Cerebral Edema

Approximately 80% of patients with FHF and advanced (stage IV) encephalopathy will develop cerebral edema and this is the most common cause of death. Young patients and those with rapid onset ("hyperacute") FHF are at higher risk for developing cerebral edema. The pathogenesis of brain swelling remains incompletely defined. The adult skull is in essence a rigid box with an internal volume occupied by brain parenchyma (80%), cerebrospinal fluid (CSF) (10%), and blood (10%). The ICP, normally less than or equal to 15 mm Hg, is a function of the volume and compliance of these 3 components. Intracranial compliance is nonlinear; initially, intracranial volume may increase from brain swelling with little increase in ICP due to displacement of CSF and a decrease in the volume of the cerebral blood. Once these compensatory mechanisms are exhausted, however, ICP will increase with even small increases in volume. ICP is dictated both by the rate and the magnitude of intracranial volume change, with slow changes producing less dramatic ICP elevations than rapid changes presumably as the former allows intracranial compliance to be fully realized.

Elevated ICP damages the brain both by brain stem compression (ie, herniation) and by reduction in cerebral blood flow (ie, cerebral ischemia), the latter is measured clinically as the cerebral perfusion pressure (CPP):

where MAP is the mean arterial pressure. Pathological intracranial hypertension exists when ICP is greater than 20 mm Hg. A CPP < 40 mm Hg for greater than 2 hours has been associated with poor neurological outcome and thus is generally considered to be a contraindication to liver transplantation.

The diagnosis of increased intracranial pressure, which develops in patient with late (stage III or IV) encephalo-pathy and not in patients who are awake and able to follow commands, is based on clinical examination, head CT and direct pressure monitoring with an ICP monitor. Examination of the FHF patient with raised ICP may reveal systemic hypertension, pupillary abnormalities, decere-brate posturing (ie, extension and pronation of extremities), disconjugate eye movements, and loss of pupillary reflexes. Unfortunately, these clinical signs are neither sensitive nor specific in the setting of FHF. For example, both decorticate and decerebrate posturing can be due to hepatic encephalopathy in the setting of FHF without increased ICP. Furthermore, CT does not appear to be sensitive for detection of cerebral edema, and ICP can be elevated even in a patient with a normal head CT.

Empiric therapy of presumed intracranial hypertension is difficult because CPP can not be monitored without measurements of ICP. For accurate assessment of ICP direct measurement is required, and this is associated with a small but definite risk of serious complications. Although there are several types of ICP monitors, euphemistically called "bolts", for practical purposes only the epidural and subdural types are used in patients with FHF because of the higher risk of bleeding with the more invasive (ie, intra-ventricular and intraparenchymal) types of monitoring systems. The risk of major complications, especially bleeding, from placement of the less invasive, but inherently less accurate ICP monitors is still significant (about 5%). The Camino (Integra Life Sciences, Plainsboro, New Jersey) fiberoptic monitor, which is placed under sterile conditions at the bedside, is the most common device used at our institution. A noncontrast head CT scan is routinely obtained prior to monitor placement in order to rule out preexisting intracerebral hemorrhage. If clear-cut edema is seen on the preprocedure CT scan, we usually begin treatment (see below) of presumed intracranial hyperten-sison while awaiting correction of coagulopathy and ICP monitor placement, which may take several hours to accomplish. As mentioned previously, a large volume of FFP is often required to correct the coagulopathy and early consideration of renal support with continuous dialysis is appropriate to prevent fluid overload because this may exacerbate intracranial hypertension.

The use of ICP monitoring has been associated with decreased mortality in patients with traumatic brain injury, but has not been shown yet to improve the outcome of patients with FHF and brain edema. Thus the use of ICP monitoring in this setting remains controversial. Because of the lack of clear impact on patient outcome, as well as the risk of bleeding and infection with ICP monitor placement, there has been significant interest in development of less invasive systems for monitoring ICP, including jugular venous bulb saturation measurements and transcranial doppler ultrasound. However, to date, these systems have not been widely adopted.

