eMedicine Specialties > Gastroenterology > Liver

Acute Liver Failure: Treatment & Medication

Author: Gagan K Sood, MD, Associate Professor, Department of Medicine and Surgery, Baylor College of Medicine
Contributor Information and Disclosures

Updated: Jun 25, 2009

Treatment

Medical Care

The most important step is to identify the cause of liver failure. Prognosis of acute liver failure is dependent on etiology. A few etiologies of acute liver failure demand immediate and specific treatment. It is also critical to identify those patients who will be candidates for liver transplantation.

The most important aspect of treatment in patients with acute liver failure is to provide good intensive care support.^13,16,17,18 Patients with grade II encephalopathy should be transferred to the intensive care unit (ICU) for monitoring. As the patient develops progressive encephalopathy, protection of the airway is important.

Most patients with acute liver failure tend to develop some degree of circulatory dysfunction. Careful attention should be paid to fluid management, hemodynamics, metabolic parameters, and surveillance of infection. Maintenance of nutrition and prompt recognition of gastrointestinal bleeding are crucial. Coagulation parameters, CBC count, and metabolic panel should be checked frequently. Serum aminotransferases and bilirubin are generally measured daily to follow the course of infection. Intensive care management includes recognition and management of complications.

• Airway protection
  • As the patients with fulminant hepatic failure drift deeper into coma, their ability to protect their airway from aspiration decreases. Patients who are in stage III coma should have a nasogastric tube (NGT) for stomach decompression. When patients progress to stage III coma, intubation should be performed.
  • Short-acting benzodiazepines in low doses (eg, midazolam 2-3 mg) may be used before intubation or propofol (50 mcg/kg/min) may be initiated before intubation and continued as an infusion. Propofol is also known to decrease the cerebral blood flow and ICH. It may be advisable to use endotracheal lidocaine before endotracheal suctioning.
• Encephalopathy and cerebral edema
  • Patients with grade I encephalopathy may sometimes be safely managed on a medicine ward. Frequent mental status checks should be performed with transfer to an ICU warranted with progression to grade II encephalopathy.
  • Head imaging with CT scanning is used to exclude other causes of decline in mental status, such as intracranial hemorrhage.
  • Sedation should be avoided if possible; unmanageable agitation may be treated with short-acting benzodiazepines in low doses.
  • Patients should be positioned with the head elevated at 30°.
  • Efforts should be made to avoid patient stimulation. Maneuvers that cause straining or, in particular, Valsalva-like movements may increase ICP.
  • There is increasing evidence that ammonia may play a pathogenic role in the development of cerebral edema. Reducing elevated ammonia levels with enteral administration of lactulose might help prevent or treat cerebral edema.
  • ICP monitoring helps in the early recognition of cerebral edema. The clinical signs of elevated ICP, including hypertension, bradycardia, and irregular respirations (Cushing triad), are not uniformly present; these and other neurologic changes, such as pupillary dilatation or signs of decerebration, are typically evident only late in the course.
  • CT scanning of the brain does not reliably demonstrate evidence of edema, especially at early stages. A primary purpose of ICP monitoring is to detect elevations in ICP and reductions in cerebral perfusion pressure (CPP; calculated as mean arterial pressure [MAP] minus ICP) so that interventions can be made to prevent herniation while preserving brain perfusion.
  • The ultimate goal of such measures is to maintain neurologic integrity and prolong survival while awaiting receipt of a donor organ or recovery of sufficient functioning hepatocyte mass. Additionally, refractory ICH and/or decreased CPP is considered a contraindication to liver transplantation in many centers.
• Cardiovascular monitoring
  • Homodynamic derangements consistent with multiple organ failure occur in acute liver failure. Hypotension (systolic, <80 mm Hg) may be present in 15% of patients. Most patients will require fluid resuscitation on admission. Intravascular volume deficits may be present on admission due to decreased oral intake or gastrointestinal blood loss. Hemodynamic derangement resembles that of sepsis or cirrhosis with hepatorenal syndrome (low SVR with normal or increased cardiac output). An arterial line should be placed for continuous blood pressure monitoring.
  • A Swan–Ganz catheter should be placed and fluid replacement with colloid albumin should be guided by the filling pressure. If needed, dopamine or norepinephrine can be used to correct hypotension.
• Management of renal failure: Hemodialysis may significantly lower the mean arterial pressure such that cerebral perfusion pressure is compromised. Continuous veno-venous hemofiltration is preferred.
• Management of coagulopathy¹⁹
  • In the absence of bleeding, it is not necessary to correct clotting abnormalities with fresh frozen plasma (FFP); the exception is when an invasive procedure is planned or in the presence of profound coagulopathy (INR >7). (PT and PTT become prolonged when plasma coagulation components are diluted to less than 30%, and abnormal bleeding occurs when they are less than 17%. One unit of FFP increases the coagulation factor by 5%; 2 units increase it by 10%.) FFP of 15 mL/kg of body weight or 4 units correct deficiency. If the fibrinogen level is very low (<80 mg/dL), consider cryoprecipitation.
  • Recombinant factor VIIa may be used in patients whose condition is nonresponsive to FFP. It is used in a dose of 4 µg/kg IV push over 2-5 minutes. PT is normalized in 20 minutes and remains normalized for 3-4 hours.
  • Platelet transfusions are not used until the count is less than 10,000/µL or if an invasive procedure is being done and the platelet count is less than 50,000/µL. Six to 8 random donor platelets (1 random donor unit platelet/10 kg) will increase the platelet count to greater than 50,000/µL. The platelet count should be checked after 1 hour and 24 hours. Transfused platelets survive 3-5 days.
• Managing poisonings (eg, acetaminophen, mushroom) requires specific treatment distinct from other, more general issues related to fulminant hepatic failure.
  • Treat acetaminophen (paracetamol, APAP) overdose with N-acetylcysteine (NAC). Researchers theorize that this antidote works by a number of protective mechanisms. Early after overdose, NAC prevents the formation and accumulation of N-acetyl-p-benzoquinone imine (NAPQI), a free radical that binds to intracellular proteins, nonspecifically resulting in toxicity.
  • NAC increases glutathione stores, combines directly with NAPQI as a glutathione substitute, and enhances sulfate conjugation. NAC also functions as an anti-inflammatory and antioxidant and has positive inotropic and vasodilating effects, which improve microcirculatory blood flow and oxygen delivery to tissues. These latter effects decrease morbidity and mortality once hepatotoxicity is well established.
  • The protective effect of NAC is greatest when administered within 8 hours of ingestion; however, when indicated, administer regardless of the time since the overdose. Therapy with NAC has been shown to decrease mortality in late-presenting patients with fulminant hepatic failure (in the absence of acetaminophen in the serum).
  • A phalloides mushroom intoxication is much more common in Europe as well as in California. Treat with IV penicillin G, even though its mode of action is unclear. Silibinin, a water-soluble derivative of silymarin, may be administered orally, and oral charcoal may be helpful by binding the mushroom toxin.

