Chapter 83. Fulminant Hepatic Failure

• Fulminant hepatic failure (FHF) is defined as the onset of hepatic encephalopathy (HE) within 8 weeks of the onset of liver-related symptoms.
• Common complications in patients with FHF include encephalopathy, cerebral edema, cardiovascular instability, renal failure, and infection.
• Supportive management of FHF consists of (1) airway protection, (2) intracranial pressure monitoring in the sickest patients, and (3) treatment of complications and vigilance for infection.
• Orthotopic liver transplantation (OLT) is the definitive therapy for FHF. Extracorporeal liver support remains investigational.

Fulminant hepatic failure (FHF) describes a clinical syndrome of progressive hepatocyte necrosis resulting in the dysfunction of virtually every major organ system. Consequently, management of patients with FHF is complicated and unpredictable, where many of the therapies initiated have not been proven effective in controlled clinical trials. Management of this syndrome requires early recognition and treatment of organ system deterioration because overall patient survival is inversely related to the number and extent of extrahepatic organ dysfunction. Therefore, treatment of these organ failures should be highly individualized and tailored toward anticipation and prevention of multisystem organ failure while waiting for recovery of hepatic function or liver transplantation.

Perhaps the most difficult dilemma in treating patients with FHF is the inability to predict which patients will recover adequate liver function and survive an episode of FHF without liver transplantation. Among patients with FHF who have progressed to grade 3 or 4 encephalopathy, expected recovery with medical management alone is approximately 10% to 40%.1 The advent of liver transplantation has improved survival markedly to 60% to 80% and is currently considered the treatment of choice for progressive FHF.1 Thus the overall treatment strategy has evolved into early stabilization of the FHF patient, optimization of the patient's general condition, and early and continued evaluation for liver transplantation.

Trey and Davidson2 originally proposed the term fulminant hepatic failure, which describes a condition of massive hepatic cell necrosis (Fig. 83-1) that is clinically evident by the progression to encephalopathy within 8 weeks of the onset of jaundice. Since this initial definition, numerous alterations and terms have been proposed that often complicate rather than clarify understanding of this disease process. A more concise definition proposed by O'Grady and colleagues3 attempts to precisely categorize liver failure into three types based on the time interval between the onset of jaundice and the emergence of encephalopathy: hyperacute (0 to 7 days), acute (8 to 28 days), and subacute (29 days to 12 weeks). The utility of this terminology is supported by the different clinical features and associated mortalities within each category (Table 83-1). Patients with hyperacute FHF tend to have rapidly progressive cerebral edema, to improve with medical management, and to have an overall favorable prognosis. Patients with acute FHF also have rapidly progressive FHF, but they tend to have a worse prognosis without liver transplant. Subacute FHF patients have a lower incidence of cerebral edema but an overall poor prognosis. It is important to distinguish hyperacute and acute FHF from subacute FHF. A recent modification of the nomenclature for liver failure was presented by the International Association for the Study of Liver (IASL) stressing the differences between hyperacute and acute versus subacute liver failure.4 The modified terminology includes only two groups, acute and subacute liver failure. However, there are temporal subcategories within acute liver failure that include hyperacute (onset less the 10 days), fulminant (onset 10 to 30 days), and acute hepatic failure not otherwise specified (AHF-NOS) that use the time from onset of jaundice to the onset of encephalopathy as the main differentiating feature. Subacute FHF is characterized by persistent, irreversible hepatitis leading to the development of ascites and/or encephalopathy over a protracted period of time (5 to 24 weeks). Wider acceptance of this new classification system will continue when analysis of FHF using this schema becomes more prevalent. Regardless of the classification system used, categorization of FHF is useful for retrospective analyses of patients but does not provide prospective guidelines for initial management. Therefore, all patients should be assumed to have an unpredictable clinical course that may require liver transplantation.

