Cerebral edema presents clinically as hepatic encephalopathy and may vary from subtle changes in affect, insomnia, and difficulty with concentration (stage 1) to deep coma (stage 4) (Ede and Williams 1986; Hoofnagle et al. 1995). Cerebral edema is a common neurologic component of FHF with the vast majority of cases progressing to stage 4 (Table 1) (Ede and Williams 1986). Cerebral edema leading to intracranial hypertension (ICH) is one of the major causes of morbidity and mortality in patients with FHF, accounting for the cause of death in the majority of patients due to brain herniation (Gazzard et al. 1975; Ede and Williams 1986; Pathikonda and Munoz 2010). The pathogenesis of cerebral edema and ICH in FHF appears to be multifactorial. Ammonia is converted in brain white matter to active glutamine, which osmotically causes cerebral edema (Bjerring et al. 2009). Other factors such as impaired cerebral blood flow, impaired autoregulation, systemic inflammatory response, and ischemic injury have also been proposed as a mechanism for the formation of cerebral edema.

Basic interventions for the management of cerebral edema should be applied universally in patients with high-grade hepatic encephalopathy. These interventions include elevation of the head of the bed to 30°, maintenance of a neutral neck position, endotracheal intubation, minimizing painful stimuli, and control of arterial hypertension (Frontera and Kalb 2011; Wang et al. 2013). Propofol is a reasonable choice for sedation because it may protect from worsening ICH. Intracranial pressure (ICP) monitoring by placement of epidural, subdural, or parenchymal catheter should be considered in FHF patients with high-grade hepatic encephalopathy, in centers with expertise in ICP monitoring, as well as in patients awaiting liver transplantation (Lidofsky et al. 1992). ICP monitoring can detect elevations in ICP to direct interventions, which may preserve brain perfusion and prevent cranial herniation. Generally, the goal of therapy in FHF is to maintain ICP less than 20 mmHg and cerebral perfusion pressure (CPP) more than 60 mmHg. CPP less than 40 mmHg for more than 2 h indicates reduced neurological blood flow to maintain intact brain function and could lead to poor posttransplantation prognosis (Hoofnagle et al. 1995). There are also several tools available for indirect measurement of cerebral blood flow, including jugular bulb catheter, transcranial Doppler, and xenon-enhanced computed tomography (Sundaram and Shaikh 2011). Factors that increase ICP need to be avoided and include hypercapnia, hyponatremia, frequent movements, neck vein compression, fluid overload, fever, hypoxia, coughing, sneezing, seizures, and endotracheal suctioning.

In patients with persistently elevated ICP, osmotic therapy with mannitol can be considered. Mannitol reduces ICP by osmotically drawing water from the brain parenchyma into the intravascular space (Larsen and Bjerring 2011). Hypothermia, although controversial, is thought to have some benefit in reducing ICP as it lowers brain energy metabolism, reduces arterial ammonia concentration and extraction of ammonia by the brain, and reverses systemic inflammatory reactions therefore reducing cerebral edema (Jalan et al. 1999). In addition to its neurological effect, studies have shown that hypothermia results in significant improvement of cardiovascular hemodynamics, as manifested by increased mean arterial pressure (MAP) and systemic vascular resistance, and reduction in noradrenaline requirements (Jalan et al. 1999; Vaquero and Blei 2004). Potential hazards include cardiac arrhythmias, infection, and bleeding complications (Stravitz and Larsen 2009). Therapeutic hypothermia (cooling to a core temperature of 34–35 °C) is probably well tolerated and effective, but randomized, controlled trials are needed to confirm the benefits of hypothermia before it is recommended routinely. Additionally, there may be challenges with the re-warming of patients.

