Complications
Hepatic encephalopathy may progress rapidly in ALF. As the grade of encephalopathy increases, the risk of cerebral edema increases to as high as 35% for grade 3 encephalopathy and as high as 75% for grade 4 encephalopathy.[137] Although commonly used in the management of hepatic encephalopathy and associated hyperammonemia, lactulose therapy does not appear to have a significant impact on outcomes in ALF. Once encephalopathy progresses to grades 3 or 4, elective tracheal intubation should be performed.[4][138] Obtaining a computed tomography scan of the head should be considered following tracheal intubation to assess for cerebral edema or other causes of altered mental status such as intracranial bleeding.[99] A transcranial Doppler, with estimation of cerebral perfusion pressure and intracranial pressure, may also be considered in patients with grade 3 to 4 hepatic encephalopathy who are at risk of intracranial hypertension or for those in whom developing cerebral edema is expected.[57]
Coagulopathy is a defining feature of ALF, yet the incidence of significant acute bleeding is low. Coagulation parameters have prognostic value and may be monitored to assess for ongoing hepatic dysfunction or resolution in ALF. Vitamin K may be given for possible vitamin K deficiency; however, correction of coagulopathy is not recommended unless clinically significant bleeding occurs or prior to invasive procedures.[4][99] In these cases, fresh frozen plasma, platelets, and cryoprecipitate may be given. Recombinant factor VIIa may also be administered, although it is possibly associated with an increased risk of thrombotic events.[142]
Infection occurs frequently in ALF and remains a primary cause of mortality in this population. Bacterial infections have been reported to occur in over 80% and fungal infections as frequently as 30%.[134] Regular surveillance cultures have been suggested.[4] Prophylactic antimicrobial therapy does not appear to influence outcome and is not recommended.[4][103] However, empirical antimicrobials are recommended if a patient develops positive surveillance cultures, refractory hypotension, progression to grade 3 or 4 hepatic encephalopathy, evidence of Systemic Inflammatory Response Syndrome; and in all patients who are listed for liver transplant.[99]
Renal dysfunction is common in ALF and occurs more frequently in the setting of acetaminophen overdose, in which it may appear earlier during the course. The presence of renal failure is highly predictive of mortality in acetaminophen overdose, as serum creatinine levels >3.4 mg/dL on presentation may be associated with a mortality rate >75%.[64] Etiologies of renal failure may include hypovolemia, acute tubular necrosis, and hepatorenal syndrome. If a patient develops renal or circulatory dysfunction, volume status should be monitored closely, and renal replacement therapy with continuous veno-venous hemodialysis is preferred over intermittent hemodialysis due to improved stability of intracranial pressure and cardiovascular parameters.[135][136] If vasopressors are required, norepinephrine or dopamine are recommended.[99]
Acid-base disturbances may occur, particularly if renal dysfunction is present. Electrolyte and metabolic derangements should be corrected promptly as they may contribute to worsening hepatic encephalopathy and cerebral edema. Hyponatremia should be corrected with a target serum sodium concentration of 140-145 mmol/L.[51] Abnormalities in serum phosphate, potassium, and magnesium are common. Hypoglycemia occurs as a result of impaired gluconeogenesis and decreased hepatic glycogen production. Continuous infusions of glucose at 10% to 20% solutions are preferred over bolus administration.[8] Serum glucose should be corrected to ±140 mg/dL.[51] Hyperglycemia may worsen cerebral edema and should be avoided.
Cerebral edema with intracranial hypertension is one of the primary causes of death in ALF and is more commonly associated with a hyperacute presentation. Once cerebral edema develops, factors that may precipitate elevations of intracranial pressure should be minimized. The head of the patient's bed should be raised to approximately 30 degrees and surrounding stimuli reduced to a minimum.[51] Placement of an intracranial pressure (ICP) monitor may also be considered, particularly in patients who are listed for liver transplant.[139] Noninvasive assessment of intracranial pressure with modalities such as transcranial Doppler may also have a role in estimating cerebral perfusion pressure in patients with cerebral edema.[57]
Specific therapies for elevated ICP include intravenous mannitol bolus, which may be given if the ICP is ≥25 mmHg for >10 minutes. Renal function should be monitored closely or renal replacement therapy initiated as these are essential for mannitol clearance. Repeat boluses may be given if the ICP continues to be ≥25 mmHg and serum osmolality <320 mOsm/L.[99] Boluses of hypertonic saline can also be used to reduce ICP.[51]
Hyperventilation to achieve PaCO2 of 25-30 mmHg produces a short-lived reduction in ICP, and may be used to delay uncal herniation in patients with life-threatening intracranial hypertension that is not controlled by other measures.
Additional specific therapies for cerebral edema with intracranial hypertension have been described, including induced moderate hypothermia, induced pentobarbital or thiopental coma, and administration of intravenous indomethacin.[99][138][140] One large multicenter retrospective study evaluating the role of therapeutic hypothermia in this setting found no difference in overall transplant-free survival; however, young individuals with acetaminophen-associated ALF may benefit from this practice.[141]
Seizures increase ICP and should be treated with anticonvulsants.[8]
Patients with ALF are at risk of gastrointestinal bleeding due to coagulopathy and the requirement for mechanical ventilation.[8] An international normalized ratio of >1.5 cannot accurately predict bleeding risk in patients with ALF.[4][68] Proton-pump inhibitors or H2 antagonists should be administered as prophylaxis.[8]
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