The causes of FHF are numerous and not always known at the time of presentation. Careful history taking from the patient, family, and significant others is mandatory and may provide valuable information for identifying the etiology of FHF. Additionally, certain causes require specific therapies or influence the appropriateness of liver transplantation. In the United States, acetaminophen toxicity has replaced acute viral hepatitis as the most common cause of FHF.5 Usually, metabolites of acetaminophen are direct hepatotoxins as compared with the hypersensitivity reactions associated with other drugs that cause FHF (e.g., halothane, antidepressants, and nonsteroidal anti-inflammatory drugs). Cellular damage secondary to acetaminophen intoxication is not isolated to the liver and often is associated with other signs of systemic toxicity, most commonly renal dysfunction. In addition to intentional ingestion of large doses of acetaminophen, therapeutic doses of acetaminophen can result in FHF. This therapeutic misadventure occurs when therapeutic doses of acetaminophen undergo rapid conversion to the toxic metabolite at a rate that exceeds the detoxification reaction. The potential for this situation exists in patients with hepatic enzymes that have been induced by exposure to drugs (alcohol, barbiturates, phenytoin, etc.) or in patients with malnutrition resulting in limited detoxification capacity.6 Of the viral causes of FHF, hepatitis A and hepatitis B are the most common. Hepatitis C infection rarely causes FHF unless coinfection with another hepatitis virus exists.7 In rare instances, categorized as non-A, non-E hepatitis, no etiologic cause of FHF is clearly evident, but the course is consistent with a viral etiology. Additional causes of FHF are listed in Table 83-2, including rare causes, which always need to be considered, especially when no clear basis for FHF is evident.

Initial Assessment

Patients suspected of having FHF should be managed in a critical care unit associated with an active liver transplant program. A multidisciplinary team composed of critical care specialists, hepatologists, transplant surgeons, and neurointensivists is essential for evaluating the patient and defining a plan of treatment. Ideally, this multidisciplinary care will be provided throughout the ICU admission, and members will participate in the decision making for liver replacement. The diagnosis of FHF is made by careful history, clinical assessment, and biochemical confirmation. A history of preexisting liver disease, toxin exposure (e.g., alcohol, acetaminophen, NSAIDs, etc.), acute viral illness, or a predisposing medical condition should increase suspicion of FHF in a patient presenting with altered mental status, transaminase elevation, and synthetic dysfunction. The latter is best reflected by an elevation in the International Normalization Ratio (INR) of prothrombin time. A rising INR coincident with falling liver transaminases is an ominous sign suggestive of nonrecoverable ongoing hepatic necrosis.

During the initial evaluation, the importance of a detailed history and physical examination cannot be overstated. Interviews with the patient, friends, and family and direct contact with referring physicians may provide insight into the acuity of the illness, social background, and possible coexisting medical conditions that may alter the patient's expected recovery and candidacy for transplantation. Medical records of patients transferred from outside institutions should be reviewed for evidence of administration of sedatives that may have an impact on the initial neurologic examination. Patients with FHF may present with confusion or combative behavior, which is often treated with benzodiazpines or narcotics. Administration of flumazenil or naloxone may be necessary, depending on the amount and type of benzodiazapine or narcotic exposure, to allow for an accurate baseline neurologic evaluation.

Monitoring

The degree of neurologic dysfunction, as measured by encephalopathy grade, should guide the initial level of invasive monitoring. This monitoring strategy is supported by the observation that hemodynamic instability in FHF is usually a late finding and most often occurs among patients in grade 3 or 4 encephalopathy. Large-bore peripheral intravenous lines, a nasogastric tube (or an orogastric tube if there is an uncorrected coagulopathy), a urinary catheter, an electrocardiogram, noninvasive blood pressure monitoring, and pulse oximetery are adequate for patients presenting with grade 1 or 2 encephalopathy. Excessive initial monitoring with invasive catheters is unnecessary and is associated with an increased risk of complications and infection. Among patients with grade 3 or 4 encephalopathy, endotracheal intubation is necessary for maintaining airway patency, oxygenation, and control of respiratory acidosis. Because patients with grade 3 or 4 encephalopathy may become combative and require sedation or have lapsed into coma, intracranial pressure (ICP) monitoring is strongly recommended. Extradural catheter monitoring is preferred in this setting for its safety and ease in placement.8 This subset of patients also may benefit from central venous or pulmonary artery monitoring, especially those receiving vasoactive drugs or mannitol to treat intracranial hypertension. Central venous, arterial, and extradural catheters can be inserted safely by experienced staff in the setting of an INR between 2 and 3. The risk of hemorrhage can be reduced further by choosing compressible sites, and using ultrasound guidance for venous and arterial access. For patients with greater degrees of coagulopathy, fresh frozen plasma (FFP) should be given in a limited window during which all necessary invasive procedures are planned. Repeated and intermittent FFP infusion obscures the clinician's ability to assess hepatic synthetic recovery and poses the additional risks of fluid overload and transfusion reaction.

