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Brain Edema

a.  Definition of Brain Edema

Brain edema is an excess accumulation of water in the intracellular and/or extracellular 

spaces of the brain. Brain edema after traumatic brain injury is a frequent finding. Grossly in

older terminology of brain edema, the cut surface oozes fluid ( Hirn Edem). In Brain

Swelling, the cut surface is dry ( Hirn Swelling ).1,2 Although cytotoxic edema seems more

frequent than vasogenic edema in patients after traumatic brain injury (TBI), both entities

relate to increased ICP and secondary ischemic events. Microscopic and ultrastructural

studies reveal increased fluid in interstitial space in vasogenic edema, whereas increased

intracellular fluid is present in cellular or cytotoxic edema. Diffusion weighted imaging can

differentiate between vasogenic and cytotoxic (cellular) edema by tissue water 

measurements.1 

b. Types of Brain Edema

Basicly brain edema subdivided into vasogenic and cytotoxic types. But there is other 

labels of edema such as osmotic, interstitial (hydrostatic), or hyperemic. Interstitial

attributable to periventricular exudation of cerebrospinal fluid through the ependymal lining 

of the ventricles into the periventricular white matter. This type of edema is seen with

hydrocephalus, and osmotic, attributable to movement of water into the interstitial spaces

induced by osmotically active products of tissue injury and blood clot. Vasogenic edema is

defined as fluid originating from blood vessels that accumulates around cells. Cytotoxic

edema is defined as fluid accumulating within cells as a result of injury. The most common

cytotoxic edema occurs in cerebral ischemia. Cytotoxic edema develops in the first hours

after the onset of ischemic stroke and can be detected as a decrease in the apparent diffusion

coefficient (ADC) of water.2,3,4 Heretofore, the edema specific to TBI has generally been

considered to be of vasogenic origin, secondary to traumatic opening of the BBB. However,

 both forms of edema can coexist. This is a critical problem, as effective treatment will clearly

depend on the major type of edema contributing to the swelling process.4,5 

In the case of vasogenic edema, protein extravasation secondary to barrier compromise

was implicated in the edematous process. This was in line with Klatzos’ theory that a

 breakdown of the extracellular proteins would increase the osmotic gradient and cause more

water to exude from the vessels. It was shown that protein in the extracellular space retards

the clearance of fluid, but no evidence to date has been put forth to substantiate that

extracellular protein increases fluid entry into brain. Just as protein in the extracellular space

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has been shown to retard clearance, lowering the ICP enhances clearance of fluid from the

 brain, while steroids have negligible effect on the clearance process. Mediator compounds

such as bradykinin, glutamate, arachidonic acid, and leukotrienes are released upon brain

injury and cause brain swelling. Pharmacological treatments in the laboratory setting have

shown positive effects to varying degrees however, these treatments have not been translated

to the patient. Moreover, mannitol, which is in common use after stroke, has not been shown

to be effective, despite a plethora of nonrandomized in-hospital trials.4,5 

c.  Cellular Edema in Ischemia

Results of both experimental and clinical studies have indicated that cerebral edema

develops following acute regional ischemia and can cause mass effect and herniation that

results in a further decrease in CBF. Complete interruption of CBF, as induced in cardiac

arrest, results in the rapid breakdown of all electrophysiological and metabolic functions of 

the brain. The edema associated with ischemia has a characteristic time course and begins

with a cytotoxic phase in which energy failure results in intracellular fluid accumulation

associated with shifts in sodium and potassium between intra- and extracellular 

compartments of the brain. With ongoing ischemia, the core region of impaired metabolism

expands, leading to gradual infarction of the penumbra. Treatments for the combination of 

ischemic edema and eventual vasogenic edema secondary to barrier compromise have not

 been successful, and more work needs to be done, not only to elucidate the pathophysiology

 but to better understand the process of cellular edema resolution.3,4 

d. Edema Development Following Intracerebral Hemorrhage

The vasogenic and cellular components of edema following trauma and/or ischemia are

well described. However, the cause of the edema development following intracerebral

hemorrhage remains unknown. Studies involving stereotactic injection of various blood

 products such as concentrated blood cells, serum from clotted blood, and plasma from

unclotted blood all failed to produce experimental edema in rodents. However, the

introduction of prothrombinase to plasma to activate the coagulation cascade produced brain

edema. Authors of subsequent studies have demonstrated that thrombin increased brain

