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Home , Acute liver failure, Liver failure

The new england journal of

review article

CRITICAL CARE MEDICINE Failure

William Bernal, M.D., and Julia Wendon, M.B., Ch.B.

cute is a rare but life-threatening critical ill- From the Liver Intensive Therapy Unit, ness that occurs most often in patients who do not have preexisting liver Institute of Liver Studies, King’s College London, London. Address reprint re- . With an incidence of fewer than 10 cases per million persons per quests to Dr. Bernal at the Liver Intensive A Therapy Unit, Institute of Liver Studies, year in the developed world, is seen most commonly in previ- ously healthy adults in their 30s and presents unique challenges in clinical manage- King’s College London, Denmark Hill Campus, King’s College Hospital, Den- ment. The clinical presentation usually includes hepatic dysfunction, abnormal mark Hill, London SE5 9RS, United King- liver biochemical values, and ; may develop, with mul- dom, or at [email protected]. 1-3 tiorgan failure and death occurring in up to half the cases (Fig. 1). N Engl J Med 2013;369:2525-34. The rarity of acute liver failure, along with its severity and heterogeneity, has DOI: 10.1056/NEJMra1208937 resulted in a very limited evidence base to guide supportive care.4 However, rates Copyright © 2013 Massachusetts Medical Society. of survival have improved substantially in recent years through advances in critical care management and the use of emergency .5 In this review, we outline the causes and clinical manifestations of acute liver failure and discuss current approaches to patient care.

The Clinical Problem

Definition and Presentation The original term “ hepatic failure,” defined as “a severe liver injury, po- tentially reversible in nature and with onset of within 8 weeks of the first symptoms in the absence of pre-existing ,”6 remains relevant today. More modern definitions recognize distinct disease phenotypes and quantify the interval between the onset of symptoms and the development of en- cephalopathy7 (Fig. 2). This interval provides clues to the cause of disease, likely complications, and prognosis with supportive medical care alone.8-10 In hyperacute cases, this interval is a week or less, and the cause is usually acetaminophen toxic- ity or a viral infection. More slowly evolving, or subacute, cases may be confused with and often result from idiosyncratic drug-induced liver injury or are indeterminate in cause. Patients with subacute causes, despite having less marked coagulopathy and encephalopathy, have a consistently worse outcome with medical care alone than those in whom the illness has a more rapid onset.

Causes Acute liver failure is much less common in the developed world than in the develop- ing world, where viral infections ( A, B, and E) are the predominant causes. Public health measures (e.g., vaccination and improved sanitation) are among the factors resulting in the reduced incidence of these infections in the United States and much of Western Europe, where drug-induced liver injury is the most common cause of acute liver failure (Fig. 3).

Viruses Globally, and E infections are probably responsible for the majority of cases of acute liver failure, with rates of death of more than 50% reported from the

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Brain Hepatic encephalopathy Cerebral Intracranial hypertension

Lungs Acute injury Heart Acute respiratory distress syndrome High output state Frequent subclinical myocardial injury

Liver Pancreas Loss of metabolic function , particularly in Decreased: acetaminophen-related disease Gluconeogenesis Lactate clearance clearance hyperammonemia Adrenal gland Synthetic capacity coagulopathy Inadequate glucocorticoid production contributing to

Kidney Bone marrow Frequent dysfunction or failure Frequent suppression, particularly in viral and seronegative disease

Portal hypertension May be prominent in subacute disease and confused with chronic liver disease Circulating leukocytes Impaired function, with immunoparesis contributing to high risk of Systemic inflammatory response High energy expenditure or rate of catabolism

Figure 1. Clinical Features of Acute Liver Failure.

developing world.11,12 Acute liver failure may also tive in prevention.14 Other rare viral causes of acute occur after infection,13 which is a com- liver failure include herpes simplex virus, cytomeg- mon cause in some Asian and Mediterranean alovirus, Epstein–Barr virus, and parvoviruses.15 countries. Particularly poor survival has been seen in patients with reactivation of previously Drug-Induced Liver Injury stable subclinical infection with the hepatitis B Drug-induced liver injury is responsible for ap- virus without established chronic liver disease. proximately 50% of cases of acute liver failure in This scenario is most common in patients with the United States.16,17 Such injury may be dose- treatment-induced immunosuppression during or dependent and predictable, as exemplified by after therapy for cancer. The identification of acetaminophen-induced , which is at-risk patients and the use of antiviral prophy- the most common cause of acute liver failure in laxis before the initiation of chemotherapy, im- the United States. It may also be idiosyncratic, munotherapy, or glucocorticoid therapy are effec- unpredictable, and probably independent of dose.

