A guide to managing acute liver failure

Cerebral edema and intracranial hypertension

Cerebral edema is the leading cause of death in patients with acute liver failure, and it develops in nearly 40% of patients.³⁶

The mechanism by which cerebral edema develops is not well understood. Some have proposed that ammonia is converted to glutamine, which causes cerebral edema either directly by its osmotic effect^37,38 or indirectly by decreasing other osmolytes, thereby promoting water retention.³⁹

Cerebral edema leads to intracranial hypertension, which can ultimately cause cerebral herniation and death. Because of the high mortality rate associated with cerebral edema, invasive devices were extensively used in the past to monitor intracranial pressure. However, in light of known complications of these devices, including bleeding,⁴⁰ and lack of evidence of long-term benefit in terms of mortality rates, their use has come under debate.

Treatments. Many treatments are available for cerebral edema and intracranial hypertension. The first step is to elevate the head of the bed about 30 degrees. In addition, hyponatremia should be corrected, as it can worsen cerebral edema.⁴¹ If patients are intubated, maintaining a hypercapneic state is advisable to decrease the intracranial pressure.

Of the two pharmacologic options, mannitol is more often used.⁴² It is given as a bolus dose of 0.5 to 1 g/kg intravenously if the serum osmolality is less than 320 mOsm/L.¹ Given the risk of fluid overload with mannitol, caution must be exercised in patients with renal dysfunction. The other pharmacologic option is 3% hypertonic saline.

Therapeutic hypothermia is a newer treatment for cerebral edema. Lowering the body temperature to 32 to 33°C (89.6 to 91.4°F) using cooling blankets decreases intracranial pressure and cerebral blood flow and improves the cerebral perfusion pressure.⁴³ With this treatment, patients should be closely monitored for side effects of infection, coagulopathy, and cardiac arrythmias.¹

l-ornithine l-aspartate was successfully used to prevent brain edema in rats, but in humans, no benefit was seen compared with placebo.^44,45 The underlying basis for this experimental treatment is that supplemental ornithine and aspartate should increase glutamate synthesis, which should increase the activity of enzyme glutamine synthetase in skeletal muscles. With the increase in enzyme activity, conversion of ammonia to glutamine should increase, thereby decreasing ammonia circulation and thus decreasing cerebral edema.

Patients with cerebral edema have a high incidence of seizures, but prophylactic antiseizure medications such as phenytoin have not been proven to be beneficial.⁴⁶

Infection

Nearly 80% of patients with acute liver failure develop an infectious complication, which can be attributed to a state of immunodeficiency.⁴⁷

The respiratory and urinary tracts are the most common sources of infection.⁴⁸ In patients with bacteremia, Enterococcus species and coagulase-negative Staphylococcus species⁴⁹ are the commonly isolated organisms. Also, in patients with acute liver failure, fungal infections account for 30% of all infections.⁵⁰

Infected patients often develop worsening of their encephalopathy⁵¹ without fever or elevated white blood cell count.^49,52 Thus, in any patient in whom encephalopathy is worsening, an evaluation must be done to rule out infection. In these patients, systemic inflammatory response syndrome is an independent risk factor for death.⁵³

Despite the high mortality rate with infection, whether using antibiotics prophylactically in acute liver failure is beneficial is controversial.^54,55

Gastrointestinal bleeding

The current prevalence of upper gastrointestinal bleeding in acute liver failure patients is about 1.5%.⁵⁶ Coagulopathy and endotracheal intubation are the main risk factors for upper gastrointestinal bleeding in these patients.⁵⁷ The most common source of bleeding is stress ulcers in the stomach. The ulcers develop from a combination of factors, including decreased blood flow to the mucosa causing ischemia and hypoperfusion-reperfusion injury.

Pharmacologic inhibition of gastric acid secretion has been shown to reduce upper gastrointestinal bleeding in acute liver failure. A histamine H₂ receptor blocker or proton pump inhibitor should be given to prevent gastrointestinal bleeding in patients with acute liver failure.^1,58

EXPERIMENTAL TREATMENTS

Artificial liver support systems

Membranes and dialysate solutions have been developed to remove toxic substances that are normally metabolized by the liver. Two of these—the molecular adsorbent recycling system (MARS) and the extracorporeal liver assist device (ELAD)—were developed in the late 1990s. MARS consisted of a highly permeable hollow fiber membrane mixed with albumin, and ELAD consisted of porcine hepatocytes attached to microcarriers in the extracapillary space of the hollow fiber membrane. Both systems allowed for transfer of water-soluble and protein-bound toxins in the blood across the membrane and into the dialysate.⁵⁹ The clinical benefit offered by these devices is controversial,^60–62 thus limiting their use to experimental purposes only.

Hepatocyte transplant

Use of hepatocyte transplant as a bridge to liver transplant was tested in 1970s, first in rats and later in humans.⁶³ By reducing the blood ammonia level and improving cerebral perfusion pressure and cardiac function, replacement of 1% to 2% of the total liver cell mass by transplanted hepatocytes acts as a bridge to orthotopic liver transplant.^64,65

PROGNOSIS

Different criteria have been used to identify patients with poor prognosis who may eventually need to undergo liver transplant.

The King’s College criteria system is the most commonly used for prognosis (Table 4).^37,66–69 Its main drawback is that it is applicable only in patients with encephalopathy, and when patients reach this stage, their condition often deteriorates rapidly, and they die while awaiting liver transplant.^37,66,67

The Model for End-Stage Liver Disease (MELD) score is an alternative to the King’s College criteria. A high MELD score on admission signifies advanced disease, and patients with a high MELD score tend to have a worse prognosis than those with a low score.⁶⁸

The Acute Physiology and Chronic Health Evaluation (APACHE) II score can also be used, as it is more sensitive than the King’s College criteria.⁶

The Clichy criteria^66,69 can also be used.

Liver biopsy. In addition to helping establish the cause of acute liver failure, liver biopsy can also be used as a prognostic tool. Hepatocellular necrosis greater than 70% on the biopsy predicts death with a specificity of 90% and a sensitivity of 56%.⁷⁰

Hypophosphatemia has been reported to indicate recovering liver function in patients with acute liver failure.⁷¹ As the liver regenerates, its energy requirement increases. To supply the energy, adenosine triphosphate production increases, and phosphorus shifts from the extracellular to the intracellular compartment to meet the need for extra phosphorus during this process. A serum phosphorus level of 2.9 mg/dL or higher appears to indicate a poor prognosis in patients with acute liver failure, as it signifies that adequate hepatocyte regeneration is not occurring.