours
                                                                          accounting for 20% - 25% of all battle
              post-injury.
                                                                          incurred wounds in the modern theatre of
             Table 1. In-hospital mortality rate for penetrating brain    war (the leading cause of combat injury is
             injury.                                                      limb injury). Bellamy estimated that 50% of
                                                                          PBI casualties will die immediately or
               By comparison, the mortality rate in                       shortly after wounding (killed in action,
             civilian PBI amongst all-comers admitted to                  KIA). He also estimated that 80% of those
             neurosurgical centres varies between 34%                     with TBI, surviving to reach medical care,
             and 79% (9-17). If patients in the series that               have PBI (24). Of those with craniocerebral
             had no dural penetration (11,14) and ‘mild’                  injuries who reach medical care, 43%
             injuries (GCS 14-15) (15) are excluded, the                  ultimately die of wounds (DOW) (25).
             mortality rates are uniformly above 60% for                  These figures suggest that, of those
             civilian PBI – less die outside medical                      combatants receiving a TBI, the total
             facilities because they are transported                      mortality rate from PBI is approximately
             quickly to hospital.                                         67%, consisting of the 50% who are KIA on
                                                                          the battlefield (assuming that they all died of
             Civilian incidence of PBI mortality. In                      PBI) and the additional 17% who DOW
             her reassessment of the epidemiology of                      under medical supervision. The latter figure
             trauma deaths in a civilian trauma centre in                 agrees well with the known fatality rates of
             the US, Sauaia reported that the most                        between 10% - 30% of PBI in various
             common mechanism of death following                          conflicts who are accounted for because they
             trauma was penetrating injury at 49%.                        survive to reach medical care (2-8). These
             Gunshot wounds accounted for 42%, stab                       figures also compare very favourably to
             wounds represented a further 6% and other                    those found in the civilian environment,
             objects caused 1% of penetrating injury                      where the total mortality rate from PBI is
             (18). The most frequent cause of post-injury                 between 83% - 93% and a “died in hospital
             death was central nervous system (CNS)                       rate” of 60% or more (Table 2).
8                                                                                                     Penetrating Brain Injury


     Penetrating Brain Injury                  Military                                Civilian
                                               Incurred on the battlefield
     Overall Incidence                         20%                                     8%
     Percent of all traumatic injuries
     Hospital Mortality                        10 – 30%                                60 – 79%
     Percent of admissions                     Died of wounds
                                               Low available      7.5%                 Low available energy   60 – 79%
                                               energy missile                          missiles predominantly
                                               High available     23 – 50%
                                               energy missile
     Pre-hospital mortality                    50%                                     7 – 17%
                                               Killed in action
     Total Mortality                           67%                                     83 – 93%
     Percent of all PBI casualties

    Table 2. Estimates of the incidence and mortality of PBI in military and civilian environments.

      Whilst it is true that few will survive a                     The incidence and mortality figures
    perforating, through-and-through PBI and                      presented here are summarised and shown in
    any injury to the head from a high available                  Table 2. All the figures are approximate and
    energy projectile is invariably fatal, many                   derived from a number of studies. The table
    penetrating and tangential PBI injuries with                  enables a comparison to be made between
    skull and dural penetration, are survivable.                  military and civilian PBI. The high overall
    Aarabi analysed outcome in 435 casualties                     mortality in the civilian environment prob-
    suffering PBI with dural penetration from all                 ably results from the high incidence of
    missiles (low and high-energy) in the Iran-                   suicide by gunshot.
    Iraq war who survived to reach a                                If the soldier survives the initial trauma and
    neurosurgery centre (8) (Table 3).                            reaches medical attention (a 50% chance),
                                                                  he/she then has a 57% chance of survival
     Type of penetrating Incidence (%) Mortality (%)              following PBI from projectiles, presumably,
     brain injury
                                                                  of lower energy. In other words, up to 30% of
     Penetrating                   61              19.9           victims of TBI (PBI) survive and will also
     Tangential                    29              15.6           subsequently lead a reasonable quality of life
     Perforating                     9             48.8           (27). This bears very favourable comparison
                                                                  to civilian PBI, (but not to civilian TBI that is
    Table 3. Penetrating brain injury type and mortality (from    associated with an 80% survival rate as it is
    Aarabi (8)).
