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
1

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

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
3

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
4

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
5

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 Reyes syndrome. Reyes 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 (25C), and a relative sweetness of 50 (sucrose=100). It melts between 165-169C (7.6 torr), and boils at 295C 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

 Adult -

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

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 administered within 6 hours after stroke onset. The results of some animal studies do not prove the
7

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
8

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,
9

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.10

10