Encephalopathy and Cerebral Edema in the Setting of Acute Liver Failure: Pathogenesis and Management

Abstract

Cerebral edema is a potential life-threatening complication in patients with acute liver failure who progress to grade III/IV encephalopathy. The incidence is variably reported but appears to be most prevalent in those patients with hyperacute liver failure as opposed to subacute forms of liver failure. In those patients who are deemed at risk of cerebral edema and raised intracranial pressure, insertion of an intra-cranial pressure monitoring device may be considered to optimize treatment and interventions. The pathogenesis of cerebral edema in this setting remains controversial, although recent work suggests a pivotal role for arterial ammonia, whose effects appear to be potentiated by the presence of systemic inflammation. Recent work has also suggested the import of free radical formation occurring at a mitochondrial level as being the potential mediator of cellular dysfunction as opposed to ammonia per se. Treatment of such patients requires a multi-disciplinary approach incorporating both hepatology and critical care. In a significant proportion of such cases, consideration of liver transplantation may be required. Treatment should be focused at optimizing liver function and regenerative capacity and minimizing the inflammatory milieu. Controlled studies are lacking and much of the management has been extrapolated from neurocritical care. Sustained elevation of intracranial pressure may be responsive to mannitol or hypertonic saline bolus, and in those with hyperemia indomethacin has been reported as beneficial in case series. Recently, interest has developed into the use of cooling in the management of patients with acute liver failure and raised intracranial pressure. Animal studies support this treatment option as do case series, although randomized trials are still awaited.

Loss of Ability To Self-Heal Malaria upon Taurine Transporter Deletion

“…The malaria-induced increase in the systemic ammonia levels of taut Ϫ/Ϫ mice ultimately contributes to injuries in other organs, which also suffer from the lowered taurine levels due to the breakdown of taurine homeostasis. In particular, it is known that increased ammonia levels lead to hepatic encephalopathy, characterized by astrocyte swelling and low-grade cerebral edema (19,36,55). Our data reveal that the brains of the taut Ϫ/Ϫ mice that succumbed to malaria were massively damaged.…”

Acute Liver Failure : Management Update

“…12 HE is determined by serial clinical evaluations of behavior, cognition, neurological examination, and, occasionally, electroencephalogram (EEG) to categorize the patient into one of five clinical stages of encephalopathy, ranging from stage 0 (minimal or no evidence of neurological dysfunction) to stage IV (coma). 13 Initial treatment of HE includes minimizing excess stimulation, head elevation up to 30 degrees, treating suspected sepsis, and, if possible, removing sedative medications that might affect mental status. For patients with progressive HE, medical therapy with lactulose is used empirically although there is only weak evidence to suggest that it is effective.…”

“…This is because ALF reduces both procoagulant proteins (eg, factor V, VII, X, and fibrinogen) and anticoagulant proteins (eg, antithrombin, protein C, and protein S). 11,13 This balanced reduction in the procoagulant and anticoagulant proteins may account for the relative infrequency of clinically important bleeding in the pediatric acute liver failure patient in the absence of a provocative event such as infection or increased portal hypertension.…”

Intensive Care Management of Severe Acute Liver Failure

“…Brainstem herniation is a common cause of death in acute liver failure and occurs because of severe cerebral swelling causing refractory intracranial hypertension. The pathophysiology of acute liver failure-associated cerebral edema is complex, but the accumulation of metabolic toxins, such as ammonia [3], and the loss of cerebral autoregulation resulting in hyperemia [4] are two key drivers. Ammonia is a waste product of nitrogen metabolism and undergoes detoxification via the urea cycle.…”

“…Many patients may actually manifest a strong tendency to pro-thrombotic complications and caution is, therefore, warranted regarding the administration of clotting factors except where invasive procedures are necessary or actual bleeding occurs. In the absence of major bleeding events, reasonable targets include an INR of < 6, platelet count of > 20/mm 3 , and a fibrinogen concentration of more than 1.0 g/l. Clotting factor support may include fresh-frozen plasma (FFP), prothrombin concentrate, pooled platelets and cryoprecipitate.…”