Fulminant Hepatic Failure (FHF) by Bharesh Dedhia

Bharesh Dedhia
Liver disease is a major source of morbidity and mortality in the intensive care unit . Cirrhotic patients admitted to the medical ICU have increased mortality (40 to 90%) and a poor prognosis.Fulminant hepatic failure is a clinical syndrome characterized by the rapid onset of hepatic encephalopathy in conjunction with a marked decline in hepatic synthetic function within 28 days of the onset of symptoms in those without a history of chronic liver disease .The National Institutes of Health Acute Liver Failure Study Group reported the etiology of fulminant hepatic failure in 308 patients as follows: acetaminophen hepato-toxicity (39%), idiosyncratic drug reaction (13%), hepatitis B (6%), hepatitis A (6%), and indeterminate cause (17%) (3).
Overall survival is poor without liver transplantation, with a reported mortality of 90 to 97% .The advent of liver transplantation and aggressive medical care in the ICU has improved the mortality rate .

Diagnosis
Hepatic encephalopathy and severe coagulopathy are the hallmark features of fulminant hepatic failure . Severe coagulopathy often precedes evolution of hepatic encephalopathy to coma. Patients with fulminant hepatic failure can rapidly progress from mild hepatic encephalopathy to deep coma .As soon as the diagnosis is made, it is important to establish the cause. Certain etiologies demand immediate specific treatment, including N-acetylcysteine for acetaminophen ingestion, penicillin for Amanita mushroom poisoning, delivery of the infant in acute fatty liver of pregnancy, or zinc and trientine therapy for Wilson's disease. Patients should be admitted to the ICU and transferred to a transplantation center, given that liver transplantation is the only effective therapy for this devastating disease .

Management
Management starts with supportive measures including nutrition (amino acids, lipids, glucose, and essential elements), electrolyte balance, frequent glucose monitoring .Infection in patients with fulminant hepatic failure is a major source of mortality, as 44 to 80% of patients with fulminant hepatic failure develop bacterial infections. Empiric, broad-spectrum antibiotics should be initiated on clinical suspicion of infection .Cerebral edema is a common complication of fulminant hepatic failure, occurring in up to 80% of patients with Grade IV coma, but requires a high level of clinical suspicion. The diagnosis may be difficult to establish as head computed tomography scan is insensitive, being useful only to rule out hemorrhage, and clinical signs of cerebral edema, such as decerebrate posturing, systemic hypertension, and pupillary abnormalities, are typically observed only in advanced disease. Cerebral edema often leads to intracranial hypertension and subsequent herniation of the cerebral uncus, cerebral ischemic injury, and death. Intracranial hypertension can also cause a reduction in the cerebral perfusion pressure (mean arterial pressure minus intracranial pressure), which may produce cerebral ischemia. A cerebral perfusion pressure of more than 60 mm Hg is crucial to maintain intact neurologic function .Direct intracranial pressure monitoring is recommended in patients suspected of cerebral edema or intracranial hypertension, with a target intracranial pressure of less than 20 mm Hg .The placement of extradural intracranial pressure monitors is considered safer than subdural catheters. Recombinant Factor VIIa can reverse coagulopathy in those patients requiring intracranial pressure monitor placement , and may prove preferable to fresh frozen plasma if additional studies are confirmatory. The patient's head should be elevated 10 to 20°. Maneuvers that increase intracranial pressure, such as tracheal suction or high positive end-expiratory pressure, should be avoided. Use of sedation is usually avoided so that mental status may be assessed. However, an agitated patient with Grade III coma may require the use of short-acting benzodiazepenes, the preferred agents .Mannitol is first-line therapy for treating cerebral edema and intracranial hypertension, administered at 0.3 to 0.4 g/kg body weight. In patients with renal failure, mannitol may accumulate in astrocytes and cause increased rebound swelling .Thiopental may be used in this setting (250 mg over 15 minutes). Hyperventilation may also reduce cerebral edema, but it is effective only for a few hours.In one case series, seven patients with fulminant hepatic failure were given propofol for deteriorating cerebral edema .A decrease in intracranial pressure was seen in five patients. However, only three survived, with one undergoing liver transplantation. Additional studies are needed before a recommendation to use propofol in this setting can be made. Another therapeutic adjunct, moderate hypothermia to 32-33°C, may be useful in decreasing intracranial pressure as a bridge to liver transplantation ., or while transplantation is being performed .Liver transplantation offers the best long-term survival with an overall, posttransplantation 1-year survival of about 60% .Unfortunately, prediction of the need for transplantation remains problematic. The King's College Hospital criteria are the most widely used prognostic indicator for survival in fulminant hepatic failure .These criteria include an arterial pH of less than 7.30 after adequate fluid resuscitation, or the combination of a prothrombin time greater than 100 seconds, a creatinine level greater than 3.3 mg/dl, and Grade III or IV encephalopathy. These criteria exhibit a sensitivity, specificity, positive predictive value, and negative predictive value of 55, 94, 87, and 78%, respectively. A metaanalysis investigated several prognostic criteria for determining the need for liver transplant in acetaminophen-induced fulminant hepatic failure including King's College criteria, pH, prothombin time, Factor V levels, and creatinine, but found that none of these was sufficiently sensitive in predicting the need for liver transplantation .Arterial blood lactate greater than 3.5 mmol/L 4 hours after presentation to the hospital has been shown to have a sensitivity of 67%, a specificity of 95%, a positive likelihood ratio of 13%, and a negative likelihood ratio of 35% for survival in acetaminophen-induced fulminant hepatic failure .

Advances in Artificial and Bioartificial Support Systems
Short-term extracorporeal support for patients with fulminant hepatic failure may ultimately serve to improve overall survival and provide support as a bridge to liver transplantation, but remains experimental. A metaanalysis of artificial and bioartificial support systems for fulminant hepatic failure examined a total of 8 randomized controlled trials, involving 139 patients, and found no improvement in mortality compared with standard supportive care (relative risk, 0.95; 95% confidence interval, 0.71-1.29) .In addition, the interventions were not found to be useful as a bridge to liver transplantation (relative risk, 0.60; 95% confidence interval, 0.29-1.23). The support systems appeared to have an increased risk of bleeding associated with their use. A future option is hepatocyte transplantation. In one series, three of six patients with fulminant hepatic failure survived between 14 and 52 days after transplantation of 10^sup 10^ human hepatocytes .To date, no randomized, controlled studies have examined this therapeutic option.
Recommendations
Once the diagnosis is made, all necessary supportive measures should be employed in an ICU setting. Neurologic evaluation and glucose monitoring should be performed frequently. Coagulopathy should be corrected when there is overt bleeding or an invasive procedure is planned. An emergent head computed tomography scan should be performed if there is a change in mental status or signs of increased intracranial pressure. Intracranial pressure monitoring is recommended to maintain an adequate cerebral perfusion pressure of greater than 60 mm Hg. Currently, liver transplantation offers the best long-term survival in patients likely to die of fulminant hepatic failure.
Bharesh Dedhia