edema is a clinical problem seen in trauma, tumors, ischaemia, infections
and other inflammatory problems. The term edema was first used to describe
the wet and soft appearance of cut brain at autopsy. The tough and dry
appearance was called brain swelling. The fluid can accumulate either
inside the cells or extracellularly.
of brain edema:
type is due to BBB (blood brain barrier) changes and increased cell
permeability. It is seen in trauma, tumors, inflammation and late
ischemia. The extracellular space is enlarged; later stages the cells
swell as well.
formation is not increased. Both the white and the grey matter are
(brain swelling) type is an intracellular swelling due to derangement of
pump in the glial membrane and cell metabolism resulting in Na+ and H2O
accumulation. This is seen in early ischaemia, and medical conditions such
as Reye’s syndrome, intoxication etc.
is not disturbed. The CSF formation is not increased. Both the white and
the grey matter are involved.
type is due to accumulation of excess water in the brain in response to an
unfavorable osmotic gradient as in water intoxication. The chemical
potential of the plasma increases and water enters the brain due abnormal
is intact. The CSF formation is increased. Both intra and extracellular
compartments are affected.
type is due to movement of protein-free transudate into the extracellular
space due to capillary dilatation as a result of elevated transcapillary
pressure. Acute arterial hypertension is the usual cause.
is intact and the CSF formation is not increased. The edema is confined to
the white matter.
Interstitial type is due to acute
elevation of CSF pressure, resulting in periventricular (extracellular)
seepage of water as in acute hydrocephalus.
confined to the white matter. The BBB is undisturbed and the CSF formation
differentiation among the above types is artifactual; one type will
eventually lead to another, and considerable overlapping occurs. However,
it helps for better understanding.
breakdown of the BBB
is a central prerequisite to the development of brain edema. Another basic
element associated with brain edema is energy depletion.
Hydrostatic and osmotic forces encourage the movement of fluid out of the
vascular compartment and into the parenchyma resulting in mass effect.
This compromises the CBF, and the CPP. The ICP increases.
abnormal diffusion of nutrients with consequent acidosis, hypoxia, and
brain injury initiate a response characterized by recruitment of
inflammatory cells and activation of endogenous substances also plays a
Histamine opens the BBB with dilatation of pial arterioles.
Bradykinin increases BBB permeability and enhances blood pressure in
Excitatory aminoacids (EAA), glutamate activates many enzyme
systems and Ca++
influx, which can result in acute cytotoxic lesions.
Arachidonic acid is released from brain tissue in response to neuronal
injury. It is the precursor of important highly vasoactive prostanoid and
leukotriene compounds. Its metabolism through cyclooxygenase pathway
generates free radicals. These radicals induce vasoconstriction of the
pial arterioles band venules without an effect on BBB permeability.
Superoxide radical, hydrogen peroxide, and hydroxyl radicals are
formed from activated neutrophils and metabolites of arachidonic acid.
They cause endothelial lesions with an increase in the ionic permeability.
The radical initiate lipid peroxidation of glial, neuronal, and
vascular cell membranes and myelin is catalyzed. If severe enough, it
causes impairment of phospholipid dependent enzymes and membrane lysis.
Free calcium is released from its
source by a variety of messenger systems. Glutamate opens the receptor
channels. Selective neuronal vulnerability in nonvascular brain lesions,
hypoglycemic coma, epileptic seizures, or following brief periods of
ischaemia is calcium related. Infarction is related to free radicals and
acidosis, and the vascular lesions in stroke are the result of
inflammatory reactions involving calcium, free radicals, and lipid
Intracellular accumulation of calcium is accompanied by a
loss of free intracellular Mg++,
which may directly relate to the extent of cellular damage, which
contributes to secondary injury. Mg++
is essential for membrane integrity, normal cell respiration, mRNA
transcription, protein synthesis, and also plays a role in glucose
utilization and energy metabolism.
acidosis due to lactic acid accumulation
and increased pCO2 can denature the proteins and alter the activities of
ph dependent enzymes. Lactate enhances brain edema.
edema alone will not produce symptoms until the
ICP reaches a
level that produces local ischemia with or without mass effect.
symptoms and signs are related to the lesion.
Edema appears as a low-density area caused by dilution of all
constituents of white matter by water. The decreased amount of
lipids, increased proteins and electrolytes leads to
underestimation of the amount of edema fluid based on the
Hounsfield number printout. There is no contrast uptake. Edema
is almost always visible in acute brain abscesses, but rarely in
acute intracerebral hemorrhage. Finger-like projections of
low-density areas are characteristic of a tuberculous abscess. The
edema associated with intracerebral hematoma is located in the
cortex and the underlying white matter whilst in acute subdural
CSF seepage in
the white and grey matter. Extensive edema suggests highly
It is very sensitive but not necessarily
specific method for
detecting lesions in cerebral white matter and thus brain edema;
this is particularly relevant in tumoral perifocal edema.