Workup

The goal of initial laboratory evaluation is to find the potential causes of FHF, as well as to evaluate other organ system function. On arrival, the patient should have a complete blood count, platelet count, chemistries, liver function tests (albumin, bilirubin, alkaline phosphatase, AST, and ALT), prothrombin time (INR), arterial blood gas, factor V level, blood glucose level, and ammonia level. The preceding tests should be performed on a scheduled basis because clinical deterioration may be swift and unpredictable. Possible causes of FHF are sought through serologic assays for hepatitis A (anti-HAV IgM) and hepatitis B (anti-HBV IgM, HBsAg, HBcAb) and serum assays for ceruloplasmin, iron-binding capacity, toxic substances, and acetaminophen. A right upper quadrant ultrasound is useful in providing information regarding the patency of the hepatic vessels, liver size, presence of acites, and degree of compression of the porta hepatitis by intraabdominal masses. The role for liver biopsy is controversial. Although transjugular liver biopsies can be performed safely, there is little correlation between the extent of hepatic necrosis and the recoverability of the liver likely owing to sampling error. Despite this, liver biopsies are useful in patients for whom the cause of FHF is uncertain, or when lymphoma is a possible cause.

Acetaminophen Intoxication

Patients suspected of acetaminophen intoxication should be treated immediately with oral N-acetylcysteine, a proven free-radical scavenger that improves overall survival among patients with acetaminophen-induced FHF.9 The biochemical basis for this therapy is that the hepatoxicity induced by acetaminophen is mediated by its metabolite N-acetyl-benzoquinoneimine, which binds sulfhydryl groups in heptocytes.10 High levels of N-acetyl-benzoquinoneimine deplete glutathione stores, which normally reduce the toxic metabolites of acetaminophen. N-acetylcysteine functions by replenishing stores of intracellular reduced glutathione, thereby detoxifying N-acetyl-benzoquinoneimine. Recently, treatment with N-acetylcysteine also has shown beneficial affects in the overall hemodynamic status of patients with FHF by an undefined mechanism.11 Regardless of the time elapsed from ingestion, there are significant benefits to giving N-acetylcysteine even 10 to 36 hours after ingestion.11 Mortality was reduced from 58% to 37%, and significantly fewer patients progressed to grade 3 or 4 encephalopathy. N-Acetylcysteine is given orally in a 5% dextrose solution with a loading dose of 140 mg/kg, followed by 17 doses of 70 mg/kg every 4 hours. The Food and Drug Administration (FDA) has not approved the use of intravenous N-acetylcysteine in the United States because of reported anaphylactic reactions and electrocardiographic (ECG) abnormalities. However, in patients who have intractable vomiting, intravenous administration of N-acetylcysteine may be the only recourse. One approach is to compound a 3% N-acetylcysteine solution dosed intravenously identically to the oral regimen.12 For patients treated with N-acetylcysteine, the INR must be evaluated cautiously because false “improvements” in coagulation have been described.13

Virus-Induced FHF

Virus-induced FHF may present as a rapidly progressive new illness or an acute decompensation superimposed on preexisting liver disease. Regardless, many of these patients will require urgent liver transplantation if criteria for FHF are met. For patients with hepatitis B (with or without hepatitis D coinfection), antiviral therapy may be beneficial. Lamivudine, a nucleoside analog, improves Childs-Pugh status among patients with chronic hepatitis B cirrhosis.14,15 Experience with its use in the setting of FHF is limited. However, preliminary evidence has demonstrated hepatitis B e-antigen seroconversion in patients with FHF.16 Although this seroconversion is largely temporary, it suggests significant antiviral activity that may help an acutely decompenstated patient with hepatitis B from progressing to FHF. Despite the lack of definitive studies in acute decompensation, we recommend early lamivudine treatment in selected patients given the severity of illness and limited therapeutic options.