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Although acute liver failure after acetamino- A O’Grady System phen ingestion can occur after consumption of Hyper- a single large dose, the risk of death is greatest acute Acute Subacute with substantial drug ingestion staggered over hours or days rather than at a single time point. 0 1 2 4 8 12 Acute liver failure is more common with late Weeks from to Encephalopathy presentation to medical attention because of un­ 18 intentional rather than deliberate self-poisoning. B Bernuau System Malnourished patients and patients with alco- Fulminant Subfulminant holism are at increased risk.19 Acetaminophen is also a potential cofactor for hepatic injury in 0 1 2 4 8 12 patients taking the drug for the relief of symp- Weeks from Jaundice to Encephalopathy toms from hepatic illness of other causes.20,21 Idiosyncratic drug-induced liver injury is rare, C Japanese System even among patients who are exposed to poten- Fulminant Late-Onset tially hepatotoxic medication, and few patients with drug-induced liver injury have progression Subclass: Acute Subacute to encephalopathy and acute liver failure.22 Fac- tors such as an older age, increased elevations in blood aminotransferase and levels, and 0 1 2 4 8 12 coagulopathy are associated with an increased Weeks from Jaundice to Encephalopathy 17,23 risk of death. Figure 2. Classification Systems for Acute Liver Failure. Data are from O’Grady et al.,8 Bernuau et al.,9 and Mochida et al.10 In the Other Causes Japanese system, the late-onset period is 8 to 24 weeks. Acute ischemic hepatocellular injury, or hypoxic hepatitis, may occur in critically ill patients with primary cardiac, circulatory, or . virus or exposure to a toxin. These cases often It may be caused by severe sepsis accompanied by follow a subacute presentation, and rates of sur- signs of cardiac failure and major, transient eleva- vival are poor without transplantation. tions in blood aminotransferase levels.24,25 This condition primarily requires supportive cardio­ Focus of Critical Care respiratory management rather than specific inter- ventions targeted at the liver injury. The prognosis Initial Care depends on both the cause of hepatic and Recognition of hepatic injury may be delayed if the severity of liver injury. A similar liver-injury confusion or agitation is the dominant present- pattern may also be seen in drug-induced liver in- ing sign, particularly in hyperacute cases in which jury caused by recreational drugs such as MDMA jaundice is minimal or in subacute cases, which (3,4-methylenedioxy-N-methylamphetamine,­ also may be mistaken for chronic liver disease. Early known as ecstasy) or cocaine. discussion with specialists at a liver center may Other causes of acute liver failure are neoplastic be crucial to guide management (Table 1) and ex- infiltration, acute Budd–Chiari syndrome, heat- pedite the safe transfer of suitable patients. stroke, mushroom ingestion, and metabolic dis- Early restoration of intravascular volume and eases such as Wilson’s disease.15,16 Acute liver systemic perfusion may prevent or mitigate the failure that occurs during pregnancy may require severity of organ failure. In patients with severe early delivery of the fetus; management should be acetaminophen poisoning, the interval between discussed with specialists at a referral center that drug ingestion and treatment with has capabilities for both neonatal care and inten- is closely related to the outcome.18,26 Acetylcys- sive management of the mother’s liver disease. teine has complex antioxidant and immunologic In many cases, the cause of acute liver failure effects that may also benefit patients with non– remains unknown, despite intensive investigation; acetaminophen-related acute liver failure. In a potential causes include infection with a novel randomized, controlled study involving such

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United Kingdom Germany HAV Japan 2% HAV Other HEV 4% Other HAV 7% 1% HEV, NT 7% 7% HBV HEV Unknown 5% HBV 1% Other 17% 18% 28% Aceta- Unknown HBV Aceta- Other drugs Unknown minophen 34% 42% 11% minophen 15% 57% 21%