                                                                  predominantly blunt trauma), and to the
                                                                  survival rates seen after cardiac arrest outside
        It is assumed that helmets were available                 hospital, (0.3%) despite the resources and
    to these combatants in the Iran-Iraq war, but                 training devoted to this disease.
    it is not stated whether they were worn or
    how effective they proved. It is estimated                    The Opportunities To Improve
    elsewhere that between 23% and 50% of                         Survival Following PBI
    high-energy bullet PBI is fatal in those who                  The majority of deaths occur on the
    reach medical care. In the case of low-energy                 battlefield before evacuation to medical
    PBI, the hospital fatality rate is estimated at               treatment facilities. Bellamy estimates that
    only 7.5% (5,26).                                             for every casualty who dies of wounds in a
        In combat, involving numerous soldiers                    medical treatment facility, up to 9 have
    (large unit or high intensity fighting), up to                already been killed in action. Thus, in order
    80% of PBI is caused by low-energy missile                    to significantly improve combat casualty care
    injury such as fragments. In some military                    and given optimal circumstances (such as
    scenarios, largely involving urban operations                 available in Vietnam), the emphasis must be
    or operations against semi-organised pseudo-                  placed on field medical care, or the pre-
    military factions (asymmetric warfare), there                 hospital phase of patient management by the
    may be a higher frequency of bullet wounds                    combat medical technician and sub-
    compared to fragmentation injuries. Thus, in                  sequently, the staff at the regimental aid post
    general, there is a high rate of PBI in the                   (24). The target should be to improve the
    military environment (80% - 90% of all                        care of casualties who become listed as KIA
    TBI), but it is predominantly low-energy in                   rather than those who are ultimately listed as
    nature (80% of all PBI) and caused by                         DOW.
    fragments and other missiles. Certain                           Advances in the composition and design of
    operations, however, will expose the soldier                  combat clothing, in particular the helmet,
    principally to high available energy bullets.                 may contribute to a reduction in PBI
    For the former, a mortality rate of 7.5%                      mortality; they will not eliminate it. Measures
    demonstrates a good chance of favourable                      to improve forward resuscitation include
    outcome (in terms of mortality) for the                       ensuring that a casualty’s airway (A) and
    soldier; the same cannot be said for the latter.              breathing (B) are scrupulously maintained
W Sapsford                                                                                                   9


             and the early recognition of haemorrhage         reduce PBI from missiles passing beneath the
             (C), either overt, and thus controllable by      rim into the base of skull (however, the
             compression, or incompressible truncal           helmet must also allow the soldier to use
             blood loss, and thus uncontrollable without      headphones and other equipment such as
             surgical intervention. There has been            respirators). An approach taken with
             renewed interest recently in the management      protection of the lower limb from anti-
             of haemorrhage, the most common cause of         personnel mines is to recognise that for
             death in both the civilian and military          wearable footwear, total protection is not
             environments at 50% mortality of both those      achievable.The strategy is to use materials to
             found dead at the scene, and those who die       attenuate the energy sufficiently to reduce
             subsequently (18,24). Emphasis is now            the clinical impact of the trauma, both
             placed on the pre-hospital management of         acutely, and with regard to remaining
             haemorrhage, hypotensive resuscitation           function. Could such an approach be taken
             protocols and different management               with PBI? Should we recognise that with
             strategies based on the need to get those with   current materials, absolute protection is not
             uncontrolled haemorrhage to surgical             achievable, and the target should be to
             treatment as rapidly as possible.There is also   further reduce energy transfer? Transposing a
             research underway in UK, US and Canada           high energy wound into a low energy one by
             to identify and assess novel fluids for          dissipating energy in the helmet penetration
             resuscitation, such as hypertonic saline         process could significantly increase the
             dextran (HSD) and liposomally encaps-            potential for survival to reach medical care.
             ulated haemoglobin-based oxygen carriers
             that can be deployed in the field. Antishock     Pre-Hospital Management–
             drugs, such as recombinant activated factor
             VII may also have a pre-hospital role in         ABCs
             arresting uncontrolled haemorrhage acutely,      There has also been a revolution in the field
             allowing time for rearward evacuation to         management of battlefield casualties with the
             take place before exanguination occurs.          widespread adoption of the principles of Pre-
             Evacuation delays, pre-treatments and the        Hospital Advanced Trauma Life Support
             delivery of medical treatment once in a          (PHTLS) (29) and Advanced Trauma Life
             hospital will also be discussed to evaluate      Support (ATLS) (30) within the military. In
             their potential impact on the survival of        the British armed forces, these principles
             casualties of PBI.                               have been incorporated into the Battlefield
                                                              Advanced Trauma Life Support (BATLS)
             Prevention – Helmet Design                       course (31), directed specifically at the first
             There is little work to identify where           responders - the Combat Medical Tech-
             improvements can be made in the pre-             nicians. All these protocols are characterised
             hospital management of patients with PBI,        by emphasis placed on the maintenance of
             50% of whom die on the battlefield. Physical     the airway and breathing in the immediate
             protection from PBI is plainly an important,     post-injury period and this is likely to have as
             but difficult issue. Current helmet              huge an impact on the outcome of casualties
             compositions and designs and high levels of      suffering from PBI as any other single
             troop discipline (which ensured soldiers         change. The opportunity to improve overall
             actually wore their helmets during the Gulf      survival of PBI casualties therefore exists by
             conflict) resulted in only one US soldier        improving the first aid skills of the soldier,
             requiring neurosurgery for a base of skull       and management of the airway and breathing
             PBI in the Gulf conflict. This compares          by the first medical attendants (especially
             favourably to the predicted incidence of four,   tracheal intubation). It remains to be seen
             from the 143 soldiers wounded by missiles        whether the salvage of potentially moribund
             (28). In the Vietnam war, the helmet             PBI casualties by the application of these
             originally designed in WWII was worn, and        principles should even be attempted on the
             helmet discipline was poor; 98% of PBI           battlefield as many will inevitably die when
             occurred to the cranial vault (28). Similarly    such care must eventually be abandoned as
             in a series from the Lebanese conflict, 87%      futile.
