Vol. 20, No.
8 August 1998 V Neurology
CE Refereed Peer Review
FOCAL POINT
★Susceptibility to secondary
brain injuries is enhanced by
alterations in neuronal energy
metabolism and excitatory
neurotransmitter handling as
well as by deranged cerebro-
vascular reactivity and local
cerebrovascular inflammation.
KEY FACTS
■ In a head-injured patient,
regional or global loss of normal
pressure autoregulation increases
susceptibility to alterations in
blood pressure and cerebral
perfusion.
■ After initial head injury, regional
cerebral inflammatory processes
can potentiate loss of pressure
and metabolic autoregulation
and instigate microvascular leak,
which potentiates energy failure,
cell death, and cerebral edema.
■ Episodes of hypotension and
hypoxemia during the postinjury
period are positively correlated
with poor neurologic outcome.
■ Hypoglycemia and hyperglycemia
are reportedly detrimental in
patients with traumatic brain
injury.
Severe Brain
Injury. Part I.
Pathophysiology
Tufts University
Jeffrey Proulx, DVM
Nishi Dhupa, BVM, MRCVS
I n veterinary patients, severe head injury can result from trauma induced by
motor vehicles, falls, or accidental or malicious attacks from humans or
other animals.1,2 Head injuries can produce primary and secondary brain
injury.3 Primary injury includes damage to intracranial structures at the time
of initial impact. This can involve intracranial hemorrhage leading to mass
compression (epidural, subdural, subarachnoid, or parenchymal contusion),
direct neuronal–axonal damage, and cerebral lacerations caused by skull frac-
tures. Veterinarians have no control over these injuries; they must be dealt with
in clinical practice. It is now evident that, in addition to primary brain injury,
severe disturbances in the regulation of cerebral blood flow and energy
metabolism will predispose cerebral tissue to ongoing injury, which can be
exacerbated by derangements in arterial blood pressure and oxygen delivery.
These phenomena are secondary brain injuries.3
Part I of this two-part presentation provides an understanding of the patho-
physiology of secondary brain injury. The second part will review current rec-
ommendations for treatment of head injury in light of these processes. As a
result, empiric therapy of head-injured veterinary patients can be tailored to
methods that protect the brain; treatments that are proven to produce negative
outcomes can be discontinued. Until large-scale prospective studies of severe
head injury are performed in veterinary medicine, treatment will be based on
the available clinical evidence in humans and laboratory animals. This article
provides a physiologic basis for adapting general supportive care for head-
injured patients to brain-specific and cerebral-protective supportive care.
Secondary brain injuries, which occur in addition to the damage inflicted by
an initial traumatic event, may happen within minutes of primary injury or
days later. They may occur in already severely damaged neuronal tissue or in
relatively normal neuronal tissue that is unaffected by the primary brain
insult.3,4 Secondary brain injury results from systemic extracranial events and
intracranial changes. Extracranial events are usually limited to episodes of
hypotension and hypoxemia; intracranial changes include increased sensitivity
Small Animal The Compendium August 1998