Other drugs 14% Other Aceta- drugs minophen 9% 0%

Bangladesh Other United States 0% HAV HAV Unknown HEV, NT 3% 4% 6% Other drugs HBV Other 3% 7% HBV 19% India Aceta- 13% Sudan minophen Aceta- Other HAV Unknown HAV 0% minophen Other 7% 2% HEV 18% 0% 39% 27% 75% HEV 5% Other Unknown HBV drugs 31% HEV 22% 44% 13% Unknown 38% HBV 15% Other Other Aceta- drugs drugs minophen 1% Acetaminophen 8% 0% 0%

Figure 3. Worldwide Causes of Acute Liver Failure. HAV denotes hepatitis A virus, HBV , HEV virus, and NT not tested.

patients, treatment with intravenous acetylcyste- hepatic regeneration.30 In the absence of an evi- ine improved survival rates, but only among pa- dence base to guide practice, we administer antibi- tients with low-grade encephalopathy.27 otics preemptively in patients who have coagulopa- Encephalopathy may progress rapidly, partic- thy and organ failure or encephalopathy and those ularly in patients with hyperacute disease. For in whom illness progression is considered likely. patients with progression to agitation or , High standards of infection control should be prac- we recommend early endotracheal intubation and ticed to minimize the risks of nosocomial sepsis. sedation for airway control in order to facilitate Overt is uncommon in patients with general care, control and carbon dioxide acute liver failure and reflects a balanced hemo- levels, and prevent aspiration pneumonitis, al- static defect. In most cases, the loss of hepatic though practice varies according to center. synthesis of procoagulant factors is paralleled by A low arterial blood pressure with systemic the loss of hepatically derived anticoagulants. vasodilatation with or without confirmed sepsis Functional testing indicates no major bleeding is common in patients with acute liver failure tendency and may even indicate the presence of and is associated with more severe encephalopa- a procoagulant state.31,32 Since serial evaluation thy and increased mortality.28,29 A later pattern of laboratory variables (e.g., the inter- of functional immunosuppression may be seen national normalized ratio and ) with secondary nosocomial sepsis and impaired is central to prognostic evaluation, the adminis-

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Table 1. Common Management Issues and Condition-Specific Elements of Care in Acute Liver Failure.*

Organ System and Common Conditions Assessment Specific Elements of Care Cardiovascular system Hypotension Invasive for all conditions; echocardiography for low and right ventricular failure Intravascular volume depletion Correction of volume depletion Vasodilatation Vasopressors Low cardiac output and right Inotropic support ventricular failure Hepatic system Evolving hepatic dysfunction Serial biochemical and coagulation testing Intravenous acetylcysteine Respiratory system Risk of aspiration pneumonitis Neurologic observation to monitor level Early for depressed level of consciousness of consciousness Metabolic and renal systems Hypoglycemia Serial biochemical testing Maintain normoglycemia Active fluid management Renal dysfunction, lactic aci­ Renal-replacement therapy dosis, hyperammonemia Impaired drug metabolism Review drug administration Central nervous system Progressive encephalopathy Neurologic observation; monitoring of Treatment of fever and hyponatremia; screening serum ammonia level; transcranial for sepsis ultrasonography; consideration of High-grade encephalopathy: endotracheal intu- intracranial-pressure monitoring bation; avoidance of Paco2 of <30 mm Hg or >45 mm Hg; target for serum sodium, 145– 150 mmol/liter; risk assessment for intracra- nial hypertension Intracranial hypertension Interventions for pressure surges: osmotherapy (mannitol, hypertonic saline); temperature control; rescue therapies (indomethacin, thiopentone) Hematologic system Coagulopathy Laboratory coagulation testing No routine correction of coagulation abnormali- ties, only for invasive procedures (including and fibrinogen) Immunologic system High risk of sepsis Clinical evaluation prophylaxis

* Paco2 denotes partial pressure of arterial carbon dioxide. tration of coagulation factors should be avoided, since specific therapies may be available for some except when needed to treat bleeding or before causes of acute liver failure (Table S1 in the Supple- invasive procedures. mentary , available with the full text of this article at NEJM.org). How­ever, inappropriately Subsequent Care prolonged investigation and medical therapy may The severity of illness, rapidity of change, and extent make transplantation impossible if be- of extrahepatic organ involvement require early crit- comes contraindicated because of the progression ical care. The cause of liver injury should be sought, of multiorgan failure and development of sepsis.