             of PBI was craniocerebral injury (7). The             TBI is frequently associated with
             Gulf experience represents a dramatic            haemorrhage from other bodily regions. In
             improvement, albeit the number of such           the US civilian environment, 35% of patients
             casualties was very small.                       with severe TBI are hypotensive on initial
                 It is possible that a helmet could be        presentation and these patients demonstrate
             produced from known materials that will          twice the mortality and a significant increase
             prevent TBI or PBI from a high available         in morbidity compared to non-hypotensive
             energy military rifle round. However, the        patients (32). It is likely that this association
             load to the head and neck from the heavy         is more frequent in the military environment
             materials such as ceramics that would be         with the preponderance of penetrating
             required to stop a high energy rifle round       injuries over blunt trauma. The attention to
             preclude general combat issue of such            appropriate resuscitation in the field, the
             technology. Alterations in design could          development of better fluids for resuscitation
10                                                                                  Penetrating Brain Injury


     and the application of the adjuncts to            the probability of being KIA by any given
     resuscitation, such as recombinant activated      wound was greater than in the Korean War.
     factor VII, may well have a significant           This was most likely to be due to the reduced
     secondary impact on survival following PBI.       evacuation times in the latter conflict – two
        Traditionally, patients with TBI are           to four hours as opposed to six to eight hours
     aggressively resuscitated with large volumes      in WWII. In Vietnam, the evacuation time
     of crystalloid with the goal of rapid volume      was reduced further to one to two hours and
     expansion to restore the blood pressure to        the percentage of casualties who received a
     normal, baseline levels (33). However, recent     severe injury and died before evacuation was
     laboratory studies and a single clinical study    20%. The British further reduced evacuation
     have demonstrated that aggressive fluid           times in Salalah, Oman in 1972-1973 and
     resusci-tation in the presence of uncontrolled    the number of similarly injured Omani
     haemorrhage from trauma results in an             casualties who died was 10% (albeit the
     increase in haemorrhage volume and greater        numbers in this conflict are small). Bellamy
     short-term mortality compared to a regimen        predicts that the KIA rate will be 20% if
     of limited, hypotensive resuscitation or no       evacuation occurs within the “golden hour”,
     resuscitation (34-38). As a result, some          26% if evacuation occurs within the
     investigators recommend that the resus-           militarily relevant “golden six hours” and
     citation of trauma patients be limited (or        32% if evacuation is delayed to 24 hours
     maintained at hypotensive levels) until           (24). In more recent warfare, the evacuation
     surgical control is achieved, thereby             time has been longer than that seen in
     converting the uncontrolled into controlled       Vietnam. In the Gulf War in 1991, the
     haemorrhage. Aggressive resuscitation can         median injury to admission interval was 4.41
     then be started with the aim of achieving         hours during the ground offensive (45), in
     physiologically normal baselines. This policy     Afghanistan in 2001 – 2, this delay increased
     has been adopted by the British military in       to 8 hours (personal communication). In the
     their Battlefield Advanced Trauma Life            Falklands conflict the evacuation delay was
     Support manual (31).                              as long as 16 hours (personal comm-
        Research is underway into the use of such      unication).
     hypotensive resuscitation regimen in                PBI requires the evacuation of casualties to
     combined models of TBI and uncontrolled           rearward specialist neurosurgical units to
     haemorrhage to establish whether this             improve the survival of these severely injured
     approach is appropriate in these patients, due    patients. This is reflected in epidemiological
     to the risk of exacerbating the secondary         statistics which show that, whilst haemorr-
     brain insult by hypotensive resuscitation         hage from all causes is responsible for most
     (39). There are also laboratory studies           early deaths following admission to a trauma
                                                       centre, TBI is a major cause of late death
     underway to evaluate TBI and haemorrhage
                                                       (greater than 48 hours following admission),
     with potentially protective drugs (personal
                                                       second only to multiple organ failure (18).
     communication) and the potential benefits of
                                                       By comparison, there are very few deaths
     HSD for resuscitation in TBI (40-44).
                                                       from haemorrhage at this stage.
