Intracranial Pressure Management

Several osmotic diuretic agents have been used to treat elevated ICP, including sucrose, albumin, urea and mannitol. Mannitol appears to be excluded from the CSF to a greater extent than other osmotic agents. Mannitol is a simple unbranched hydrocarbon with a half-life of approximately 0.25-1.7 hours. Its excretion is primarily renal, so its half-life may be extended in cases of impaired renal function. The recommended dose for mannitol is 0.25-2 g/kg intravenously every 4 hours, with a peak decrease in ICP approximately 15 minutes after administration. Use of a loop diuretic 15 minutes after the administration of mannitol has been shown to potentiate its effect. Like all osmotic diuretics, mannitol works primarily by shifting water from the brain parenchyma to the intravascular space, thereby decreasing the volume of the intracranial contents and reducing ICP. Additionally, mannitol reduces intracranial elas-tance. Mannitol may also affect the reactivity of intracerebral capillaries, leading to an overall vasconstrictive effect and decreased ICP. Finally, mannitol decreases the viscosity of whole blood, thereby decreasing intracerebral resistance. In combination with the increase in intravascular volume and cardiac output, this leads to increased CBF in the setting of decreased ICP, with an overall theoretical increase in CPP. These effects on ICP and CPP appear to be greatest in the setting of intact vascular autoregulation. The effectiveness of mannitol is also highly dependent on the intactness of, and osmotic gradient across, the BBB. Marked disruption of the BBB allows flow of mannitol into the brain parenchyma, thus antagonizing flow of blood into the intra-vascular compartment. In response to chronic osmotic therapy, the brain also accumulates "idiogenic osmoles", which act to sequester water in the brain compartment.

Barbiturates are a second-line agent for the management of elevated ICP. Their efficacy in this role remains controversial. The mechanism of action is believed to be their ability to modulate cerebral metabolism and therefore CBF. Barbiturates appear to act as cerebral vasoconstrictors, thus reducing intracerebral blood volume and lowering ICP. Barbiturates also appear to preferentially vasoconstrict normal cerebral blood vessels and increase CBF to relatively ischemic areas. Finally, barbiturates decrease CMRO2, i.e. the cerebral metabolic rate and oxygen consumption. Decreases in CMRO2 appear to result in decreased ICP. A burst-suppression EEG pattern (so-called "barbiturate coma") is often required to achieve a maximal decrease in CMRO2. This effect, however, does not come without a significant price. Large doses of barbiturates may cause systemic hypotension and act as negative inotropes, both of which act to decrease cardiac output and, ultimately, CPP in the setting of elevated ICP. Pentobarbital is the most commonly used barbiturate for the management of ICP and has a half-life of 15-50 hours, which may be even further lengthened by the large doses required to achieve a barbiturate-induced coma. This effect is due to perturbation of hepatic-clearance mechanisms and also significantly affects the metabolism of other hepatically cleared drugs. Resolution of pentobarbital coma may take days after cessation of therapy. This side-effect profile mandates the use of frequent

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