of cerebrovascular and extracellular fluid or in-

neuronal tissue, eleva- ternal stores. 9,11,12 This
tions in intracranial pres- rise in cytosolic Ca 2+
sure (ICP), and altered results in various alter-
cerebrovascular reactivity. ations, including changes
in enzyme function and
INTRACRANIAL activation of secondary
CAUSES messenger systems.5,11,13
Excitotoxicity and Normally, extracellular
Neuronal Sensitivity glutamate concentration
After traumatic brain is extremely low (0.6
injury, neuronal and sup- µmol/L; intracellular
porting tissue is parti- compartmentalized stores
cularly susceptible to are 10 mmol/L), which
secondary injury. This allows organized, con-
occurs not only in con- trolled neurotransmission
tused areas but also in stimuli.14 An extracellular
Figure 1—Elevated extracellular glutamate leads to unregulated acti-
neuronal tissue adjacent vation of glutamate-receptor–gated channels (excitotoxicity) and glutamate concentration
to contusions (the pen- massive membrane depolarization. Influx of calcium (Ca2+) and of 2 to 5 mmol/L causes
umbra), ischemic loca- sodium (Na+) secondarily causes further intracellular rises in Ca2+ by massive neuronal excita-
tions, and areas of compart- activating voltage-gated Ca2+ channels and second messenger sys- tion. 15 Typically, gluta-
mentalized hemorrhage tems responsible for the release of Ca2+ from intracellular organelles. mate is efficiently cleared
(e.g., epidural and sub- The lethal effects of elevated intracellular Ca2+ are manifested by ac- from the extracellular
dural hemorrhages). 3–5 tivation of enzymes that cause cell-membrane destruction and pro- space by high-affinity
The initial primary insult tein degradation. Activation of phospholipase A2 (PLA2) leads to and energy-dependent
triggers a cascade of in- further damage by releasing inflammatory mediators and oxygen2+ uptake transporters in
terrelated events that free radicals. The mechanisms for clearance of glutamate and Ca neuronal cells and astro-
compound the primary are inefficient because of energy failure (ATP = adenosine triphos- cytes.16 With head injury,
phate; ER = endoplasmic reticulum; K + = potassium; LT =
injury. leukotriene; PAF = platelet-activating factor; PG = prostaglandin;
however, there is uncon-
In head injury, initial PKC = protein kinase C). trolled glutamate release
impact causes massive from intracellular stores.
depolarization and ion The tremendous eleva-
fluxes in neurons and supporting tissue (astrocytes and tion in extracellular glutamate coupled with energy de-
glial cells).5,6 In an effort to reestablish normal electro- pletion causes the highly energy-dependent uptake sys-
chemical gradients, energy is expended in the form of tem to fail; glutamate clearance may be substantially
adenosine triphosphate (ATP). The sodium–potassi- compromised.5
um–ATPase pump is the main regulator of cell volume There are three types of receptors for glutamate on
as well as the primary pump that establishes the basic the neuronal cell surface: N-methyl-D-aspartate
electrochemical gradients of most other transport pro- (NMDA), α -amino-3-hydroxy-5-methyl-4-isoxa-
cesses. 7,8 This fact underscores the requirement for zolepropionate (AMPA), and kainate. They are named
sufficient ATP levels. Trauma-associated systemic according to specific synthetic compounds but only
hypotension or hypoxemia and local disruption of cere- bind glutamate in vivo.11 The NMDA receptor–gated
bral blood flow further promote ATP depletion because channel facilitates influx of sodium and Ca 2+. The
of reduced substrate delivery. Neuronal tissue is ex- AMPA receptor–gated and kainate-gated channels facil-
tremely susceptible and sensitive to ischemic injury, itate influx of sodium or Ca2+, depending on their loca-
which sets the stage for secondary cerebral injury. tion in the brain.11 With the influx of large quantities
Glutamate is among the most important neurotrans- of these positively charged ions, cell membrane de-
mitters in the brain9 and is implicated in cell damage polarization occurs and secondarily activated voltage-
that can occur minutes or days after initial injury.10 In gated Ca2+ ion channels allow further influx of Ca2+
normal cerebral tissue, glutamate is important in many into the intracellular compartment.11,12 In addition,
neural functions on a cellular level. In general, it is an Ca2+ is released from intracellular stores as a result of
excitatory neurotransmitter that directly or indirectly activation of second messenger pathways.17
2+
causes an influx of calcium (Ca ) into the cytosol from Uncontrolled, increased intracellular free Ca2+ ion