     Finally, research is taking place in related
     areas, such as the use of HSD as the initial
     fluid of resuscitation following blast and        Pre-treatments
                                                       Very little experimental research into
     haemorrhage         (both     controlled   and
                                                       penetrating brain injury has been
     uncontrolled). As the science of resuscitation
                                                       undertaken, despite the serious problem it
     in traumatic uncontrolled haemorrhage
                                                       presents both to military personnel and
     develops, so research into the impact of
                                                       civilians. Investigators have consistently
     potentially beneficial resuscitation regimen
                                                       shown that PBI causes profound cardio-
     on concomitant military trauma, such as
                                                       respiratory effects. Indeed the first to report
     blast and penetrating brain injury, must
                                                       these effects was Horsley in 1894 (46). He
     follow, just as it does in civilian TBI.          noted a transient apnoea following a side-to-
        In summary, the prompt institution of          side cerebral injury with a pistol and
     supportive care by the principles set out in      attributed this to a ‘hydrodynamic effect’ on
     the PHTLS, ATLS or BATLS and attention            the tissue of the brain that increased the
     to resuscitation of casualties with               extent of the injury beyond the projectile
     haemorrhage and PBI may improve the               diameter. This ‘hydrodynamic effect’ is
     outcome of this serious injury.                   comparable to the result of a bullet fired at a
                                                       tin can. If the tin is empty, small entry and
     Evacuation Delays To                              exit holes are seen; if it is full of water, the tin
     Medical Care                                      will explode. Crockard (47,48) investigated a
     The longer that the severely injured casualty     similar, more controlled injury in primates.
     remains on the battlefield, the greater the       He produced a ‘clean’ wound, away from
     probability of death and therefore of being       vital structures and major blood vessels, thus
     classified as “killed in action” (KIA). Bellamy   avoiding obfuscating haematoma develop-
     analysed the effect of evacuation times on the    ment and skull fragment penetration and
     KIA rates in several conflicts (24). In WWII,     permitting a study of the generalised
W Sapsford                                                                                                 11


             intracranial results of missile injury. He       to thoracic blast; 4) centrally administered
             noted a bradypnoea or transient apnoea after     methiothepin (a central 5-HTIAIC receptor
             impact, depending on the kinetic energy of       antagonist) potentiated the apnoea and
             the missile, a prolonged bradycardia lasting     bradycardia and led to an early death.
             between 10 to 30 minutes and a period of         Further work demonstrated that a centrally
             hypotension for a few minutes following          acting and centrally administered 5-HT
             injury. In the higher kinetic energy group,      agonist, 5-carboxamidotryptamine (5-CT)
             apnoea requiring immediate ventilatory           as a pre-treatment attenuated the brady-
             support and more profound bradycardia and        cardia seen following primary thoracic blast
             reduction in blood pressure were observed.       and that the respiratory stimulant doxopram
             Crockard argued that these effects were due      significantly reduced the duration of apnoea.
             to the ‘hydrodynamic effect’ of the missile      This series of studies suggested that the
             being directly relayed to the structures         reflex elicited by thoracic blast and that
             around the third ventricle and midbrain.         elicited by pharmacological stimulation of
                Subsequent workers (20,49) demonstrated       pulmonary afferent C-fibres does not share a
             similar results and drew similar conclusions.    common central nervous pathway. The work
             Carey (20) discussed the pressures induced       indicated that another as yet unknown
             by a missile in water and tissue. He             afferent pathway is activated by primary
             described: 1) an extremely high juxta-missile    thoracic blast.What is not in doubt is that the
             pressure, immediately in front of and at right   higher centres influence the response of a
             angles to the missile, responsible for tissue    model to primary blast injury.
             destruction along its path; 2) kinetic energy       Sarphie has shown fissures in the floor of
             transfer, creating the temporary cavity          the fourth ventricle in rats following a
             behind the missile; and 3) a longitudinal        penetrating injury of the sensorimotor cortex
             ‘strong shock’ (stress) wave pressure. The       (52). The respiratory and cardiovascular
             latter is a steeply rising, extremely brief      centres in the rat brain stem are just beneath
             (lasting in the region of 10µsec), high-         the floor of the fourth ventricle and the
             pressure compression front that moves            conclusion drawn was that these fissures
             spherically away from the strike point of the    damaged the brain stem respiratory and
             missile at approximately the speed of sound      cardiovascular centres causing the physio-
             in brain tissue.                                 logical triad of apnoea, bradycardia and
                A shock (or more accurately stress wave)      hypotension demonstrated in PBI. The rat
             propagating through tissues is the same          model subjected to primary blast injury to
             phenomenon seen in primary blast injury.         the thorax in the experiments had no head
             There are two critical determinants of           protection. It is conceivable that the blast
             survival following primary blast: the            waves could affect the cardiorespiratory
             pulmonary injury and the acute cardio-           brain centres in a similar manner to the stress
             respiratory responses. Guy (50,51) demon-        waves that occur in PBI, either directly, or via
             strated a reflex triad of apnoea, bradycardia    transmission of the stress waves from the
             and hypotension following moderate thoracic      chest to the CSF and the brain. If so, brain
             primary blast injury in a rat model and          stem damage from blast waves might
             showed that is not evident following blast       influence the physiological triad of responses
             injury to the abdomen. He proposed that the      that occurs following primary blast injury.