Central to the care of patients with FHF is the management of encephalopathy and cerebral edema. Starling forces of hydrostatic and osmotic pressure gradients appear to favor cerebral edema in FHF patients.17 Dysfunction of cerebral blood flow autoregulation, cerebral vasodilation, and a disrupted blood-brain barrier all contribute to the accumulation of interstitial cerebral fluid, resulting in increased ICP. A direct causative relationship between encephalopathy and cerebral edema has not been proven, and in patients with chronic liver failure, worsening encephalopathy is not associated with cerebral edema. In the acute setting, however, cerebral edema clearly is evident in patients with grade 3 or 4 encephalopathy. Progressive cerebral edema leading to uncal herniation and death unfortunately is the end point of many severely ill FHF patients who do not receive a liver transplant.

The extent of cerebral dysfunction should be determined repeatedly through careful neurologic examination. Owing to the limited sensitivity of computed tomography in detecting cerebral edema, repeated clinical evaluations and gradings of encephalopathy are required18 (Table 83-3). Repeated examinations by the same critical care or neurointensivist staff are optimal because assessment is subjective. Recognizing external factors that can exacerbate encephalopathy is important and probably underemphasized. The most common clinical scenario is that of a combative and confused patient with grade 2 encephalopathy who is treated with sedatives and then appears to progress to grade 3. When sedatives must be given to facilitate care or ensure patient safety, we recommend low-dose, short-acting benzodiazapines (e.g., 0.5 mg IV lorazepam). The mental status then should be assessed carefully and serially during the period of sedation. If sedatives are dosed repeatedly, the safest approach may be to intubate the patient electively and place an extradural monitor. Other external variables that may contribute to worsening encephalopathy include hypoglycemia, hypoxia, electrolyte abnormalities, gastrointestinal bleeding, and sepsis.19

Treatments effective in ameliorating the encephalopathy of decompensated cirrhosis, such as selective gut decontamination, lactulose, and dietary nitrogen restriction, have proven ineffective in FHF, and we do not recommend them.

Management of cerebral edema is based on principles of maintaining adequate cerebral perfusion while controlling factors that exacerbate interstitial cerebral fluid accumulation and increases in ICP. Initial measures should include avoidance of unnecessary stimulation, including respiratory suctioning in intubated patients, which may cause acute elevations in ICP. The head of the patient's bed should be elevated to 30 degrees, and the patient's head should be maintained in a neutral position. Simply avoiding, when possible, moving and provoking the patient will stabilize fluctuations in ICP and provide for more consistent assessment. Jugular venous lines risk potential obstruction of cerebral venous outflow, so some have advocated avoiding them, but the risks should be balanced against those of alternate sites (subclavian and bleeding, femoral and infection; see Chap. 12).

Brain blood flow is determined largely by the cerebral perfusion pressure (CPP), a function of mean arterial pressure (MAP) and ICP: CPP = MAP − ICP. At high levels of MAP, hydrostatic forces directly favor interstitial cerebral fluid accumulation. On the other hand, excessive lowering of MAP risks cerebral hypoperfusion if the limits of cerebral autoregulation are breached. Flow sufficiently low to cause brain hypoxia may amplify blood-brain barrier dysfunction.17 Therefore, optimal CPP is between 60 and 80 mm Hg.

Cerebral capillary osmotic pressure gradients also play an important role in the development of cerebral edema. Blood-brain barrier disruption and elevated serum ammonia levels lead to accumulating cerebral interstitial osmotic forces favoring water efflux into the cerebral interstitium. Approaches to limit this efflux include repair of the blood-brain barrier or increasing the cerebral capillary oncotic pressure. Evidence that the blood-brain barrier can be reconstituted in the setting of FHF is preliminary and involves strategies to reduce serum ammonia levels by continuous venous hemofiltration or by plasma exchange.20

The mainstay of current therapy is mannitol, which was the first treatment demonstrated to improve survival in patients with FHF21 (Fig. 83-2). By increasing cerebral capillary oncotic pressure, mannitol reduces the amount of water efflux into the interstitial space, resulting in lower ICPs. Mannitol (1 g/kg) usually is used in patients who have grade 4 encephalopathy, are intubated, and have appropriate monitoring of central venous pressure (CVP). Hypovolemic hypotension can be avoided by monitoring CVP and serum osmolarity and by ceasing mannitol infusion when osmolality exceeds 320 mOsm/L. In patients with renal failure, mannitol should be used only during continuous renal replacement therapy. In all patients, unnecessary free water should be avoided. Hypovolemia should be corrected using isotonic or hypertonic solutions.