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Complications In patients with subacute presentations, even low- grade encephalopathy indicates an extremely poor Cardiorespiratory Dysfunction prognosis, whereas in hyperacute disease, high Circulatory dysfunction and hypotension are grades of encephalopathy may clearly indicate a common in patients with acute liver failure and poor prognosis. The goal of clinical strategies is to are often multifactorial in origin. The effective prevent the onset of encephalopathy, limit its se- blood volume may initially be low owing to poor verity when it develops, and reduce the risk of ce- oral intake and fluid losses through vomiting rebral edema. Intracranial hypertension from se- and the development of vasodilatation, leading to vere remains a feared a condition consistent primarily with hypovole- and is a leading cause of death worldwide among mic . patients with acute liver failure. In many centers, Approaches to cardiovascular support in pa- intracranial hypertension is seen in only a minor- tients with acute liver failure do not differ mark- ity of patients. However, among patients in whom edly from those used in patients with other intracranial hypertension develops, the rate of sur- critical illnesses and focus on early restoration vival without transplantation remains poor.5 of circulating volume, systemic perfusion, and The pathogenesis of encephalopathy and ce- oxygen delivery. In patients who continue to rebral edema in acute liver failure is only partly have hypotension despite volume repletion, nor- understood; there is evidence that both systemic epinephrine is the preferred vasopressor, with or and local inflammation and circulating neuro- without adjunctive use of vasopressin or vaso- toxins, particularly ammonia, play a role.35,36 pressin analogues.33 Myocardial function should Encephalopathy can be precipitated by infection be assessed by means of echocardiography, since and may occur in patients with low systemic hypoxic hepatitis may result from impaired car- blood pressure and vasodilatation.37,38 Inflam- diac function. Relative may matory mediators may trigger or worsen en- be present in patients with cardiovascular insta- cephalopathy through the alteration of cerebral bility and is associated with increased mortality, endothelial permeability to or the but whether supplemental glucocorticoids im- initiation of inflammatory responses and altered prove survival is unclear.34 cerebral blood flow.39 Although endotracheal intubation is often re- In liver failure, the normal detoxification of quired to manage a reduced level of conscious- ammonia to urea is impaired, and levels of cir- ness, respiratory dysfunction is uncommon early culating ammonia increase. There is a close re- in the clinical course of acute liver failure. It is lationship between an elevated arterial ammonia more common later, during the phase of hepatic level and the development of encephalopathy, regeneration or in association with nosocomial with the risk of intracranial hypertension great- sepsis. The goals of respiratory care are similar to est when there is a sustained level of ammonia those in other critical illnesses; hyperventilation to of 150 to 200 μmol per liter (255 to 340 μg per induce hypocapnia may be used for emergent con- deciliter).37,40 Ammonia increases intracellular os- trol of intracranial hypertension if the condition is molarity through its cerebral metabolism to glu- associated with cerebral hyperemia, but sustained tamine and induces changes in hyperventilation should be avoided. Spontaneous synthesis and release and in mitochondrial func- hyperventilation is averted by means of appropri- tion; altered cerebral function and swelling re- ate sedation and mandatory modes of ventilation. sult.35,36 The speed of development of hyper­ ammonemia is such that the usual osmotic Neurologic Conditions compensatory mechanisms are ineffective in The central place of encephalopathy in the defini- cases of acute liver failure — in contrast to tion of acute liver failure reflects its key prognostic cases of subacute or chronic disease, in which importance, and its development reflects critically these compensatory mechanisms are function- impaired liver function (Table S2 in the Supple- ing and intracranial hypertension is uncom- mentary Appendix). However, depending on the mon.35,36 Treatments that are used in chronic speed with which encephalopathy develops, its liver disease may be inappropriate in acute liver presence has differential prognostic importance. failure. In particular, the role of neomycin, rif­