             responses were reflex in nature, as they are     However, since the apnoea and bradycardia
             not instantaneous, and that the apnoea and       following a blast injury are abolished by
             bradycardia can be prevented by bilateral        bilateral vagotomies, the most important
             vagosympathectomy. He further postulated         effects are mediated via the yet to be
             that one possible pathway is the reflex          elucidated afferent pathway from the chest.
             elicited by pulmonary afferent C-fibres             If similar brain stem damage occurs
             (pulmonary J-receptors), activation of which     following blast injury as has been
             produces the triad of apnoea, bradycardia        demonstrated in PBI, there is an opportunity
             and hypotension. Currently unpublished           for research into treatments to abolish the
             work for the Ministry of Defence, in which       apnoea, bradycardia and hypotension
             various pharmacologic interventions were         following PBI, just as has occurred in
             used as pre-treatments to try to favourably      primary blast injury research. In particular,
             influence the physiological triad, showed that   if the apnoea could be abolished or
             blockade of the known chemical transmitters      attenuated, this may lead to a significant
             in the pulmonary C-fibre did not influence       improvement in survival both following PBI
             the physiological triad. This work               and primary blast injury. It has already been
             demonstrated that: 1) bilateral cervical         demonstrated that the central respiratory
             vagosympathectomy abo-lished the apnoea          stimulant doxapram, peripherally admin-
             and bradycardia and attenuated the               istered within seconds of a primary blast
             hypotension; 2) atropine only attenuated the     injury to the chest, was able to stimulate
             bradycardia; 3) peripherally administered        respiration and significantly reduced the
             ondansetron (a 5-HT3 antag-onist which           period of apnoea. It also attenuated the
             interacts with 5-HT activated pulmonary C-       hypotension somewhat. Veterinary surgeons
             fibre afferents) did not modify the response     use a soluble form of doxapram that dissolves
12                                                                                Penetrating Brain Injury


     on the tongue to stimulate respiration in         Protection: The current composition and
     neonatal lambs. Could this type of approach       design of helmets (supported by a doctrine of
     be useful in PBI?                                 use) have already had a substantial impact on
        Carey (20) argues that following PBI, the      PBI from low energy projectiles and some
     integrity of the medullary centres is the         bullets. A wearable helmet capable of
     predominant factor in determining whether         stopping high available energy projectiles
     an individual lives or dies, provided excessive   remains elusive. However the very different
     intracranial bleeding does not occur. The         survival rates following penetrating brain
     energy transfer of the missile may determine      injury by high energy compared to a low-
     whether apnoea occurs and its duration,           energy missiles (50% and 7.5% respectively)
     ultimately causing death where the                suggest that improvements in helmet design
     medullary centres are irreversibly damaged.       to convert high energy projectiles to the
     Some casualties who have sustained                helmet into low energy wounds to the head
     hemispherical brain damage and are                may significantly improve survival following
     rendered temporarily apnoeic may possibly         PBI.
     be saved by prompt respiratory support (the
     aforementioned principles of first aid and the    Medical management: There has already
     ABC of resuscitation) and respiratory             been a revolution in the field of first aid and
     stimulants, either as pre-treatments or as        the skills of first medical responders
     post-injury therapies administered in the         following the introduction of the principles
     field. Such pre-treatments or acute               of ATLS in the late 1970’s - a ‘gold’ standard
     respiratory support would raise notable           of trauma care. These principles have since
     logistic, operational and doctrinal issues.       been widely disseminated through courses,
     Current practice should not inhibit a review      such as ATLS, PHTLS and BATLS. Prompt
     of the benefits of reversing the inevitable       assessment and maintenance of the airway
     apnoea from PBI and blast injury.                 and breathing in a casualty following PBI is
                                                       likely to be the most important intervention
     Post Admission To Definitive                      in their survival.
                                                          Haemorrhage management is undergoing
     Medical Care                                      a major review. It seems likely that the
     There is scope to reduce the mortality from       standard ATLS guidelines - that all casualties
     PBI once a casualty is delivered to definitive    who are shocked following trauma, should
     medical care. Definitive medical care, in this    receive a bolus of two litres of crystalloid (or
     context, refers to a field hospital where the     20 mL/kg) rapidly - will change to
     full protocol of the ATLS can be delivered,       incorporate the concepts of hypotensive
     including definitive haemorrhage control,         resuscitation, especially in the case of non-
     CT scanning and surgical decompression            compressible haemorrhage into a body
     and debridement of intracranial lesions.          cavity. This recognises the need for rapid
     Mortality from PBI in this setting is,            evacuation to surgical care where hae-
     however, frequently the result of a formal        morrhage can be definitively controlled. The
     declaration of brain death and also from          management of TBI is also following suit. A
     other     conditions     that   subsequently      casualty, dying from poorly managed
     complicate the management of any severely         uncontrolled haemorrhage, is less likely to
     injured casualty, such as sepsis and multiple     survive a TBI, as hypotension contributes to
     organ failure; thus these deaths do not apply     secondary brain injury, and consequently
     specifically to PBI. It is conceivable that       significantly increases mortality.There is also
     some of those dying of wounds in the PBI          interest in novel fluids of resuscitation, such
     category could be salvaged by improved            as small volume hypertonic solutions of
     surgical and/or anaesthetic management of         saline (HSD) and haemoglobin-based
     those casualties dying from sepsis and            oxygen carriers, and pharmacological agents
     multiple organ failure.These are traditionally    with the potential to arrest non-compressible
     areas of interest amongst intensive care          haemorrhage such as recombinant activated
     physicians and surgeons and a large fraction      factor VII.The impact of these developments
     of trauma research funding is already spent       in fluid resuscitation on the management of
     on these problems. Nevertheless complete          blunt brain injury is being reviewed; should
     salvage of these casualties would only have a     this not also be extended to penetrating brain
     modest impact on combat casualty care as          injury?