Surgical Care

Liver transplantation is the definitive treatment in liver failure, but a detailed discussion is beyond the scope of this article. Although, 2 recent studies regarding liver transplantation are mentioned below, preoperative management is emphasized in this section. 

Lerut et al evaluated the effect of tacrolimus monotherapy in 156 adults receiving a primary liver graft, randomizing them to receive tacrolimus-placebo and tacrolimus-low-dose, short-term (64 days), steroid immunosuppression. There were no exclusion criteria at randomization, and all patients had a 12-month follow-up (range, 12-84).²⁰
 
The investigators found that the patients in the tacrolimus-steroid group had higher 3- and 12-month survival rates, as well as higher 12-month graft survival rates, relative to those in the tacrolimus-placebo group. Not only were fewer patients in the tacrolimus-steroid group administered rejection treatment at 3 and 12 months, but fewer individuals in this group and the group of 145 patients transplanted without artificial organ support demonstrated corticosteroid-resistant rejection at 3 and 12 months.²⁰

By 1 year, 82% (64/78) of those in the tacrolimus steroid group were on tacrolimus monotherapy compared with 78.2% (61/78) of those in the tacrolimus-placebo group (P = 0.54). However, when considering the 74 tacrolimus-steroid and 67 tacrolimus-placebo survivors, rates of monotherapy were lower in the tacrolimus-steroid group versus the tacrolimus-placebo group (P = 0.39).²⁰  

Lerut et al concluded that tacrolimus monotherapy can be achieved safely without compromising graft nor patient survival in a primary, even unselected, adult liver transplant population and that such a strategy may lead to further large-scale minimization studies in liver transplantation.²⁰ The investigators attributed the higher incidence of early corticosteroid-resistant rejection in the tacrolimus-placebo group to the significantly higher number of patients transplanted while being on artificial organ support and recommended that the monodrug immunosuppressive strategy would require adaptation in this setting.²⁰  

In a retrospective study, Taketomi et al evaluated donor safety in adult-to-adult living donor liver transplantation by establishing a selection criterion for donors in which the left lobe was the first choice of graft.²¹ Two hundred and six consecutive donors were divided into 2 groups according to the graft type (left [n = 137] vs right lobe [n =69]). Mean intraoperative blood loss was significantly increased in the left lobe donors compared with right lobe donors; however, mean peak postoperative total bilirubin levels and duration of hospital stay after surgery were significantly less for those in the left lobe group (P <0.05).²¹  

No donor died or suffered a life-threatening complication during the study period. The investigators noted that logistic regression analysis revealed that only graft type (left vs right lobe) was significantly related to the occurrence of biliary complications (odds ratio 0.11; P = 0.0012).²¹ However, there were no significant differences regarding the cumulative overall graft survival rates between the recipients with left lobe grafts and those with right lobe grafts.