2530 n engl j med 369;26 nejm.org december 26, 2013 The New England Journal of Medicine Downloaded from nejm.org on December 26, 2014. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. critical care medicine ax­amin, and other nonabsorbable is level of at least 150 μmol per liter despite treat- unclear, and treatment with lactulose is poten- ment, an age of 35 years or less, and concurrent tially deleterious. renal or cardiovascular organ failure.37,38,40 Neurologic care focuses on the prevention of We treat sustained increases in intracranial infection, the maintenance of stable cerebral per- pressure with a bolus of intravenous hypertonic fusion, and the control of circulating ammonia saline (at a dose of 20 ml of 30% sodium chlo- and its cerebral metabolism. The drug l-ornithine– ride or 200 ml of 3% sodium chloride, keeping l-aspartate enhances ammonia detoxification to serum sodium at <150 mmol per liter) or man- glutamine in muscle. However, in a large, ran- nitol (at a dose of 2 ml of 20% solution per kilo- domized, controlled trial, the drug did not lower gram of body weight, maintaining serum osmo- circulating ammonia levels, reduce the severity of lality at <320 mOsm per liter). Hypothermia at encephalopathy, or improve survival rates among 32 to 34°C may be used in patients with resistant patients with acute liver failure.41 cases, and a bolus of intravenous indomethacin In patients with established encephalopathy, (at a dose of 0.5 mg per kilogram) may be used treatment is focused on minimizing the risk of when cerebral hyperemia is also present.46 intracranial hypertension by lowering cerebral ammonia uptake and metabolism through the Renal Dysfunction use of sedation and prophylactic osmotherapy. Substantial renal dysfunction may occur in more In a randomized, controlled trial involving pa- than 50% of patients with acute liver failure. This tients with high-grade encephalopathy, treatment complication is more common in the elderly and with intravenous hypertonic saline solution de- in patients with acetaminophen-induced acute layed the onset of intracranial hypertension.42 liver failure.47 Although renal dysfunction is as- Hypothermia affects multiple processes involved sociated with increased mortality, the resolution in the development of cerebral edema; by slow- of liver failure is accompanied by a return to pre- ing body metabolism, it lowers systemic produc- existing levels in most cases.48 In patients requir- tion of ammonia and cerebral uptake and me- ing renal-replacement therapy, continuous rather tabolism, in addition to having hemodynamic than intermittent forms are generally used to stabilizing effects and reducing cerebral blood achieve greater metabolic and hemodynamic sta- f low.35 Clinical observations have suggested that bility.49 In addition to indications for the use of moderate hypothermia (32 to 33°C) improves renal-replacement therapy in other forms of criti- and controls refractory intracra- cal illness, such therapy may be used to control nial hypertension, but a multicenter trial of pro- hyperammonemia and other biochemical and phylactic moderate hypothermia (34°C) in pa- acid–base disturbances. tients with high-grade encephalopathy did not show a delay in or reduced severity of intracra- Treatment nial hypertension.43,44 A pragmatic approach to temperature management is to avoid fever and Metabolic and Nutritional Support maintain a core body temperature of 35 to 36°C. The goal of treatment is to achieve overall meta- The most effective mode of neurologic moni- bolic and hemodynamic stability, with the rea- toring to guide therapy in patients with high- sonable, though yet unproven, idea that such grade encephalopathy is not clear. Direct mea- therapy will greatly improve conditions for he- surement of is associated patic regeneration and minimize the risk of com- with uncommon but definite risks, particularly plications. In patients with acute liver failure, .45 In view of the poten- this type of support is provided as it is for other tial complications and the decreasing incidence critically ill patients, with specific caveats. Patients of intracranial hypertension, we monitor intra- with acute liver failure are at increased risk for cranial pressure only in patients with clinical hypoglycemia, which can be prevented by an intra- signs or evidence of evolving intracranial hyper- venous glucose infusion. Large-volume infusions tension. Other indicators of increased risk in- of hypotonic fluids, which may result in hypona- clude an arterial ammonia concentration of tremia and cerebral swelling, should be avoided. more than 200 μmol per liter or a sustained Patients with acute liver failure have high energy