     sepsis and/or organ failure currently cause          Logistical considerations determine the
     only two to three percent of total combat         delay in evacuation of an injured soldier to
     mortality (24).                                   medical care. Ideally the gold standard of less
                                                       than one hour should apply, as in civilian
     Summary                                           practice, but this is rarely possible. In
     The foregoing suggests that there is merit in     Vietnam, evacuation delays of a little as one
     research into protection of the head from         hour were possible and TBI casualties were
     high available energy projectiles, and in some    often transferred directly to a neurosurgical
     aspects of the management of penetrating          centre. Hammon states that this rapid
     brain injury.                                     evacuation helped save countless lives and
W Sapsford                                                                                                          13


             preserved function, although it also increased    haemorrhage management on penetrating
             the number of near-terminal patients who          brain injury, similar to those currently in use
             died within minutes (5).                          to investigate the effect of controlled and
                Pre-treatments have been studied in            uncontrolled haemorrhage on traumatic
             primary blast injury, some of which show the      brain injury.
             potential to reduce the potentially harmful
             effects of the physiological responses, though    References
             no fully satisfactory pre-treatment has been      1. Carey ME. Political interference with research?
             identified yet. Similar patterns of response          JAMA. 1991; 266: 3285-3286 (Letter in reply).
                                                               2. Small JM, Turner EA. A surgical experience of
             occur in PBI. In the case of PBI the                  1200 cases of penetrating brain wounds in battle,
             physiological response is likely to be caused         NW Europe, 1944-1945. Br J Surg. 1947; War
             by stress waves influencing medullary areas           Surgery Supplement I: 62-74.
             important in cardiorespiratory control. In        3. Meirowsky AM. Penetrating wounds of the brain.
             the case of thoracic blast injury the response        In: Coates JB Jr, Meirowsky AM. (eds). Neurological
                                                                   Surgery of Trauma. Washington DC: Office of the
             is reflex, with a vagal afferent pathway,             Surgeon General. 1965; pp 103-130.
             although a contribution from a stress wave in     4. Matson DD. In: The treatment of acute craniocerebral
             the medulla cannot be excluded. However,              injuries due to missiles. Springfield IL: Charles C
             since both responses to PBI and primary               Thomas; 1948.
             blast injury (to the thorax) involve the same     5. Hammon WM, Kempe LG. Analysis of 2187
                                                                   consecutive penetrating wounds of the brain from
             efferent pathways there is scope for                  Vietnam. J Neurosurg. 1971; 34: 127-131.
             interaction between these responses. Thus a       6. Brandvold B, Levi L, Feinsod M, George ED.
             model of primary blast injury to the brain            Penetrating craniocerebral injuries in the Israeli
             may be useful in modelling PBI and pre-               involvement in the Lebanese conflict, 1982-1985:
             treatments may be equally effective in both           analysis of a less aggressive surgical approach. J
                                                                   Neurosurg. 1990; 72: 15-21.
             situations. Experimental models of primary
                                                               7. Levi L, Borovich B, Guilburd JN, et al. Wartime
             blast injury already exist and a model of PBI         neurosurgical experience in Lebanon, 1982-85, I:
             should be developed to compare and                    penetrating craniocerebral injuries. Isr J Med Sci.
             contrast the physiological responses,                 1990; 26: 548-554.
             especially the apnoea, and relate the dose-       8. Aarabi B. Surgical outcome in 435 patients who
                                                                   sustained missile head wounds during the Iran-Iraq
             response of PBI and primary blast injury to
                                                                   war. Neurosurgery. 1990; 27: 692-695.
             brain stem damage. This may demonstrate           9. Byrnes DP, Crockard HA, Gordon DS, Gleadhill
             some common pathways and/or interactions              CA. Penetrating craniocerebral missile injuries in
             between PBI and primary blast injury.                 the civil disturbances in Northern Ireland. Br J
             Control of apnoea is probably the principal           Surg. 1974; 61: 169-176.
             intervention that can make a difference in        10. Clark CW, Muhlbauer MS, Watridge CB, et al.
                                                                   Analysis of 76 civilian craniocerebral gunshot
             reducing the mortality from PBI.                      wounds. J Neurosurg. 1986; 65: 9-14.
