Osmotherapy

Molecular structure of Urea

Urea with σ=.59 was introduced in 1956 due to low molecular weight and slow penetration of BBB. However, it can cause rebound effects and side effects such as intravascular hemolysis and phlebitis.[1] When Urea is administered, the dosage is 1.5 g/kg or 0.5 g/kg (for elderly).[3]

Molecular structure of Glycerol

Glycerol with σ=.48 was introduced in 1964, but it has a likelihood of exhibiting rebound effects and causing side effects such as hemolysis, hemoglobinuria, renal failure, hyperosmolar coma and nausea.[1] When Glycerol is used, the dosage is 1.2 g/kg followed by 0.5-1 g/kg for 3–4 hours.[3]

Molecular structure of Mannitol

Mannitol is an alcohol derivative of simple sugar mannose, and its use has been investigated since 1962. With a σ=.9, molecular weight of 182 daltons, half life of 2–4 hours, ease of preparation, chemical stability and free radical scavenging properties, it's been regarded as the principal osmotic agent for clinical use. However, it could cause diuresis, renal failure, hyperkalemia and hemolysis.[1] If mannitol is administered, the dosage used is mannitol 20% solution of 1-1.5 g/kg, followed by 0.25-1 g/kg doses as needed every 1 to 6 hours depending on the ICP.[2]

Saline solution prepared for medical use by dissolving NaCl in water

Hypertonic Saline with σ=1 has been of interest since early 1980s. Hypertonic Saline which contains sodium chloride works in regulating ICP, intravascular volume and cardiac output without causing significant diuresis, but there are theoretical side effects ranging from neurological complications to subdural hematoma. Hypertonic saline solution has been choice of neuro critical care for the past few years.[1] Hypertonic Saline solution used varies and could be 3%, 7.5%, 10%, or 24.3% saline solution.[5] When Hypertonic Solution is administered, the dosage is 2 g/kg.[6]

Reductive Ventricular Omotherapy (RVOT) could be a novel treatment that manages cerebral edema without the use of osmotic agents. RVOT uses catheters permeable to water vapor to increase osmolarity of CSF. Ex vivo experiments have been carried out to test the efficiency of RVOT. RVOT is done locally, therefore, it's more likely to be efficient in severe cases of cerebral edema. Sweep gas, any gas used to flow through the hollow fiber, flows through RVOT catheter made up of hollow fiber with semipermeable walls to remove free, unbound water from ventricles in the form of water vapor.[8]

If Osmotherapy using osmotic agents fails in treating cerebral edema, other therapies using barbiturates and corticosteroids could be developed. Barbiturates like pentobarbital can act like free radical scavengers as well decrease intracranial blood volume by reducing cerebral metabolic demand. However, administration of barbiturates poses risks such as hypotension, induced coma and infection limiting their potential clinical application. Although corticosteroids are not very effective in treating cerebral edema resulting from ischemic stroke and intracerebral hemorrhage, they are very effective in treating vasogenic edema resulting from brain tumors. Idea behind administration of both barbiturates and corticosteroids is to provide space for cerebral swelling resulting from edema, thus, these are very non specific treating methods.[9]

Some research focuses on identifying novel targets that prevents formation of cerebral edema. In order to develop strategies that prevent cerebral edema, it's important understand cerebral edema at a molecular level. Targets identified includes: NKCC1, SUR1/ TRPM4 channel, Vasopressin receptor antagonist.[9]

During early and reperfusion stage of ischemia, there is an upregulation of secondary active cotransporter NKCCl. NKCCl play an important role in modulating loading of sodium and chloride in neurons, glia, endothelial cells and choroid plexus. The upregulation of NKCCl is followed by increased deposition of sodium and chloride in endothelial cells and Na+K+ATPase activity plays a role in expelling Na followed by chloride and water from endothelial cells into extracellular space leading to vasogenic edema. Thus, preventing NKCCl upregulation has the potential to prevent cerebral edema from forming. Bumetanide which can be delivered across the blood brain barrier is an inhibitor of NKCCl.[9] Bumetanide significantly reduces inflammation resulting from TBI.[10] Identifying the right dose of bumetanide that acts as an inhibitor of NKCCl could prevent cerebral edema to some extent. This represents the ATP dependent stage of cerebral edema formation.[9]

There is an upregulation of this SUR1/ TRPM4 nonselective cation channel followed by brain tumor, ischemic injury, and traumatic brain injury. This channel which is activated by ATP depletion is found on neurons, neuroglia and endothelium. This channel enables the passive transport of water and solute and represents the ATP independent stage of cerebral formation. Opening of these channels result in cellular depolarization and blebbing causing cytotoxic edema. This can be prevented by using glyburide (glibenclamide) which inhibits these channels.[9]

Vasopressin receptors activated by vasopressin are found on the basolateral membrane of the cells lining the collecting ducts of the kidneys. Aneurysmal subarachnoid hemorrhage (aSAH) results in hyponatremia which leads to water retention and antidiuretic hormone release causing increase in intracranial pressure and formation of cerebral edema. This can be prevented by administration of conivaptan, a safe FDA approved drug that treats euvolemic hyponatremia. Through the process of aquaresis, conivapten which is a vasopressin receptor antagonist improves serum sodium concentration while eliminating free water without having any negative effect on systolic blood pressure and pulse rate. Since it can decrease cerebral volume and ICP, it has a potential to treat many forms of cerebral edema.[9][11]