Hyperventilation is no longer advocated to treat intracranial hypertension, except in a crisis (see Chaps. 65 and 93). Although hyperventilation is effective in the short term, tachyphylaxis follows. Moreover, the overall reduction in cerebral blood flow that results from hyperventilation-induced cerebral vasoconstriction may cause further disruption of the blood-brain barrier. The use of barbiturate coma is controversial, but it may be used in patients who have uncontrollable intracranial hypertension, often exacerbated by status epilepticus. Intentional hypothermia, sometimes used in conjunction with barbiturate coma to lower the metabolic demands of the brain, requires continuous electroencephalographic monitoring for titration of barbiturate doses to appropriate levels of sedation. There are many complications associated with barbiturate coma, including persistent posttransplant sedation, myocardial depression, and increased susceptibility to infection.22 These patients should be placed on empirical prophylactic antimicrobial agents directed toward nosocomial organisms. Despite the risks, coma should be induced with barbiturates on an individualized basis in patients with refractory intracranial hypertension.

Progression of FHF may lead to significant hemodynamic instability. Often, the hemodynamic changes resemble those associated with septic shock and include a hyperdynamic heart and a decreased systemic vascular resistance. Episodes of hypotension require aggressive evaluation and correction to prevent cerebral hypoperfusion, worsening injury to the blood-brain barrier, and multisystem organ failure. Although FHF is itself a common cause of hypotension (perhaps mediated by endotoxin23), each episode must be evaluated critically in order to recognize new sepsis, hemorrhage, myocardial dysfunction, or arrhythmia.24

Contrary to the management of septic shock, aggressive volume resuscitation has undesirable effects in FHF patients. Hypervolemia may contribute to pulmonary and cerebral edema from hydrostatic forces. Therefore, central venous or pulmonary artery monitoring are necessary to guide fluid and vasoactive drug use. When the ICP is being measured, CPP serves as the major parameter for titration of fluid and vasoactive therapy (goal >60 mm Hg) rather than the MAP. N-Acetylcysteine has shown some benefit in hemodynamic stabilization and improved oxygen consumption in FHF patients,25 but its use has not expanded beyond acetaminophen-induced FHF.

Acute renal failure is a frequent occurrence in the patients with FHF and is associated with a poor prognosis.26 The incidence of renal insufficiently approaches 75% among patients with acetaminophen-induced FHF and 30% to 50% among patients with FHF from other causes.27 Prerenal azotemia, acute tubular necrosis, hepatorenal syndrome, and nephrotoxic drugs may contribute to renal dysfunction and should be treated. One should maintain adequate intravascular volume, avoid and eliminate nephrotoxic agents, and ensure renal perfusion. Difficulties in the management of acute renal failure in the setting of FHF arise when indications for acute hemodialysis are met. Significant fluctuations in hemodynamic pressure and ICP have been demonstrated with intermittent hemodialysis in patients with FHF.28 For this reason, continuous renal replacement therapies (e.g. CVVHD) are preferred in this setting. Regardless of the method, baseline serum osmolarity should be monitored and maintained under tight control because rapid changes in osmolarity may exacerbate interstitial cerebral edema.

The onset of hypoxic respiratory failure usually is associated with the development of multisystem organ failure and predicts an overall poor prognosis. As an isolated event, hypoxia may be attributed to atelectasis, aspiration, pulmonary hemorrhage, acute respiratory distress syndrome (ARDS), or pneumonia. Diagnostic and therapeutic bronchoscopy generally should be avoided in these patients because of the potential to raise the ICP dramatically.

In patients with significant pulmonary dysfunction, the decision on suitability for liver transplantation is based largely on oxygen requirement and control of sepsis rather than on radiographic appearance. However, the presence of hypoxemia requiring greater than 60% FiO2 is likely to present difficulties with posttransplant management and survivability. During a liver transplant, reperfusion of a donor liver graft may exacerbate underlying pulmonary dysfunction, resulting in immediate right-sided heart failure. In addition, higher levels of positive end-expiratory pressure (PEEP) may reduce portal venous flow to the new graft,29 provoking hepatoctye dysfunction. Thus preoperative assessment and optimization of respiratory function will have a significant impact on survival of a patient during and following liver transplantation.