The goals of treatment are to keep ICP < 20 mm Hg and CPP > 60 mm Hg. Interventions should generally be made for sustained ICP > 20 mm Hg. Treatment usually proceeds in a stepwise fashion and includes head elevation, sedation, head positioning to facilitate venous outflow from the brain, hyperventilation to a carbon dioxide partial pressure of approximately 30 mm Hg, IV mannitol, IV barbi-tuates, and possibly hypothermia.

The patient's environment should be as quiet as possible and the head of the bed should be raised approximately

20 degrees above the horizontal. The patient's head should be placed in the midline to facilitate venous drainage, and agitation, gagging, excessive head turning, fever, seizures, and hypertension should be avoided or, if present, aggressively treated as they can increase ICP. The patient should be sedated and paralyzed before intubation. Care should be taken to minimize potential increases in ICP during intubation and pretreatment with intravenous lidocaine (1 mg/kg) has been suggested but not proven to help prevent the potential rise of ICP associated with intubation. Hypotension, hypoxemia and hypercapnia should be avoided as they can increase ICP. Cerebral blood flow, which determines the volume of intracranial blood, increases with hypercapnia and hypoxemia, thus the rationale for mild hyperventilation and maintaining normal oxygen partial pressure. Hyperventilation resulting in a moderate reduction of carbon dioxide partial pressure (to ~30 mm Hg) may decrease ICP at least transiently but excessive hyperventilation may lead to severe cerebral vasoconstriction and brain ischemia and should be avoided.

Mannitol, an osmotic diuretic, reduces brain volume by drawing free water out of brain tissue. A 20% solution of mannitol, which should be kept at the patient's bedside for rapid use, can be administered as a rapid bolus infusion (0.5 to 1.0 mg/kg over 5 minutes) for sustained rises in ICP > 30 mm Hg, or for signs of neurological deterioration. Repeat boluses can be given every 6 to 8 hours as needed, but serum osmolality should be monitored and mannitol should only be administered if the serum osmolality remains less than 320 mOsm/L. The effect on ICP is rapid, peaks at about 1 hour, and may last for up to 24 hours. However, there may be a rebound increase in ICP following mannitol administration, presumably reflecting entry of mannitol into the brain through a damaged blood-brain barrier. Other complications of mannitol therapy include volume depletion or expansion, electrolyte problems and metabolic acidosis.

If intracranial hypertension is refractory to the above measures, use of barbituates, such as thiopental or pento-barbital, may be administered in an effort to lower ICP by reducing brain metabolism and cerebral blood flow. Pentobarbital boluses (100 to 150 mg every 15 minutes for 1 hour) followed by a continuous infusion (1 to 3 mg/kg/hour) may be quite effective in controlling intracranial hypertension, but often cause hypotension necessitating pressor (eg, neosynephrine) administration to maintain CPP. Alternatively, thiopental may be given as an IV bolus to a maxium of 500 mg over approximately 15 minutes with a subsequent infusion of 50 to 250 mg/hour, but causes similar hemodynamic changes. Continuous electroencephalogram (EEG) monitoring is commonly performed with barbituate coma to confirm a burst suppression pattern and an indication of maximal dosing, and is also useful to exclude subclinical seizure activity which should be treated aggressively if present. Seizures can both result from and exacerbate elevated ICP, and subclinical seizure activity was reported in one study to be common in patients with FHF and advanced coma. In this study, prophylactic phenytoin decreased seizure activity, pupillary changes, and cerebral edema but did not improve overall outcome. Because the neurological exam is lost and the EEG "flat lines" during barbituate coma, a cerebral perfusion scan is often used to determine brain death in this setting.

Induction of moderate hypothermia (ie, 32°C to -33°C) has recently been advocated as a method of controlling refractory intracranial hypertension in the setting of FHF based both on preclinical and early clinical studies. Hypothermia decreases cerebral metabolism, thus decreasing CBF and ICP, and may also decrease hepatic ammonia production. Hypothermia is achieved via cooling blankets or gastric lavage to a core temperature of 32°C to -34°C. However, the utility of hypothermia for improving outcome from cerebral edema, even from closed head trauma, remains controversial, and an area of continued investigation. Decompressive craniectomy may result in a prompt and dramatic reduction of ICP, and has been shown to improve outcome with brain trama and stroke, but has not been reported in FHF presumably secondary to the risk of bleeding.

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