GLUTAMATE ■ ENERGY DEPLETION ■ CELL MEMBRANE DEPOLARIZATION

The Compendium August 1998 Small Animal

concentration produces from approximately 50 to

multiple cytotoxic effects13 150 mm Hg. 20 In severe
(Figure 1). High free in- head injury, if vascular re-
tracellular Ca2+ leads to un- activity is lost regionally or
coupling of oxidative phos- globally, cerebral blood flow
phorylation, making energy depends on CPP alone.19,20
production highly ineffi- Although this pressure may
cient and further depleting be normal, blood flow may
ATP stores. Several enzyme be marginal relative to the
systems are activated, in- needs of a particular vascular
cluding protein kinase C, bed when pressure autoregu-
phospholipases, proteases, lation is lost (Figure 2).
endonucleases, and nitric Metabolic autoregulation
oxide synthase. Phospholi- of cerebral blood flow in-
pase A2 activation initiates Figure 2—Normal pressure autoregulation of blood flow (solid volves two processes. As in
the arachidonic acid cas- line) maintains appropriate cerebral blood flow despite fluctu- any other vascular bed, the
cade, resulting in the pro- ations in mean arterial pressure. With impaired pressure auto- degree of cerebral cellular
duction of platelet-acti- regulation, cerebral blood flow (broken line) becomes directly metabolic activity will affect
vating factor and reactive proportional to mean arterial pressure. Despite normal mean the local pH and adenosine
arterial blood pressure (e.g., 75 mm Hg), blood flow may be
oxygen species. inadequate if pressure autoregulation is absent.
concentration. These are
Uncontrolled activation theorized to affect local
of these enzyme systems and blood flow by influencing
production of oxygen free radicals can result in irre- vascular tone (metabolic coupling).7,8 With increased
versible cell injury or death through degradation of metabolic activity, pH and adenosine concentration
DNA, RNA, enzymes, structural proteins, and mem- fall; local vasodilation occurs to provide greater oxygen
brane phospholipids. Uncontrolled rises in free intracel- and nutrient delivery to support the vascular bed. Vaso-
lular Ca2+ are lethal to neuronal tissue; this condition constriction results from decreased metabolic activity.
may be compounded by systemic hypoxemia or hy- By a different mechanism, arterial CO2 partial pres-
potension and localized areas of disrupted cerebral sure (PCO2) controls global blood flow.7,8,21 In fact, PCO2
blood flow. 3,4 In addition to the process of cellular is the main determinant of global cerebral blood flow.
necrosis, there is evidence that programmed cell death Increased PCO2 causes a global increase in cerebral blood
(apoptosis) may be a component of cell death after flow that exceeds demand (and consequently increases
traumatic brain injury.18 ICP); decreased PCO2 decreases cerebral blood flow to
levels that may be below tissue demand. In head trauma,
Vascular Sensitivity there is regional variability in response to PCO2.22–24 Some
Cerebral vasculature in a normal brain is regulated by localized vascular beds may be hyperresponsive to de-
several mechanisms (e.g., metabolic autoregulation, creases in PCO2. This has important ramifications in the
pressure autoregulation, and oxygen availability) that use of hyperventilation in controlling intracranial hyper-
depend on normally functioning vasculature and nor- tension.
mal ICP.7,8,19 Normal cerebral perfusion pressure (CPP) Loss of vasoreactivity probably stems from intrinsic
is defined as mean arterial pressure (MAP) minus cere- problems in the endothelium and vascular smooth
bral venous pressure.7,8 In head injury associated with muscle tissue. The production of nitric oxide and en-
increased ICP, the ICP limits blood flow and is deter- dothelin by endothelial cells causes localized vasodila-
mined by the following equation19: tion and constriction, respectively.25,26 In normal tissue,
the level of blood flow is finely regulated by these
CPP (mm Hg) = MAP (mm Hg) – ICP (mm Hg) mechanisms to match appropriate flow to tissue need
of substrate and oxygen. Derangements in the balance
Pressure autoregulation of blood flow is a mechanism of nitric oxide and endothelin lead to inappropriate
that works throughout the body to guard against changes vascular responses, which potentiate regional and global
in blood flow despite fluctuations in systemic arterial cerebral ischemia and secondary brain injury.27 In addi-
7,8
blood pressure. The normal cerebrovascular bed has tion, localized hemorrhage and tissue damage resulting
a constant metabolic rate and maintains a consistent from primary injury produce a local inflammatory re-
blood flow with mean systemic arterial pressures ranging sponse that leads to neutrophil activation and adhesion