Prolongation of T2 can be a reflection of a pathological increase
in tissue water and/or demyelination processes.
perifocal edema is seen early on T2. 25% of single photon emission
computer tomography (SPECT) scans fail to show alterations in BBB
The treatment has three objectives:
projections in Tb.ab
edema-high grade glioma
evacuation of masses or CSF diversion provides an immediate decompression
of the intracranial space, helps to establish a favorable gradient between
swollen tissue and CSF cavities, and washes proinflammatory agents.
for contusions is controversial.
failure, acidosis, alterations in calcium, cytotoxic and later vasogenic
edema, free radical formation and excitotoxicity are the events that may
lead to irreversible damage in a cerebral insult.
protective measures aim at increasing the CBF (triple H therapy),
providing adequate blood substrates such as oxygen, and glucose, and
restoration of blood brain interface integrity.
a) CBF augmentation:
consists of augmentation of CBF by means of
blood volume expansion, hemodilution, and pharmacologically induced
Hypervolaemic hemodilution is the first step. The blood viscosity should
be maintained between 0.3 and 0.34 hematocrit. If the hematocrit falls
below 0.3, packed cells should be given. Preferred solutions (5% or 20%
albumin or fresh frozen plasma) are those that expand the intravascular
space with less extracellular distribution. It is given in 4-6 divided
doses/day, each administered over 30-60 minutes. Crystalloids remain in
the intravascular space for only 60-90 minutes.
hemodilution does not produce the desired result, cardiac output may be
enhanced with dobutamine before trying pharmacologically induced
hypertension, which is associated with dangerous side effects.
Pharmacologically induced hypertension may be instituted only after
optimal intravascular volume and cardiac output enhancement. The systolic
blood pressure may be elevated to160mm Hg in a previously normotensive
patient and 180 in previously hypertensive patients.
triple H therapy is withdrawn gradually starting with hypertension and
later the hypervolaemia once the desired result is achieved. Dopamine or
epinephrine is commonly used.
hyperperfusion state of this therapy should be monitored by the patient's
cardiac output through a pulmonary artery catheter. The CPP can best be
monitored with an ICP monitor and concomitant use of arterial pressure
monitor. Frequent laboratory analyses of the patient's hematocrit provide
information on the hemodilution component of therapy. Often, the patient
requires sedation and may also need endotracheal intubation and mechanical
is to keep the hematocrit between 0.3 and 0.34, hemoglobin to 10-12 gm/dl,
serum sodium at 135-145 mmol/l, serum osmolality at 290-300mOsm/l, and
pulmonary wedge pressure at 14-18mm Hg. The CPP is to be maintained over
therapy is an effective therapy for reversing the neurological
deficit, especially in vasospasm associated with SAH and aneurismal
surgery; it is potentially dangerous to other bodily systems. There is a
25% risk of pulmonary edema and 30% of the patients show aggravation of
brain edema. Anemia and decreased oxygen carrying capacity are other
undesirable side effects.
therapy is contraindicated in established infarction and severe brain or
pulmonary edema and in anemic patients.
new strategy aiming to reduce the hydrostatic capillary pressure using
dihydro-ergotamine combined with a b1-antagonist
(metoprolol) and a2-agonist
(clonidine) has recently been described.
Attention to energy requirements:
therapy has been used in some centers. This increases O2
concentration in the inspired air and provides
increased O2 to
the injured brain. 100% O2
is used widely in pneumocephalus.
Long-term use of O2
therapy may result in acute respiratory distress syndrome (ARDS).
The blood glucose should be maintained at normal levels. Tissue
acidosis as a result of lactic acid accumulation (due to anaerobic
utilization of glucose), may affect the metabolic recovery. Ideally the
glucose should be maintained at the normal level. There is no definite
evidence to suggest hypoglycemia helps the recovery.
attention to fluid and electrolytes is mandatory.
Sodium is the most
by depressing neuronal function, reduce CMR, CBF, and ICP. It has been
found effective if given within 4 hours of the insult. They have profound
cardiovascular depressive effect, which should be monitored.
Etomidate, a short acting anesthetic, produces similar effects as
barbiturates with minimal cardiovascular depressive effects.
by reducing CMR, the release of glutamate and other excitatory
influx, help edema formation. Profound hypothermia (22-24 degrees C) is
associated with cardiac irritability, ventricular fibrillation, metabolic
disturbances, coagulopathy etc. Mild hypothermia has been found useful.
c) Restoration of blood brain interface
compounds, most of them currently on trial, are claimed to stabilize BBB
at the endothelial level.
can inhibit lipid peroxidation and
stabilize lysosomal membrane. Their effectiveness in post-traumatic and
ischaemic edema is not proven; newly developed synthetic 21-aminosteroids
(lazaroids) lack glucocorticoid and mineralocorticoid activity and are
potent inhibitors of iron dependent lipid peroxidation.
Alpha-21-aminosteroids (U-74006F) appears to have great potentials.
Antioxidants, free radical scavengers,
phospholipase inhibitors have
been reported to increase oxygen consumption, glucose incorporation into
amino acids, and phospholipid and GABA synthesis. Alpha-tocopherol (vitamin
E) has beneficial effects on brain edema and ischaemia. It inhibits
both fatty acid release and lipooxygenase activity and plays a fundamental
role in the stabilization of polyunsaturated fatty acids in membrane
phospholipids. It may also interact with cellular membrane and prevent
peroxide formation by acting as hydrogen donor. Dimethylsulphoxide
(DMSO) combined with mannitol possibly act as specific scavenger for
hydroxyl radicals as can ascorbic acid (vitamin C), glutathione,
catalase, superoxide dismutase (SOD).
induces cylooxygenase inhibition, modulates arachidonic acid metabolism,
and reduces peptidoleukotrienes, which are responsible for increased
vascular permeability leading to edema.
reduces calcium influx through voltage-sensitive channels; but has the
hazard of producing hypotension. In high doses (60mgm every 4 hour), it is
reported to have beneficial effect on injured brain. Some studies lately
have found no benefit. Among other compounds trifluoperazine
inhibits calcium binding to calmodulin and inhibits Ca++
efflux at synaptic membranes.
adrenergic antagonists such as propanolol decrease lactic acid
production and reduce edema. The adrenal response can be reduced by
alpha-2- agonist clonidine.
antagonists have shown the greatest neuro protective efficacy of any drug
in ischaemia. Continuing clinical trials are on.