edema when concentrations as low as 1 U/ml were infused into rodent brain. Work is ongoing

to develop strategies for combating initiation of the coagulation cascade.4

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e.  Cellular Edema in TBI

Results of recent studies of TBI have indicated that the predominant type of edema in

these injuries is cellular. These results have been confirmed by other investigators. It has been

documented that ionic dysfunction occurs with TBI and that extracellular K+ is transiently

increased as a result of the depolarization synchronous with mechanical insult. This loss of 

ionic homeostasis should be accompanied by a concomitant movement of sodium. Seminal

studies by Betz and Gotoh et al measured unidirectional movement of sodium into brain

following an ischemic injury, and work by Aldrich et al has demonstrated a clear relationship

 between tissue water content and sodium accumulation in spinal cord injury. Traumatic brain

injury is thought to trigger a cascade of events, including mechanical deformation,

neurotransmitter release, mitochondrial dysfunction, and membrane depolarization, that can

lead to alterations in normal ionic gradients. Excitatory amino acids released via mechanical

deformation and membrane depolarization can activate ligand-gated ion channels, which

allow ions to move down their electrochemical gradients. In addition, membrane

depolarization resulting from ionic flux and trauma may trigger voltage-sensitive ion

channels, providing further routes for ionic movement. These ionic disturbances are

identified by an increase in extracellular K+ with a concomitant decrease in extracellular 

 Na+, Ca2+, and Cl – . Restoration of ionic homeostasis can either occur via energy-dependent

co- and countertransport processes such as the Na+-K+ adenosine triphosphatase, the Na+/

K+/2Cl – cotransporter, the Na+-H+ transporter, and the Na+- Ca2+ exchanger or via simple

washout into the vascular or CSF compartment. It is reasonable to suspect that the net balance

of ionic movement that accompanies brain injury results in the movement of cations out of 

the extracellular space into cells. The movement of Na+ and Ca –  is passively followed by

Cl –  to maintain electroneutrality and is followed isosmotically by water. If sustained, these

ionic disturbances result in cellular swelling and cytotoxic edema, which has have shown to

 be the primary contributor to raised ICP.4

f.  Pathophysiology of Brain Edema

Disruption of the BBB is the most important prerequisite for edema formation. Both

vasogenic and cytotoxic edema results in increased intra-cranial pressure and eventually

decreased cerebral perfusion pressure. This is in line with the Monroe  –  Kellie hypothesis

which states that ‘the sum of the intracranial volumes of blood, brain, CSF and other 

components is constant and that an in increase in any one of these must be offset by an equal

decrease in another. Elevated ICP diminished cerebral perfusion and can lead to tissue

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ischaemia. Ischaemia in turn may lead to vasodilation via autoregulatory mechanisms

designed to restore cerebral perfusion. However vasodilation increases cerebral blood

volume, which in turn then increases ICP, lower CPP and provokes further ischaemia. After 

Traumatic brain injury, CBF autoregulation is impaired or abolished in most patients. When

 pressure autoregulation is impaired or absent ICP decreases and increases with change in

cerebral perfusion pressure (CPP). Also, autoregulatory vasoconstriction seems to be more

resistant compared with autoregulatory vasodilation which indicated that patients are more

sensitive to damage from low rather than high CPPs.1 

g.  Role of Neurotransmitters and Vasoactive Substances in the Pathogenesis of Brain

Edema

Studies on experimental models have shown several neurotransmitters like glutamate,

acetylcholine and vasoactive substance i.e., serotonin, histamine, prostaglandins, amino acids,

lactic acid etc. to mediate initiation and propagation of brain edema. Platelets are rich source

and such substances are released due to their clogging in capillaries. Serotonin accumulation

and diffusion to the surrounding tissue is seen in histoflourescence studies in edematous and

contused tissue from human brain. So role of serotonin in pathogenesis of vasogenic cerebral

edema is strongly implicated. Cortical serotonin (5-HT) metabolism increased following

 brain injury and this increase is temporarily related to depression of glucose utilization.

Moreover, Pappius et al showed that administration of the serotonin synthesis inhibitor,

Pchlorphenylalamine, attenuated depression of glucose utilization and post injury increases in

cortical serotonin. Histamine is released from the mast cells or histaminergic neurons which

influence the BBB function. Both H1 & H2 receptors are present within the endothelium and

Histamine H2 receptors are known to be involved in the BBB disruption following trauma.