DEPLETION OF ATP STORES ■ PROGRAMMED CELL DEATH ■ LOCAL VASODILATION

Small Animal The Compendium August 1998

to endothelial cells.28–30 This humans.34 The development

disrupts endothelial func- of continuous pulse oxim-
tion by causing oxidative etry, electrocardiographic
damage, inciting microvas- monitoring, and blood pres-
cular leak, and interfering sure monitoring (with alarm
with natural anticoagulant systems functional at preset
factors. Exacerbation of in- physiologic parameters) has
terstitial edema, lack of nor- allowed instant detection
mal vascular responsiveness, and intervention in episodes
and local intravascular co- of hypotension and hypox-
agulation occur and further emia.
the effects of secondary in- Extracranial causes of hy-
sults.5,27 poxemia and hypotension
The last major regulator Figure 3—The normal microvasculature includes a continu- include cardiovascular, hema-
of cerebral blood flow is the ous endothelial cell layer that consists of the blood–brain bar- tologic, and pulmonary dys-
cerebral ischemic response. rier, normal vascular reactivity (allowing appropriate blood function. For example, car-
This global response to is- flow in relation to demand), and natural anticoagulant sys- diac arrhythmia, preexisting
chemia depends on an in- tems for preventing intravascular coagulation. The natural heart disease, hypovolemia,
tact vasomotor center and is anticoagulant properties of endothelial cells involve anti- anemia, pulmonary contu-
a relatively late or final at- thrombin III (ATIII), thrombomodulin (TM), the tissue fac- sion, pleural space disease
tempt to restore adequate tor inhibitor pathway (TFIP), and prostaglandin I2 (PGI2). (pneumothorax or hemo-
.) mediates vascular smooth muscle relax-
7,8
perfusion to the brain. In- Nitric oxide (NO thorax), hypooncotic states,
ation in response to vasodilatory stimuli (PMN = polymor-
creases in ICP cause a de- and abnormal blood CO 2
phonuclear leukocyte; RBC = red blood cell).
crease in cerebral perfusion. tension can directly or indi-
The consequently increased rectly compromise oxygena-
CO2 is detected by the vasomotor center; a direct sym- tion and blood flow to cerebrovascular beds. Regardless
pathetic response occurs and leads to an elevated heart of the mechanism, the major determinant of secondary
rate and intense systemic extracranial vasoconstriction, brain insult is deficient oxygen delivery.3,32,33
all to support cerebral perfusion. A patient without brain injury may tolerate a margi-
If systemic arterial blood pressure is severely elevated nal decrease in oxygen delivery, but a patient with se-
in response to increased ICP, heart rate may actually vere head injury and increased neuronal and cere-
slow by the baroreceptor reflex (Cushing’s response). brovascular sensitivity cannot tolerate the same level of
Such systemic signs in a head-injured patient usually deficient oxygen delivery. Secondary brain insults can
suggest extreme ICP increases limiting cerebral blood easily occur.
flow. Because treatment directed at systemic hyperten-
sion will compromise cerebral blood flow by further de- Other Causes
creasing CPP, primary treatment must involve measures Extracranial causes of secondary brain injury are not
to reduce intracranial hypertension.31 If there is vaso- limited to decreases in oxygen delivery. Hypoglycemia
motor center damage, sympathetic response capabilities and hyperglycemia are reportedly detrimental to pa-
may be lost; therefore, the lack of the ischemic response tients with traumatic brain injury.35,36 Glucose is the
does not rule out extreme intracranial hypertension. primary respiratory fuel for neuronal tissue in non-
ketotic states, and even brief periods of hypoglycemia
EXTRACRANIAL CAUSES can limit energy substrate for the production of ATP.35
Decreased Oxygen Delivery Deranged neuronal energy metabolism combined with
The common factors that incite secondary brain in- hypoglycemia represents an insult that may not be tole-
jury are systemic hypotension and hypoxemia, or de- rated by a neuron.
creased oxygen and nutrient delivery to already dam- Hyperglycemia reportedly furthers neuronal cell
aged neuronal tissue.32,33 In human medicine, episodes damage by providing substrate to cells with impaired
of hypotension and hypoxemia are significantly and mitochondrial function and oxidative phosphory-
definitively correlated with a poor neurologic out- lation.35–38 Anaerobic glycolysis creates cellular acidosis,
32,33
come. Vigilant, continuous monitoring and inter- which further contributes to cellular and local tissue
vention in response to hypoxemia and hypotension damage. It is not known whether this occurs only in
have improved outcome after traumatic brain injury in hypoxic tissue or in well-oxygenated tissue with ineffi-