                                                               11. Grahm TW, Williams FC Jr, Harrington T, Spetzler
             Conclusions                                           RF. Civilian gunshot wounds to the head: a
             In the opinion of this author PBI does merit          prospective study. Neurosurgery. 1990; 27: 696-700.
                                                               12. Hernesniemi J. Penetrating craniocerebral gunshot
             more research. There are three particular             wounds in civilians. Acta Neurochir (Wien). 1979;
             areas where research in this area may benefit         49: 199-205.
             a PBI casualty. Research into concepts for        13. Jacobs DG, Brandt CP, Piotrowski JJ, McHenry
             further attenuating the impact of high-               CR. Transcranial gunshot wounds: cost and
             energy military rifle bullets to the helmet to        consequences. Am Surg. 1995; 61: 647-654.
                                                               14. Kaufman HH, Levi ML, Stone JL, et al. Patients
             produce only low available energy wounds to           with Glasgow Coma Scale scores 3,4,5 after
             the head may reduce the number of soldiers            gunshot wounds to the brain. Neurosurg Clin North
             who are killed in action from PBI. This               Am. 1995; 6: 701-714.
             strategy would recognise that stopping a          15. Kennedy F, Gonzales P, Dang C, Flemming A,
             high available energy rifle bullet is not             Sterling-Scott R. The Glasgow Coma Scale and
                                                                   prognosis in gunshot wounds to the brain. J
             possible with lightweight helmet designs and          Trauma. 1993; 35: 75-77.
             that low available energy transfer wounds         16. Shaffrey ME, Polin RS, Phillips CD, et al.
             have a higher incidence of survival than              Classification of civilian craniocerebral gunshot
             those with high available energy transfer.            wounds: a multivariate analysis predictive of
               Research into a model of PBI could also             mortality. J Neurotrauma. 1992; 9(suppl 1): S279-
                                                                   S285.
             be utilised to investigate the similarities and   17. Suddaby L,Weir B, Forsyth C.The management of
             differences between the physiological and             .22 calibre gunshot wounds of the brain: a review of
             pathological responses to PBI and thoracic            49 cases. Can J Neurol Sci. 1987; 14: 268-272.
             blast injury, in particular the apnoea seen       18. Sauaia A, Moore FA, Moore EE, et al.
             following both injuries. Such a model may             Epidemiology of trauma deaths: a reassessment. J
                                                                   Trauma. 1995; 38: 185-193.
             facilitate the development of strategies          19. Jagger J, Dietz PE. Death and injury by firearms:
             and/or pre-treatments to attenuate the                who cares? JAMA. 1986; 255: 3143-3144 (Letter).
             deleterious effects of the pathophysiological     20. Carey ME, Sarna GS, Farrell JB, Happel LT.
             responses to these injuries and especially to         Experimental missile wound to the brain. J
             abolish or reduce the apneic period.                  Neurosurg. 1989; 71: 754-764.
                                                               21. Siccardi D, Cavaliere R, Pau A, et al. Penetrating
               Finally, a model of penetrating brain
                                                                   craniocerebral missile injuries in civilians: a
             injury should be developed to study the               retrospective analysis of 314 cases. Surg Neurol.
             effects of the recent developments in                 1991; 35: 455-460.
14                                                                                              Penetrating Brain Injury


     22. Nagib MG, Rockswold GL, Sherman RS, et al.            37. Stern SA, Dronen SC, Birrer P, et al. Effect of blood
         Civilian gunshot wounds to the brain: prognosis           pressure on haemorrhage volume and survival in a
         and management. Neurosurgery. 1986; 18: 533-537.          near-fatal haemorrhage model incorporating a
     23. Aldrich EF, Eisenberg HM, Saydjari C, et al.              vascular injury. Ann Emerg Med. 1993; 22: 155-163.
         Predictors of mortality in severely head-injured      38. Stern SA, Dronen SC, Wang X. Multiple
         patients with civilian gunshot wounds: a report           resuscitation regimens in a near-fatal porcine aortic
         from the NIH traumatic coma data bank. Surg               injury haemorrhage model. Acad Emerg Med. 1995;
         Neurol. 1992; 38: 418-423.                                2: 89-97.
     24. Bellamy RF. The causes of death in conventional       39. Stern SA, Zink, BJ, Mertz M, et al. Effect of initially
         land warfare: implications for combat casualty            limited resuscitation in a combined model of fluid-
         research. Mil Med. 1984; 149: 55-62.                      percussion brain injury and severe uncontrolled
     25. Arnold K, Cutting RT. Causes of death in United           haemorrhagic shock. J Neurosurg. 2000; 93: 305-
         States military personnel hospitalised in Vietnam.        314.
         Mil Med. 1978; 143: 161-164.                          40. Walsh JC, Zhuang J, Shackford SR. A comparison of
     26. Carey ME. Learning from traditional combat                hypertonic to isotonic fluid in the resuscitation of
         mortality and morbidity data used in the                  brain injury and haemorrhagic shock. J Surg Res.
         evaluation of combat care. Mil Med. 1987; 152: 6-         1991; 50: 284-292.
