The rapid onset, severity and complexity of organ failure in patients with severe acute liver failure necessitate
urgent admission to the ICU in the majority of cases. Patients with acute liver failure exhibiting any combination of
encephalopathy, acute renal failure, hypotension, lactic acidemia or hypoglycemia should be admitted to the ICU as fulminant
deterioration is likely.
Cerebral Edema and Intracranial Hypertension
Cerebral edema occurs in many patients with high-grade encephalopathy. 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 , and the loss of cerebral autoregulation
resulting in hyperemia  are two key drivers.
Ammonia is a waste product of nitrogen metabolism and undergoes detoxification via the urea cycle. The liver is
responsible for most of this detoxification activity and hyperammonemia is a cardinal feature of severe liver
failure. Ammonia readily crosses the blood brain barrier and the increasing brain tissue concentrations cause
neuroexcitation, astrocyte swelling and disruption of many crucial neuronal processes. A range of crucial astrocyte
signaling and intracellular functions are also impacted, causing further central nervous system (CNS) impairment. Ammonia
concentrations more than 117 µmol/l are highly associated with the development of severe cerebral edema and intracranial
hypertension . Severe acute liver failure also results in the accumulation
of false neurotransmitters, CNS depressants, and inflammatory mediators, which may reduce consciousness. Like ammonia,
these neurotoxic substances are generally small and water-soluble and may, therefore, be removed by extracorporeal
Cerebral blood flow is normally tightly regulated across a wide range of systemic arterial pressures. Autoregulation
is lost in patients with severe acute liver failure due to abnormal regulation of vasoactive mediators within the
CNS. This leads to cerebral hyperemia and vasogenic edema in severely encephalopathic patients.
Features of severe cerebral edema with resultant intracranial hypertension are difficult to detect in critically ill
patients with multiple organ failure and regular clinical evaluation is necessary.
A vasodilated, hyperdynamic circulation is present in most patients with acute liver failure. Relative or absolute
hypovolemia may develop due to poor fluid intake prior to presentation, abnormal external fluid losses, loss of
intravascular volume into the interstitium and vasodilatation. Many patients will be shocked and require vasopressor
therapy . Occasional patients may exhibit a low cardiac output state, (for
example, due to pre-existing cardiac pathology), and require inotropic support. Circulatory failure results in generalized
malperfusion ultimately leading to critical dysfunction in multiple organ systems.
Acute liver failure patients with multi-organ dysfunction are at high risk of infective complications , especially overwhelming Gram-negative and fungal sepsis. Pathogens may emerge from a
patient’s own microbiological flora or may be acquired from the hospital environment. Common sites of infection include
the lower respiratory tract, the urinary tract and invasive vascular access devices.
Coagulopathy is one of the defining features of hepatic decompensation. Hepatic synthesis of clotting factors fails
and many patients also develop significant thrombocytopenia. Bleeding may complicate the insertion of invasive devices, or
occur spontaneously. While spontaneous intracranial hemorrhage is very rare, the consequences can be
devastating. Sometimes, despite severe derangement of measured clotting parameters, a hypercoaguable state develops
 and may result in thrombotic complications, such as digital ischemia,
portal vein thrombosis or lower limb deep venous thrombosis. A patient’s clotting profile can be a guide to the severity
of their liver failure and normalization of a prolonged prothrombin time or international normalized ratio (INR) in the
absence of clotting factor support suggests hepatic regeneration and recovery of synthetic function.
Whether as a result of the primary pathology that also affects the liver (e.g., paracetamol overdose) or as a
consequence of systemic inflammatory response with shock, renal failure is a common problem in patients with acute liver
failure. Consequences of renal failure include electrolyte derangement and fluid balance problems, both of which
contribute significantly to the complex pathophysiology of acute liver failure. Severe uremia is relatively uncommon due
to disruption of the urea cycle.
Fluid and Electrolyte Management
Patients with acute liver failure will tend to accumulate a positive fluid balance and electrolyte abnormalities due
to the administration of fluid boluses for circulatory support, clotting factors and various other intravenous therapies,
such as antimicrobials. This can have several undesirable consequences including a predisposition to cerebral