Histamine has the capacity to induce brain edema by its direct effect on the cerebral

endothelial cells to influence nitric oxide (NO) formation probably via histamine H2

receptors. Since NO is a potential contributor of the BBB breakdown, brain edema and cell

injury, blockade of NO by Histamine receptors blockers like ranitidine, cimetidine may

 provide neuroprotection. Studies conducted by Mohanty et al have shown ranitidine to be

more effective than cimetidine in reducing brain edema induced by hyperthermia.1

Prostaglandins of E series E1 & E2 released from the severed blood vessels and damaged

 platelets. The possible mechanisms by which the released PGs are involved in brain edema

are 1) increased permeability of cerebral capillaries, 2) ischemia by vasoconstrictor action

and 3) potentiation of action of other chemical agents like serotonin or catecholamines.1

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Treatment with indomethacin a PG synthatase inhibitor led to remarkable reduction of 

occurrence of edema as a result of injury. AQP4 channels were first cloned by Peter Agre and

co-workers who received the Nobel prize for the same. AQP4 channels is expressed in the

astroglial cells end feet membranes adjacent to blood vessels. AQP4 was responsible for the

water transport in cultured astroglial cells and might be a primary factor in ischaemia induced

ceberal edema. The perivascular pool of AQP4 allows bidirectional water flow and hence is

likely to be ratelimiting for both water influx and efflux. Perivascular AQP4 pool is anchored

through dystrophin complex (brain dystrophin isoform DP71 and a-syntrophin). Mice with

targeted deletion of a-syntrophin displayed a dramatic loss of perivascular AQP4 and a

concomitant reduction in the extent of post-ischemic edema. The transgenic mouse studies

suggests that aquaporin inhibitors may have clinical indications as diuretics and in the

treatment of cerebral edema32. Studies conducted on male Sprague-Dawley rats concluded

that magnesium decreases brain edema formation after TBI, possibly by restoring the

 polarized state of astrocytes and by down regulation of AQP4 channels in astrocytes. Trabold

et al studied the role of vasopressor receptors for post-traumatic brain edema formation and

secondary brain damage in C57/B16 mice and found that inhibition of AVP V1 receptors

reduced brain content by 45% ,ICP by 29%, and contusion volume by 18%, while inhibition

of AVP V2 receptors had no effect34. Erythropoetin is gaining intrest as a neuroprotective

agent, apparent diffusion coefficient measurements showed that rhEpo ( recombinant human

erythropoietin) decreases brain edema early and durably in the rat brain. The mechanism by

which it works is still not clear and further studies are needed to know it.1 

h. Treatment of Brain Edema

The goal of medical management of cerebral edema is to maintain regional and global

CBF to meet the metabolic requirements of the brain and prevent secondary neuronal injury

from cerebral ischaemia. Medical management of cerebral edema involves using a systemic

approach, from general measures i.e, optimal head and neck positioning for facilitating

intracranial venous outflow, proper airway, avoidance of dehydration and systemic

hypotension and maintenance of normothermia to specific therapeutic interventions like

controlled hyperventilation, administration of diuretics such as furosemide, osmotherapy such

as mannitol and hypertonic saline, and pharmacological like steroids and glycerol.4,6

Surgical decompression and use of osmotherapy to reduce brain edema and its deleterious

effect remain the mainstay of treatment even today. This only attenuates the primary injury

 but cannot abate the secondary cascade of events. Drugs which inhibit or slow the various

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secondary mechanisms are still in a experimental stage. Few have shown their efficacy in

controlled trails and further research is needed to bring these to the main stream of treatment.

The most promising of the studies are the aquaporin 4 channel inhibitors.4,6 

Mannitol

Mannitol is currently the most frequently used osmotic diuretic in several fields of 

medicine. It is widely used to decrease intracranial pressure (ICP), used in acute renal failure,

glaucoma, post-traumatic intracranial hypertension, and non-traumatic encephalopathies such

as Reye’s syndrome. Reye’s syndrome is an acute and often fatal childhood illness associated

with severely impaired liver function and a rapidly progressing raised intracranial pressure

due to brain swelling.7,8

Other reports suggest that although the beneficial effect of mannitol may be transient, that

in resource-limited settings where intensive care monitoring and nursing are often lacking,