Patients with FHF have a high incidence of bacterial and fungal infections. Most infections are diagnosed within 72 hours of hospital admission and commonly are localized to the respiratory and urinary tracts. Catheter-related sepsis is also common but usually occurs 72 hours after admission. Cultures often reveal Staphylococcus aureus, Staphylococcus epidermidis, and Candida spp. An analysis of infectious complications among patients with FHF revealed that up to 80% develop bacterial infections, whereas 30% develop fungal infections.30 In addition, 18% of all patients with FHF ultimately died of infectious-related complications. Prevention, prophylaxis, and early detection are clearly the optimal approaches. Central venous catheters should be inserted using full barrier precautions and maintained with sterile technique (see Chaps. 4 and 12). When line sepsis is suspected, all lines must be removed and (if still necessary) replaced at alternative sites. Urinary catheters can be removed from anuric patients to limit the risk of an ascending urinary tract infection. We recommend prophylactic broad-spectrum antibiotic coverage at the time of hospital admission and adding antifungal coverage if sepsis develops while the patient is on the initial antibiotic regimen. This strategy is unproven and controversial, but it is supported by success in limiting postoperative infectious complications among patients with FHF.31 Early initiation of prophylactic antibiotic therapy also can be justified on the basis that the development of infection may terminate a patient's candidacy for transplantation, the consequences of which may be lethal.

Systemic infection usually contraindicates transplantation because of the high level of immunosuppression subsequently required. However, this contraindication is not absolute when considering the patient with FHF because recovery depends so heavily on getting a transplant. Thus positive blood, urine, or respiratory cultures are acceptable in a patient urgently needing transplantation so long as there is no associated uncontrollable sepsis with hemodynamic instability. A further difficulty in the patient with FHF is assessing the severity of infection because some consequences of hepatic failure reduce the manifestations of infection (such as a reduced incidence of fever and leukocytosis), whereas others amplify them (such as vasodilatation and hyperdynamic circulation). Proceeding with transplantation in an infected patient with FHF must be a highly individualized decision, with clear delineation of the risk-benefit situation for all involved.

The emergence of liver transplantation for the treatment of FHF has improved survival dramatically and should be considered the primary mode of therapy. Patients with evidence of encephalopathy should be referred to a tertiary care medical center with liver transplant capabilities and should be listed for emergency liver transplantation. The principal clinical dilemma is determining which patients with FHF should undergo liver transplantation and which patients will recover enough of their native livers to allow a reasonable chance of survival without transplantation. Adding to the complexity of decision making, the window of opportunity to benefit from a liver transplant is narrow. Therefore, the longer one waits to assess progress, the greater is the chance of missing the best treatment. One recent study demonstrated that the pretransplant median hospital stay was 3 days, whereas patients who did not receive a transplant died on median hospital day 5.5 This underscores the need for prognostic indicators capable of predicting survivability of FHF without liver transplantation.

The U.S. Acute Liver Failure Study Group has presented data from 17 tertiary care centers on 308 consecutive patients with FHF.5 The short-term patient survival was 67%. Twenty-nine percent of patients required liver transplantation, whereas 43% survived without transplantation. The only factor consistently associated with poor outcome was level of encephalopathy at the time of admission. Short-term transplant-free survival varied with the etiology of FHF. Patients with acetaminophen-induced FHF had a 68% survival compared with 25% and 17% for drug reaction and indeterminate-cause FHF, respectively. No consistent patient characteristic could be correlated with survivability without liver transplantation.

Attempts at developing criteria for determining the need for liver transplantation have met with only limited success. The Kings College criteria, developed after retrospective analysis of 580 patients with FHF, uses the following to predict outcome in non-acetaminophen-induced FHF: prothrombin time, age, etiology, time between onset of jaundice and onset of encephalopathy, and bilirubin levels. Criteria for patients with acetaminophen-induced FHF include factor V levels, blood pH, prothrombin time, serum creatinine concentration, and grade of encephalopathy. The Clichy criteria use factor V levels to assess severity of illness. Additional investigators have proposed alternative measurements, including serial prothrombin times,32 factor VIII/V ratios,33 serum Gc protein,34 and Acute Physiology and Chronic Health Evaluation (APACHE) II score. Although both the Kings College and Clichy criteria identify factors that predict poor prognosis, neither provides a clear assessment of which individual patient will survive an episode of FHF without liver transplantation. Moreover, both criteria have failed to predict reproducibly which patients will or will not require liver transplantation.35,36 Until better prognostic indicators can be developed to ascertain which patients with FHF will recover without liver transplantation, patients must be evaluated on a case-by-case basis.