CEREBRAL ISCHEMIC RESPONSE ■ DECREASED OXYGEN DELIVERY ■ HYPOGLYCEMIA

Small Animal The Compendium August 1998

cient mitochondrial func- nitric oxide and endothelin

tion. A potential drawback production.5,27
of corticosteroid use in pa- This diffuse inflammato-
tients with head injury is ry cascade synergizes with
the antiinsulinemic, gly- abnormalities in neuronal
colytic, gluconeogenic, and and cerebromicrovascular
therefore hyperglycemic ef- tissue to culminate in fur-
fect.39 ther damage and local blood
In addition to glucose flow abnormalities. Micro-
concentration abnormali- vascular leak and disruption
ties, other systemic elec- of the blood–brain barrier
trolyte and acid–base dis- will result in interstitial ede-
turbances probably affect ma and increased ICP.
secondary brain injuries in Figure 4—The systemic or local release of inflammatory me-
sensitive neuronal and cere- diators (tumor necrosis factor [TNF], platelet-activating fac- CONCLUSION
brovascular tissue by un- tor [PAF], interleukin-1[IL1], and interleukin-6 [IL6]) leads The occurrence of sec-
known mechanisms. It may to the expression of selectin and integrin on endothelial and ondary brain injury has im-
be advisable to normalize polymorphonuclear leukocytes, respectively. This leads to portant consequences in
physiologic parameters to activation of neutrophils and adhesion to the endothelium. brain-injured patients. Un-
limit secondary brain in- The release of proteolytic enzymes and reactive oxygen (O2–) controlled glutamate release
jury. species causes endothelial damage, which leads to deranged and failure of energy sys-
Systemic immune re- microvascular reactivity and abnormal control of blood flow. tems in neuronal and sup-
sponses may also play a role Inflammatory mediators also affect endothelial contraction, porting tissues directly cause
exacerbating interstitial edema and diapedesis.
in secondary brain injury. cell death mediated by high
The systemic inflammatory intracellular Ca2+. Derange-
response syndrome can oc- ments in normal cerebrovas-
cur in any severely trauma- cular reactivity caused by in-
tized patient. 40 The syn- flammation and endothelial
drome is characterized by damage instigate a mis-
the production and release match of oxygen delivery to
of such proinflammatory cy- tissue demand, which may
tokines as interleukin-1 and cause local or global is-
interleukin-6, tumor necro- chemia. These intracranial
sis factor–α, and platelet-ac- changes are compounded by
tivating factor, among many systemic alterations that are
others. Systemically circulat- common in trauma patients.
ing cytokines cause diffuse Hypoxemia, hypotension,
activation of endothelial and metabolic disturbances, and
immune-effector cells (e.g., Figure 5—The expression of endothelial tissue factor is in- systemic inflammatory con-
polymorphonuclear leu- duced by the production of inflammatory mediators (tumor ditions may lead to further
necrosis factor [TNF], platelet-activating factor [PAF], inter-
kocytes) and might lead to leukin-1[IL1], and interleukin-6 [IL6]). Microvascular intracranial damage as neu-
whole-body microvascular thrombosis occurs secondary to the activation of factor VII ronal cells and cerebrovascu-
derangements27 (Figures 3, by tissue factor and the resultant activation of the extrinsic lar tissue are rendered espe-
4, and 5). These include al- pathway of the coagulation cascade. cially sensitive to marginal
tered endothelial anticoagu- blood flow.
lant systems predisposing to An understanding of the
disseminated intravascular coagulation41; endothelial pathophysiologic events that occur in patients with
cell contraction with resultant fluid extravasation to head injury should help the clinician to comprehend
the interstitium42; expression of leukocyte-adhesion the ramifications of the various forms of therapy used
molecules on endothelial cells, with consequent neu- in these patients. The second part of this article will
trophil adhesion and activation and local tissue damage consider treatment of secondary brain injuries by
caused by reactive oxygen species and proteolytic en- means of fluid therapy, oxygen, corticosteroids, and
zymes27; and disruption of vasomotor control by altered hyperventilation.

SYSTEMIC IMMUNE RESPONSES ■ VASOMOTOR CONTROL DISRUPTION ■ HYPOXEMIA

Small Animal
About the Authors
Drs. Proulx and Dhupa are affiliated with the Department
of Clinical Sciences, School of Veterinary Medicine, Tufts
University, North Grafton, Massachusetts. Dr. Dhupa is a
Diplomate of the American College of Veterinary Internal
Medicine and the American College of Veterinary Emer-
gency and Critical Care.
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