• In selected patients for whom no allograft is immediately available, consider support with a bioartificial liver. This is a short-term measure that only leads to survival if the liver spontaneously recovers or is replaced.^22,23,24,25
• In the future, hepatocyte transplantation, which has shown dramatic results in animal models of acute liver failure, may provide long-term support, but it remains investigational.
• Artificial liver support systems
  • Artificial liver support systems can be divided into 2 major categories: biologic (bioartificial) and nonbiologic.
  • The bioartificial liver is composed of a dialysis cartridge with mammalian or porcine hepatocytes filling the extracapillary spaces. These devices have undergone controlled trials. One multicenter trial reported improved short-term survival for a subgroup of patients with acute liver failure who were treated with a porcine hepatocyte-based artificial liver.²⁵
  • Nonbiologic extracorporeal liver support systems, such as hemodialysis, hemofiltration, charcoal hemoperfusion, plasmapheresis, and exchange transfusions, have been used; however, no controlled study has shown long-term benefit.
  • These modalities permit temporary liver support until a suitable donor liver is found. Although extracorporeal hemoperfusion of charcoal and other inert substances provide some measure of excretory function, no synthetic capacity is provided.
  • Among the liver support systems currently available, albumin dialysis using the molecular adsorbent recirculating system (MARS) is the one that has been most extensively investigated. In this device, blood is dialyzed across an albumin-impregnated membrane against 20% albumin. Charcoal and anion exchange resins columns in the circuit cleanse and regenerate the albumin dialysate. Clinical studies have shown that it improves hyperbilirubinemia and encephalopathy.
  • Two other systems based on the removal of albumin bound toxins, the Prometheus, using the principle of fractionated plasma separation and adsorption (FPSA), and the single pass albumin dialysis (SPAD), are also undergoing clinical studies for acute liver failure.
  • Currently available liver support systems are not routinely recommended outside of clinical trials.

Consultations

Managing fulminant hepatic failure is a team effort. Consultations in the areas of intensive care, gastroenterology, infectious diseases, hematology, neurology, neurosurgery, and transplantation surgery may be needed to address the myriad complex issues that can confront the medical staff.

Diet

• Patients with acute liver failure are, by necessity, nothing by mouth (NPO). They may require large amounts of IV glucose to avoid hypoglycemia.
• When enteral feeding via a feeding tube is not feasible (eg, as in a patient with paralytic ileus), institute total parenteral nutrition (TPN). (See also Nutritional Requirements of Adults Before Transplantation and Nutritional Requirements of Children Prior to Transplantation)
• Restricting protein (amino acids) to 0.6 g/kg body weight per day was previously routine in the setting of hepatic encephalopathy, but this may not be necessary.

Activity

Bedrest is recommended.

Medication

Multiple medications may be necessary in patients with acute liver failure because of the wide variety of complications that may develop from fulminant hepatic failure. Decreased hepatic metabolism and the potential for hepatotoxicity become central issues. Antidotes that effectively bind or eliminate A phalloides toxin and toxic metabolites of acetaminophen are essential.

Acetaminophen ingestion of more than 10 g may be hepatotoxic due to formation of a highly reactive toxic intermediate metabolite, which is ordinarily metabolized further in the presence of glutathione to N -acetyl-p-aminophenol-mercaptopurine. Administering NAC permits restitution of intrahepatic glutathione. NAC is most effective when administered within 12-20 hours following acetaminophen overdose. Never administer aminoglycosides and NSAIDs, because the potential for nephrotoxicity is exaggerated greatly in this setting.

Antidotes

Antidotes neutralize toxic agents.

Penicillin G (Pfizerpen)

First DOC. Treatment of Amanita poisoning is with IV penicillin G, although mode of action is unclear.

Silibinin (Silibinin Plus)

Water-soluble derivative of silymarin, which is the active ingredient in herbal preparation milk thistle. Possesses antioxidant properties that may benefit liver disease management.

Activated charcoal (Actidose-Aqua, Liqui-Char, CharcoAid)

If ingestion has been recent, Amanita toxin may be bound to charcoal and absorption prevented.

N-acetylcysteine (Mucomyst, Mucosil)

First DOC in acetaminophen overdose. Provides reducing equivalents to help restore depleted intrahepatic glutathione levels.

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