**2.4 Organ-specific management**

#### **2.4.1 Hepatic encephalopathy**

322 Liver Transplantation – Basic Issues

medications known to provoke ALF in susceptible patients include antimicrobials, antidepressants, antiepileptics, anti-hypertensives, HIV therapy, chemotherapeutic agents, lipid-lowering agents, and glucose-lowering agents. Analgesics and recreational drugs are

Additional etiologies of ALF include viral infections, including Hepatitis A, B, C, D, and E, as well as herpes simplex virus, varicella zoster virus, cytomegalovirus, and Epstein-Barr virus. Toxins responsible for ALF include *amanita phyloides* (mushrooms), herbal preparations, organic solvents, and bacterial toxins, such as *bacillus cereus*. Pregnancy-related conditions include the HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) and the acute fatty liver of pregnancy syndrome. Lymphoma, metastatic disease, hepatic ischemia, wilson disease, heat stroke, Budd-Chiari syndrome, autoimmune hepatitis, and extensive hepatic resection are other causes of ALF. Approximately 15-20% of patients with

Potential causes of ALF must be actively sought in the initial workup, as certain etiologies have specific life-saving treatments. Acetaminophen toxicity is treated with N-acetylcysteine, autoimmune hepatitis with corticosteroids, herpes simplex and varicella zoster viruses with intravenous acyclovir, acute fatty liver of pregnancy and HELLP syndrome by delivery of the fetus. Recent data suggests that the use of N-acetylcysteine (NAC) improves the outcome of patients with ALF, independent of the etiology (*Lee et al., 2009*). Many transplant centers advocate the use of NAC for all patients with ALF. NAC can be administered intravenously at a dose of 150 mg/kg over 15 minutes followed by 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours. Adverse effects of NAC include bronchospasm and anaphylaxis and are managed by coadministration of antihistamines and corticosteroids as well as reduction of infusion rate. Oral preparations of NAC are also available. Discontinuation of NAC is appropriate following resolution of ALF or at the time of

In addition to ruling out reversible causes of ALF, exclusion of chronic liver disease is crucial for appropriate management. Physical examination of patients presenting with liver failure should therefore focus on stigmata of chronic liver disease, including abdominal ascites, spider angiomata, or *caput medusae*. Hepatic imaging with ultrasound, CT or MRI is useful to evaluate for the presence of portal hypertension and chronic liver disease, as well as to evaluate hepatic size and vasculature, ascites, and hepatic masses. Recommended laboratory testing for potential etiologies of ALF include autoimmune markers, viral

All patients with ALF should be monitored and treated in an intensive care unit. Many patients have progressed to multi-organ failure upon arrival, and immediate supportive measures should be undertaken. These may include interventions such as endotracheal intubation and mechanical ventilation, intravenous fluid resuscitation, placement of arterial

serologies, toxicology screen, and serum and urine testing for copper overload.

and central venous lines, and vasoactive agent support.

also known causes of drug-induced ALF.

ALF have an undetermined cause.

transplantation.

**2.3 Patient stabilization** 

**2.2 Diagnosis and initial management considerations in ALF** 

*Hepatic encephalopathy* is defined by the presence of neuropsychiatric symptoms in the absence of other causes of altered mental status. Mental status changes range from subtle cognitive impairments to frank coma. The impaired hepatic clearance of ammonia and other toxins are poorly tolerated in patients with ALF, and result in astrocyte swelling and cytotoxic cerebral edema. Hepatic encephalopathy is divided into four grades based on the West Haven Criteria (*Atterbury et al., 1978*); grade I denotes mild cognitive changes and attention deficits, grade II lethargy and apathy, grade III confusion and semi-stupor, and grade IV a comatose state.

Hepatic encephalopathy in ALF can result in cerebral edema, herniation, and death. Any patient with ALF and altered mental status should undergo an emergent head CT to rule out cerebrovascular accident, intracranial hemorrhage, or mass effect prior to treatment of hepatic encephalopathy. Those with grade III or IV encephalopathy should undergo elective endotracheal intubation and mechanical ventilation for airway protection, with maintenance of adequate sedation and patient-ventilator synchrony to reduce sudden increases in intracranial pressure. Neurosurgical placement of an intraparenchymal pressure monitor should then be strongly considered in order to continuously monitor and treat elevated intracranial pressure.

Intracranial hypertension is managed primarily with pharmacologic osmotherapy, with the goal to reduce intracranial pressure to less than 25 mmHg. Mannitol and hypertonic saline can be used for this purpose; if these measures fail, neuromuscular paralysis and therapeutic hypothermia with a target core body temperature of 32-33 degrees Celsius can be co-administered. In the setting of intracranial hypertension refractory to the above interventions, salvage therapy with barbiturate coma can be considered. Elevation of the head of the bed to 30 degrees is recommended for all patients. Furthermore, cerebral perfusion pressure, defined as the difference between mean arterial pressure and intracranial pressure, should be maintained at 60 mmHg or greater. In the setting of intracranial hypertension, this may require the use of vasoactive agents to increase the mean arterial pressure. Hyperventilation, formerly used to reduce intracranial pressure, may induce cerebral hypoxemia, and is no longer recommended for this purpose. Patients with grade I or II encephalopathy do not require intracranial pressure monitoring or endotracheal intubation for airway protection. However, serial neurologic exams are critical in these patients, as they can rapidly deteriorate to stage III or IV hepatic encephalopathy.

#### **2.4.2 Coagulopathy**

In addition to hepatic encephalopathy, *coagulopathy*, represented by an increasing INR, is a defining characteristic of progressing ALF. The synthetic function of the failing liver is diminished, and levels of clotting factors are reduced, resulting in elevations in the INR. In fact, the INR is considered the most sensitive indicator of hepatic function and is commonly used as a prognostic tool to aid prediction of spontaneous recovery or need for liver transplantation. Therefore, correction of the INR in the absence of bleeding is discouraged. For invasive procedures, the INR can be temporarily corrected with recombinant Factor VIIa (Novo-7) at a dose of 40 μg/kg. Such therapy reduces the INR to below 1.5 within 30 minutes of administration, and allows approximately 90-120 minutes for the performance of invasive procedures. Vitamin K may reduce the INR if malnutrition is contributing to coagulopathy.

Despite the coagulopathic state observed in ALF, anticoagulant proteins such as protein C and S are reduced, and patients are at risk of venous thrombotic complications. Therefore, venous thromboembolism prophylaxis with subcutaneous heparin or lowmolecular weight heparin formulations should be considered despite the presence of coagulopathy.