         13.                                                   41. Shackford SR. Effect of small-volume resuscitation
     27. Salazar AM, Schwab K, Grafman JH. Penetrating             on intracranial pressure and related cerebral
         injuries     in    Vietnam     War.     Traumatic         variables. J Trauma. 1997; 42(suppl 5): S48-S53.
         unconsciousness, epilepsy and psychosocial            42. Berger S, Schurer L, Hartl R, et al. Reduction of
         outcome. Neurosurg Clin N Am. 1995; 6: 715-726.           post-traumatic intracranial hypertension by
     28. Carey ME, Joseph AS, Morris WJ, et al. Brain              hypertonic/hyperoncotic        saline/dextran      and
         wounds and their treatment in VII corps during            hypertonic mannitol. Neurosurgery. 1995; 37: 98-
         operation Desert Storm, February 20 to April 15,          107.
                                                               43. Berger S, Schurer L, Hartl R, et al. 7.2% NaCl/10%
         1991. Mil Med. 1998; 163: 581-586.
                                                                   dextran 60 versus 20% mannitol for treatment of
     29. Prehospital Trauma Life Support Committee of
                                                                   intracranial hypertension. Acta Neurochir Suppl.
         the National Association of Accident and
                                                                   1994; 60: 494-498.
         Emergency Technicians in Cooperation with the
                                                               44. Hartl R, Medary MB, Ruge M, et al.
         Committee on Trauma of the American College of
                                                                   Hypertonic/hyperoncotic saline attenuates micro-
         Surgeons. PHTLS Basic and Advanced
                                                                   circulatory disturbances after traumatic brain injury.
         Prehospital Trauma Life Support. 4th Ed. St
                                                                   J Trauma. 1997; 42(suppl 5): S41-S47.
         Louis, Missouri. Mosby. 1999.
                                                               45. Leedhan CS, Newland C, Blood CG. A descriptive
     30. Committee on Trauma of the American College of            analysis of wounds among U.S. Marines treated at
         Surgeons. Advanced Trauma Life Support for                second-echelon facilities in the Kuwaiti theatre of
         Doctors – Course Manual. 7th Ed. Chicago                  operations. Mil Med. 1993; 158: 508-512.
         Illinois. American College of Surgeons. 1997.         46. Horsley V. The destructive effects of projectiles. Proc
     31. Army Medical Directorate [Resources and Plans].           R Institution. 1894; 14: 228-238.
         Battlefield Advanced Trauma Life Support. 2nd         47. Crockard HA, Brown FD, Johns LM, Mullan S. An
         Ed. 2000.                                                 experimental cerebral missile injury model in
     32. Chesnut RM, Marshall LF, Klauber MR, et al.The            primates. J Neurosurg. 1977; 46: 776-783.
         role of secondary brain injury in determining         48. Crockard HA, Brown FD, Calica AB, et al.
         outcome from severe head injury. J Trauma. 1993;          Physiological consequences of experimental
         34: 216-222.                                              cerebral missile injury and the use of data analysis to
     33. Joint Section on Trauma and Critical Care of the          predict survival. J Neurosurg. 1977; 46: 784-794.
         American Association of Neurological Surgeons         49. Levett JM, Johns LM, Replogle RL, Mullan S.
         and the Brain Trauma Foundation: Guidelines for           Cardiovascular effects of experimental cerebral
         the management of severe head injury. Park Ridge,         missile injury in primates. Surg Neurol. 1980; 13:
         IL: American Association of Neurological                  59-64.
         Surgeons, 1995.                                       50. Guy RJ, Kirkman E, Watkins PE, Cooper GJ.
     34. Bickell WH, Bruttig SP, Millnamow GA, et al. The          Physiologic responses to primary blast. J Trauma.
         detrimental effect of intravenous crystalloid after       1998; 45: 983-987.
         aortotomy in swine. Surgery. 1991; 110: 529-536.      51. Ohnishi M, Kirkman E, Guy RJ,Watkins PE. Reflex
     35. Bickell WH, Wall MJ, Pepe PE, et al. Immediate            nature of the cardiorespiratory response to primary
         versus delayed fluid resuscitation for hypotensive        thoracic blast injury in the anaesthetised rat.
         patients with penetrating torso injuries. N Eng J         Experimental Physiology. 2001; 86: 357-364.
         Med. 1994; 331: 1105-1109.                            52. Sarphie TG, Carey ME, Davidson JF, Soblosky JS.
     36. Gross D, Landau EH, Klin B, et al. Quantitative           Scanning electron microscopy of the floor of the
         measurement of bleeding following hypertonic              fourth ventricle in rats subjected to graded impact
         saline therapy in “uncontrolled” haemorrhagic             injury to the sensorimotor cortex. J Neurosurg.
         shock. J Trauma. 1989; 29: 79-83.                         1999; 90: 734-742.