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Nervous System
(see Fig. 37-1). The gray matter of the cerebral cortex
receives its major blood supply through short pene-
trating arteries that emerge at right angles from larger
vessels and then form a cascade as they repeatedly
branch, forming a rich capillary network. An abrupt
loss of arterial blood pressure markedly diminishes
flow through these capillary channels.
Global ischemia occurs when blood flow is inad-
equate to meet the metabolic needs of the entire brain.
3
The result is a spectrum of neurologic disorders reflect-
ing diffuse brain dysfunction. Unconsciousness occurs
within seconds of severe global ischemia, such as that
resulting from cardiac arrest. If the cerebral circula-
tion is restored immediately, consciousness is regained
quickly. The unique vulnerability of the brain is attrib-
uted to its limited tolerance of ischemia and its response
to reperfusion. The metabolic depletion of energy
associated with ischemia can result in an inappropri-
ate release of excitatory amino acid neurotransmitters,
disrupted calcium homeostasis, free radical formation,
mitochondrial injury, and activation of cell-death path-
ways.
1,4
Although the threshold for ischemic neuro-
nal injury is unknown, there is a period during which
neurons can survive if blood flow is reestablished.
Unfortunately, brain injury may be irreversible if the
duration of ischemia is such that the threshold of injury
has been reached.
Excitatory Amino Acid Injury
In many neurologic disorders, injury to neurons may
be caused by inappropriate release of excitatory amino
acid neurotransmitters such as glutamate.
1,3,5,6
The
neurologic conditions involved in excitotoxic injury
range from acute events such as stroke, hypoglycemic
injury, and trauma to chronic degenerative disorders
such as Huntington disease and possibly Alzheimer
dementia.
During prolonged ischemia, metabolic depletion of
adenosine triphosphate (ATP) results in the inappropri-
ate release of glutamate. This initiates cell damage by
allowing excessive influx of calcium ions (Ca
++
) through
glutamate–
N
-methyl-
d
-aspartate (NMDA) glutamate
channels. Excess intracellular Ca
++
leads to a series of
calcium-mediated processes called the
calcium cascade
(Fig. 37-2), which results in the release of intracellular
enzymes that cause protein breakdown, free radical
formation, lipid peroxidation, deoxyribonucleic acid
(DNA) fragmentation, mitochondrial injury, nuclear
breakdown, and eventually cell death.
The effects of acute glutamate toxicity may be
reversible if the excess glutamate can be removed or if
its effects can be blocked before the full cascade pro-
gresses. Various strategies that would protect viable
brain cells from irreversible damage in the setting
of excitotoxicity are currently under investigation.
Pharmacologic strategies being explored include those
that inhibit the synthesis or release of excitatory trans-
mitters; block the NMDA receptors; prevent initiation
of the calcium cascade; or block release of intracellular
enzymes.
Cerebral Edema
Cerebral edema, or brain swelling, is an increase in tis-
sue volume secondary to abnormal fluid accumulation.
There are two types of brain edema: vasogenic and
cytotoxic.
1,7
Vasogenic edema
occurs with conditions that impair
the function of the blood–brain barrier and allow trans-
fer of water and proteins from the vascular into the
interstitial space. It occurs in conditions such as hemor-
rhage, brain injury, and infectious processes (e.g., men-
ingitis). Vasogenic edema occurs primarily in the white
matter of the brain, possibly because the white matter is
more compliant than the gray matter. Vasogenic edema
can result in displacement of a cerebral hemisphere and
various types of brain herniation. The functional mani-
festations of vasogenic edema include focal neurologic
deficits, disturbances in consciousness, and severe intra-
cranial hypertension.
Cytotoxic edema
involves an increase in intracellular
fluid. It can result from hypoosmotic states such as water
intoxication or severe ischemia that impair the function
of the sodium–potassium membrane pump. Ischemia
also results in the inadequate removal of anaerobic meta-
bolic end products such as lactic acid, producing extra-
cellular acidosis. If blood flow is reduced to low levels
for extended periods or to extremely low levels for a few
minutes, cellular edema can cause the cell membrane to
Ca
2+
Glutamate
NMDA
receptor
Increase in intracellular calcium
Calcium cascade
Brain cell injury and death
• Release of intracellular enzymes
• Protein breakdown
• Free radical formation
• Lipid peroxidation
• Fragmentation of DNA
• Nuclear breakdown
FIGURE 37-2.
The role of the glutamate–N-methyl-
d
-aspartate
(NMDA) receptor in brain cell injury. DNA, deoxyribonucleic acid.