FHF is characterized by a hyperdynamic circulation with high cardiac output, low mean arterial pressure (MAP), and low systemic vascular resistance (Siniscalchi et al. 2010). Due to poor oral intake, transudation of fluid into the extravascular space, and possibly gastrointestinal bleeding, most patients are volume depleted and require initial fluid resuscitation. The initial treatment of hypotension should involve intravenous infusion of normal saline and a volume challenge is recommended (Stravitz and Kramer 2009; Stravitz and Larsen 2009; Siniscalchi et al. 2010; Lee et al. 2011). With progressive renal failure and pulmonary edema, a Swan-Ganz catheter may be required to guide further management. The MAP should be maintained in a narrow range to achieve a CPP of 60–80 mmHg to prevent cerebral hypoperfusion and further cerebral hyperemia. Noradrenaline, with fewer β-adrenergic side effects, could increase hepatic blood flow in parallel with minimizing tachycardia and is often the preferred vasopressor (Stravitz and Kramer 2009). Patients with uncorrectable hypotension after volume repletion and vasopressor administration should be evaluated for adrenal insufficiency, which occurs frequently in the setting of liver failure (O’Beirne et al. 2007). Adrenal insufficiency can be corrected with stress doses of corticosteroids.

The incidence of acute renal failure in FHF is as high as 50–70 %. Direct drug nephrotoxicity, hepatorenal syndrome, and acute tubular necrosis due to ischemia from hypotension are among the most important associated disease entities (Bihari et al. 1986). Management includes avoidance of nephrotoxic agents, treatment of infection, maintenance of adequate renal perfusion, and renal replacement therapy. Early targeted volume replacement and vasoactive agent administration are essential to avoid arterial hypotension and ensure adequate renal perfusion. Worsening renal failure needs to be addressed with renal replacement therapy. Continuous renal replacement therapy is recommended, as most patients with FHF tolerate intermittent hemodialysis poorly because of circulatory instability, precipitous fluid shifts, and a rise in ICP (Davenport et al. 1993).

The liver plays a central role in the synthesis of the majority of coagulation factors and many inhibitors (Pereira et al. 1996). The principal hematologic abnormalities seen in FHF include platelet dysfunction and reduced levels of anticoagulant proteins (protein C/S or antithrombin III) and procoagulation factors (II, V, VII, IX, and X) due to failure of synthesis and consumption (Pereira et al. 1996). This causes a prolongation in the prothrombin time, as well as a tendency to develop thrombotic events such as disseminated intravascular coagulation (Langley and Williams 1992).

Bleeding generally occurs from superficial mucosal lesions, especially gastric erosions. Administration of proton pump inhibitors can decrease the risk of gastric mucosal bleeding. In general, infusion of fresh frozen plasma is indicated only for control of active bleeding or during invasive procedures. Cryoprecipitate is recommended in patients who have significant hypofibrinogenemia (<1 g/L). Platelet transfusion is indicated only to aid in controlling active bleeding or during invasive procedures if the count is <50 × 10⁹/L or prophylactically if <20 × 10⁹/L (Munoz et al. 2009). Finally, vitamin K (5–10 mg subcutaneously) should be considered in all patients with FHF, because its deficiency can occur in >25 % of patients.

Metabolic abnormalities in FHF include hypoglycemia, lactic acidosis, and electrolyte derangements. Patients are prone to develop hypoglycemia because hepatocyte necrosis causes glycogen depletion and defective glycogenolysis and gluconeogenesis. Rapid development of hypoglycemia can confound hepatic encephalopathy and contribute to poor ICP control (Schneeweiss et al. 1993). Serum phosphate, potassium, and magnesium are frequently low, requiring repeated supplementation. Owing to the hypercatabolic state of FHF, nutrition is vital and enteral feedings should be initiated early. If enteral feeding is contraindicated, parenteral nutrition may be considered on a case-by-case basis (Montejo González et al. 2011).

Infections, particularly bacterial respiratory and urinary tract, develop in as many as 80 % of patients with FHF (Wyke et al. 1982; Sass and Shakil 2005). FHF patients have enhanced susceptibility to infection because of the presence of indwelling lines and catheters, dysfunction of monocytes, impaired complement system, and impaired neutrophil and Kupffer cell function (Leber et al. 2012). Infectious organisms are mainly Gram-negative enteric bacilli, Gram-positive cocci, and Candida species (Rolando et al. 1996). In addition to infection inhibiting hepatic regeneration, it is associated with progression of hepatic encephalopathy and renal failure, reduces successful rate of liver transplantation, and increases mortality in FHF (Rolando et al. 1996). One must have a high index of suspicion for infection and obtain surveillance cultures in addition to chest radiographs if there is any unexpected deterioration in the patient’s status. Empirical antibiotics should be considered upon presentation (Leber et al. 2012).