n engl j med 369;26 nejm.org december 26, 2013 2531 The New England Journal of Medicine Downloaded from nejm.org on December 26, 2014. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. The new england journal of medicine expenditure and protein catabolism, requiring nu- though the need for improved identification of tritional support to preserve muscle bulk and im- candidates for transplantation is clear. mune function.50,51 Pragmatically, in patients with encephalopathy, we administer 1.0 to 1.5 g of en- Transplantation teral protein per kilogram per day while frequently Although transplantation is a treatment option measuring blood ammonia levels, with a lowered for some specific causes of acute liver failure, protein load for short periods in patients with such treatment is not universally available, and worsening hyperammonemia or otherwise at high less than 10% of liver transplantations are per- risk for intracranial hypertension. formed in patients with acute liver failure.52,55 In such patients, especially those who are at risk for Prognostic Evaluation intracranial hypertension, intraoperative and post- Early identification of patients who will not sur- operative management is challenging, and rates of vive with medical therapy alone is of great practi- survival are consistently lower than those associ- cal importance in identifying potential candi- ated with elective liver transplantation. However, dates for transplantation. Since the progression outcomes have improved over time, with registry of multiorgan failure results in deterioration in data reporting current rates of survival after many patients who are awaiting transplantation, transplantation of 79% at 1 year and 72% at candidates for transplantation should be identi- 5 years.55 Most deaths after transplantation for fied as quickly as possible.52 acute liver failure occur from infection during Various prognostic evaluation systems, most the first 3 postoperative months. The risk of of which have features derived from analyses of death is higher among older recipients and historical patient cohorts that were treated without among those receiving older or partial grafts or transplantation, are in use worldwide. Although grafts from donors without an identical ABO the details of these systems differ, they share com- blood group.55,56 Early impaired liver-graft mon features (Table 2). The presence of encepha- function is poorly tolerated in critically ill pa- lopathy is a key indicator, with further consider- tients and predisposes them to intracranial hyper­ ation given to the patient’s age and the severity tension and sepsis.56 of liver injury, as assessed by the presence of coagulopathy or jaundice. The most well charac- Other Therapies terized evaluation system is the King’s College The limited availability of liver transplantation Criteria, with meta-analyses confirming that has led to the evaluation of other therapies in these criteria have clinically acceptable specificity patients with advanced disease. trans- but more limited sensitivity.53,54 To address these plantation involves intraportal or intraperitoneal limitations, a wide variety of alternate prognostic infusion of isolated human to aug- systems and markers have been proposed. To ment liver function. The procedure has been used date, none have achieved universal acceptance, successfully in neonates and children with inborn errors of metabolism, but to date the experience Table 2. Criteria for the Selection of Patients with Acute Liver Failure in pediatric acute liver failure has been limited.57 for Transplantation.* The cell mass that is infused represents only 5% King’s College Clichy Japanese of the theoretical liver mass, which is insufficient Factor Criteria Criteria Criteria in patients with massive hepatic , and the Age† Yes Yes Yes technique remains experimental. Cause Yes No No Other therapies seek to support the failing liver through the removal of circulating toxic Encephalopathy† Yes Yes Yes mediators, to stabilize the clinical conditions of Bilirubin level Varies No Yes the patients while they await definitive trans- Coagulopathy† Yes Yes Yes plantation, or to facilitate native liver regenera- tion. Among such extracorporeal liver-assist de- * The King’s College criteria are from O’Grady et al.,8 the Clichy criteria from Bernuau et al.,9 and the Japanese criteria from Mochida et al.10 Yes indicates­ vices are nonbiologic -based systems for that the factor is included as a criterion, and No that the factor is not included; systemic detoxification and bioartificial devices Varies indicates that the criterion is used only in cases not associated with that incorporate hepatic cells of porcine or human ­acetaminophen. † This factor is common to all prognostic models. origin to replace both detoxification and synthetic functions.58,59 The most extensively studied device

2532 n engl j med 369;26 nejm.org december 26, 2013 The New England Journal of Medicine Downloaded from nejm.org on December 26, 2014. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. critical care medicine is the molecular adsorbent recirculating sys- except on secondary analysis.61 For now, the use tem, with case series suggesting biochemical of extracorporeal devices should be restricted improvements during its use.59 A multicenter, to clinical trials. Preliminary reports suggest randomized, controlled trial involving patients that high-volume plasma exchange may be a with acute liver failure showed no survival ben- promising therapy.62 efit, but the study was confounded by a trans- Dr. Wendon reports receiving fees for board membership plantation rate of 75% soon after enrollment.60 from Pulsion and Excalenz and lecture fees from Fresenius and The porcine hepatocyte–based HepatAssist de- Asahi Kasei. No other potential conflict of interest relevant to this article was reported. vice appeared to be safe in a randomized, con- Disclosure forms provided by the authors are available with trolled trial but did not show a survival benefit the full text of this article at NEJM.org.

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