shortening the coma recovery time may have benefits for neurological disabilities. Mannitol

has also been demonstrated to have suppressive effects on free radicals and nitric oxide,

which have been implicated in the pathophysiology of cerebral malaria and neurological

abnormalities. Mannitol is administered intravenously. Because it causes the extracellular 

space to expand, it may have some undesirable effects such as cause or worsen heart failure

and pulmonary oedema, shock from excessive diuresis, headaches, nausea, and vomiting.7 

a.  Chemistry

Mannitol is a sugar alcohol; that is, it is derived from a sugar by reduction, with a

molecular weight of 182.17 g/mol, and a density of 1.52 g/mL. Other sugar alcohols include

xylitol and sorbitol. Mannitol and sorbitol are isomers, the only difference being the

orientation of the hydroxyl group on carbon 2. D-mannitol (CAS# 69-65-8) has a solubility of 

22g mannitol/ 100mL water (25°C), and a relative sweetness of 50 (sucrose=100). It melts

 between 165°-169°C (7.6 torr), and boils at 295°C at 3.5 torr, indicating a greater boiling

 point at STP conditions. The half life time of mannitol is 100 minutes, the metabolism is in

liver and excretion of mannitol is in renal.9 

The dose of mannitol intravenous :

-  Children

  First dose : 0,25 g/kg

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  Maintanance : 0,25-0,5 g/kg (4-6 hours)

-  Adult

  First dose : 0,2-1 g/kg

 Maintanance : 0,25-0,5 g/kg (4-6 hours)

  Daily dose : 20-200 g/day

-  For brain edema : 0,25-1,5 g/kg/dose intravenous in 20%-50% solution for >30

minutes

b. The Application of Mannitol

Mannitol is used clinically in osmotherapy to reduce acutely raised intracranial pressure

until more definitive treatment can be applied, e.g., after head trauma and during intracranial

operations. It is also used to treat patients with oliguric renal failure. It is administered

intravenously, and is filtered by the glomeruli of the kidney, but is incapable of being

resorbed from the renal tubule, resulting in decreased water and  Na+ reabsorption via its

osmotic effect. Consequently, mannitol increases water and Na+ excretion, thereby

decreasing extracellular fluid volume.8,9 

Mannitol can also be used as a facilitating agent for the transportation of pharmaceuticals

directly into the brain. The arteries of the  blood-brain barrier  are much more selective than

normal arteries. Normally, molecules can diffuse into tissues through gaps between the

endothelial cells of the blood vessels. However, what enters the brain must be much more

rigorously controlled. The endothelial cells of the blood-brain barrier are connected by tight

 junctions, and simple diffusion through them is impossible. Rather, active transport is

necessary, requiring energy, and only transporting molecules that the arterial endothelial cells

have receptor signals for. Mannitol is capable of opening this barrier by temporarily shrinking

the endothelial cells, simultaneously stretching the tight junctions between them. An

intracarotid injection of high molarity mannitol (1.4-1.6M), causes the contents of the artery

to be hyperosmotic to the cell. Water leaves the cell and enters the artery in order to recreate

an osmotic equilibrium. This loss of water causes the cells to shrivel and shrink, stretching

the tight junctions between the cells.9 

Mannitol is reported to decrease cerebral edema, infarct size, and neurological deficit in

several experimental models of ischemic stroke, although primarily when administeredwithin 6 hours after stroke onset. The results of some animal studies do not prove the

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 beneficial effects of mannitol in rodent or monkey models of ischemic stroke. The worsening

of cerebral edema by multiple-dose mannitol was also reported in cats, and a harmful effect

of a single very large dose was assumed although not found in complete middle cerebral

artery infarcts in humans. Mannitol has been used in human ischemic brain damage for 30

years. Cerebral edema in humans is regularly treated with mannitol, which is known to

decrease ICP in several diseases and was found to decrease case fatality in cerebral edema

due to hepatic failure. In a study of middle cerebral artery territory stroke, treatment

modalities for elevated ICP, including osmotherapy, were initially effective, but ICP control

could only be sustained in a minority of patients.3 

The most common complications of mannitol therapy are fluid and electrolyte imbalances,

cardiopulmonary edema, and rebound cerebral edema. Mannitol might cause kidney failure in

therapeutic doses, and hypersensitivity reactions may also occur. Although there are several

reports that could not prove the beneficial effects of mannitol in ischemic or hemorrhagic