The high mortality associated with FHF has prompted the use of many innovative treatments in an effort to improve outcomes. Most of these treatments were embraced initially for their potential but failed in clinical trials. Some of these continue to be of interest for their potential benefit; none, however, are of proven benefit.

High-Volume Plasma Exchange

High-volume plasma exchange is conducted similar to standard plasmapheresis protocols but with exchange volumes in excess of 8 L to improve the clearance of “harmful substances” that accumulate in FHF. The rationale for this approach is to reduce serum ammonia, control coagulopathy, and lower the metabolic demands on the injured liver. High-volume plasma exchange has been shown to reduce serum ammonia levels37 and improve hemodynamics in the setting of FHF.38 Although ammonia levels appear to be correlated with severity of encephalopathy, the exact mechanism involved is unknown.39 In the pediatric population, high-volume plasma exchange has been shown to improve homeostasis and coagulation profiles.40,41 All the studies have been uncontrolled, and none showed an improvement in overall survival. Randomized, controlled studies are needed before this potential treatment can be advocated.

Steroids

Steroid therapy has been tested under controlled conditions and does not confer benefit in clinical course or survival of patients with FHF.42 Moreover, steroid therapy is ineffective for established cerebral edema.43 Because steroids probably raise the risk of sepsis while being of no proven benefit, they have no role in the treatment of most FHF patients. One exception is the occasional patient with autoimmune hepatitis, in whom ongoing hepatic inflammation has culminated in FHF. For such patients, steroid therapy is beneficial and can significantly reverse liver failure.44

Prostaglandin E

Prostaglandins E1 and E2 (PGEs) have cytoprotective effects and raise hepatic arterial perfusion, both characteristics that could benefit FHF patient survival. However, two clinical trails from Europe and Canada have shown that use of PGEs is not associated with an improved outcome.45,46 PGEs also may lower MAP, which could compromise CPP in patients with cerebral edema. Thus, until more compelling evidence is available, PGEs cannot be recommended.

Auxiliary Liver Transplantation

Auxiliary liver transplantation has gained interest in Europe as a potential therapeutic option for FHF.47 Essentially, a reduced-size liver graft, obtained from living or deceased donors, is transplanted without removal of the recipient's native liver. The potential advantage of this procedure is to provide temporary hepatic function while awaiting recovery of the native liver and then to halt immunosuppression, causing atrophy of the (now redundant) auxiliary liver graft. This approach has not been tested in controlled clinical trials, and it should only be carried out only in highly specialized liver transplant centers with experience in reduced-size and other innovative techniques in liver transplantation.

Extracorporeal Liver Support

Extracorporeal liver-assist devices aim to provide temporary liver function as a bridge to liver transplant or to provide time for recovery of native liver function. There have been many different approaches to supporting liver function extracorporally, including ex vivo whole-organ perfusion,48 nonbiologic systems using dialysis against charcoal and anion-exchange adsorption (Molecular Adsorbent Recirculating System [MARS]49), combined nonbiologic-biologic systems that use both synthetic dialysis adsorption and hepatocyte cell mass (HepatAssist50), and purely biologic systems that use porcine hepatocytes (AMC Bioreactor51) or human hepatoma cell lines (ELAD).52 Many of these systems continue to be investigational, but some are promising. The combined nonbiologic-biologic system HepatAssist was evaluated in the largest, randomized phase I and II trails reported for extracorporeal liver support systems. A total of 171 patients with FHF (n = 147) or primary nonfunction (PNF) (n = 24) following liver transplant were randomized to receive standard medical management or medical management with the addition of HepatAssist. Overall, there was no statistically significant survival difference between the groups. However, subgroup analysis demonstrated a significant improvement in outcome following liver transplant in the HepatAssist group and a considerable improvement in a secondary end point (time to death) in patients with acetaminophen toxicity who ultimately underwent liver transplantation. Although extracorporeal liver-assist systems retain promise, they are only available investigationally.