strokes in humans, the guidelines of the American Heart Association currently recommend

the use of mannitol in certain clinical conditions in selected cases of acute stroke. Mannitol is

widely used in acute stroke throughout the world. Almost 70% of physicians in China use

mannitol or glycerol routinely in acute stroke, and mannitol is used routinely in acute stroke

in several European countries as well. For example, mannitol is listed among recommended

therapeutic interventions by the consensus statement of the Hungarian Stroke Society for 

cases when increased ICP is proven in stroke. Although treatment with osmotic diuretics

seems logical from a physiological point of view, and mannitol has some effect on the brain

in ischemic stroke, it is presently not clear whether the routine use of mannitol results in

increased survival and decreased dependency in stroke patients.3 

c.  Mechanism of Mannitol

Despite its widespread use for over 40 years, the precise mechanisms of action of mannitol

remain incompletely defined. This is due at least in part to the multiple effects exerted by this

agent that may contribute to its therapeutic benefit. The 2 main mechanisms are osmotic and

hemodynamic. The osmotic effect is based on the fact that mannitol does not cross the

cellular membrane or the intact blood-brain barrier. Hence, mannitol increases intravascular 

tonicity, thereby establishing a concentration gradient across the blood-brain barrier that

forces movement of water from the edematous brain tissue to the intravascular space. This is

followed by rapid renal excretion of mannitol and water. However, the timing and dose of 

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mannitol required to exert a change in brain water content in animal models is not consistent

with the changes in ICP that are seen in clinical practice. Effective changes in ICP clinically

occur at much lower doses of mannitol than those used in animal experiments. It has also

 been experimentally documented that the decline in ICP precedes the fall in brain water 

content that occurs after a bolus of mannitol, arguing in favor of a mechanism other than

dehydration being responsible for the early effects of the agent. Still, mannitol does reduce

 brain water content as proven by experimental evidence, intraoperative biopsies in trauma

 patients, and radiologic studies with CT and MRI.6 

The hemodynamic effects of mannitol are proposed to be mediated by a reduction in blood

viscosity that would lead to increased cerebral blood flow and a subsequent reduction in

cerebral blood volume due to passive vasoconstriction. The rheologic changes are caused by

dilution of blood and increased deformability of erythrocytes. These changes can occur quite

rapidly and could account for the early drop in ICP observed prior to the fall in brain water 

content. However, this theory is not substantiated by other studies that actually found rises in

cerebral blood volume after administration of mannitol.6 

Other proposed mechanisms of action of mannitol include free radical scavenging,

inhibition of apoptosis, and augmentation of cerebral perfusion pressure leading to

autoregulatory vasoconstriction and consequent reduction in cerebral blood volume. The

latter mechanism is theoretically appealing but probably not clinically significant since it

contends that mannitol causes systemic blood pressure elevation as a result of intravascular 

volume expansion, a finding that is rarely seen in practice. In addition, it depends on

conservation of normal autoregulatory responses, which are actually often abolished in many

conditions associated with brain edema. The incomplete understanding of the mechanisms

underlying the effects of mannitol on ICP and the lack of systematic studies of mannitol

treatment in humans explain the lack of agreement on what is the optimal way of 

administering the agent.6 

d. Caution in using Mannitol

Possible side effect in using mannitol is increased urination, nausea, runny nose, vomiting,

or may appear severe side effect such as severe allergic reactions (rash, hives, itching,

difficulty breathing, tightness in the chest, swelling of the mouth, face, lips, or tongue),

 blurred vision, chest pain, chills or fever, confusion, decreased alertness, difficulty urinating,

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extreme dizziness, extreme thirst or dry mouth, fast or irregular heartbeat, headache, muscle

cramps, pain, redness, or swelling at the injection site, weakness.10

Some medical conditions may interact with Mannitol, however, no specific interactions

with Mannitol are known at this time. Any conditions like pregnant, taking any prescription

or nonprescription medicine, herbal preparation or taking dietary supplement, have an

allergies to medicines, foods, or other substances, and have swelling, kidney problems, or 

heart problems (eg, congestive heart failure) need to concern.10

Mannitol should be used with extreme caution in children younger than 12 years old;

safety and effectiveness in these children have not been confirmed. While in elderly they may

 be more sensitive to its effects. It is not known if Mannitol can cause harm to the fetus.

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