recommendations used for full Practice Guidelines(Table 13). These recommendations are fully endorsed These recommendations provide a data-supported ap- proach. They are based on the following: (1) formal re-view and analysis of recently-published world literatureon the topic [Medline search], (2) American College of Introduction
Physicians Manual for Assessing Health Practices and De- Acute liver failure (ALF) is a rare condition in which signing Practice Guidelines,1 (3) guideline policies, in- rapid deterioration of liver function results in altered cluding the AASLD Policy on the Development and Use mentation and coagulopathy in previously normal indi- of Practice Guidelines and the AGA Policy Statement on viduals. U.S. estimates are placed at approximately 2,000 Guidelines,2 (4) the experience of the authors in the spec- cases per year.4 The most prominent causes include drug- induced liver injury, viral hepatitis, autoimmune liver dis- Intended for use by physicians, the recommenda- ease and shock or hypoperfusion; many cases (Ϸ20%) tions in this document suggest preferred approaches to have no discernible cause.5 Acute liver failure often affects the diagnostic, therapeutic and preventive aspects of young persons and carries a high morbidity and mortality.
care. They are intended to be flexible, in contrast to Prior to transplantation, most series suggested less than standards of care, which are inflexible policies to be 15% survival. Currently, overall short-term survival with followed in every case. Specific recommendations are transplantation is greater than 65%.5 Because of its rarity, based on relevant published information. This docu- ALF has been difficult to study in depth and very few ment has been designated as a Position Paper, since the controlled therapy trials have been performed. As a result, topic contains more data based on expert opinion than standards of intensive care for this condition have not on randomized controlled trials and thus is not consid- ered to have the emphasis and certainty of a PracticeGuideline. Nevertheless, it serves an important pur-pose of facilitating proper and high level patient care Definition
and we have characterized the quality of evidence The most widely accepted definition of ALF in- supporting each recommendation, in accordance with cludes evidence of coagulation abnormality, usually an the Practice Guidelines Committee of the AASLD INR Ն1.5, and any degree of mental alteration (en-cephalopathy) in a patient without preexisting cirrho-sis and with an illness of Ͻ26 weeks duration.6 Patients Abbreviations: ALF, acute liver failure; NAC, N-acetylcysteine; HELLP, Hemo- lysis, Elevated Liver Enzymes, Low Platelets syndrome; ICH, intracranial hyperten- with Wilson disease, vertically-acquired HBV, or auto- sion; ICP, intracranial pressure; CT, computerized tomography; US ALFSG, immune hepatitis may be included in spite of the pos- United States Acute Liver Failure Study Group; CPP, cerebral perfusion pressure; sibility of cirrhosis if their disease has only been MAP, mean arterial pressure; SIRS, systemic inflammatory response syndrome; FFP, fresh frozen plasma; rFVIIa, recombinant activated factor; GI, gastrointestinal; H2, histamine-2; PPI, proton pump inhibitors; CVVHD, continuous venovenous he- have been used including fulminant hepatic failure and modialysis; APACHE, Acute Physiology and Chronic Health Evaluation; AFP, fulminant hepatitis or necrosis. Acute liver failure is a alpha fetoprotein; MELD, Model for End-stage Liver Disease. better overall term that should encompass all durations From the Division of Digestive and Liver Diseases, University of Texas South- western Medical School Department, Dallas, Texas. up to 26 weeks. Terms used signifying length of illness Received March 9, 2005; accepted March 10, 2005. such as hyperacute (Ͻ7 days), acute (7-21 days) and Address reprint requests to: Julie Polson, M.D., or William M. Lee, M.D., subacute (Ͼ21 days and Ͻ26 weeks) are not particu- University of Texas, Southwestern Medical School, Division of Digestive and LiverDiseases, 5323 Harry Hines Boulevard, Dallas, TX 75390-9151. E-mail: larly helpful since they do not have prognostic signifi- julie.polson@utsouthwestern.edu or william.lee@utsouthwestern.edu. cance distinct from the cause of the illness. For Copyright 2005 by the American Association for the Study of Liver Diseases. example, hyperacute cases may have a better prognosis Published online in Wiley InterScience (www.interscience.wiley.com). but this is because most are due to acetaminophen DOI 10.1002/hep.20703Potential conflict of interest: Nothing to report. Table 1. Quality of Evidence on Which a Recommendation
bodies (anti-nuclear and anti-smooth muscle antibodies) Is Based3
and a pregnancy test in females. Plasma ammonia, pref- Definition
erably arterial,7,8 may also be helpful. A liver biopsy, most often done via the transjugular route because of coagu- lopathy, may be indicated when certain conditions such as autoimmune hepatitis, metastatic liver disease, lym- Multiple time series, dramatic uncontrolled experiments phoma, or herpes simplex hepatitis are suspected. As the Opinions of respected authorities, descriptive epidemiology evaluation continues, several important decisions must bemade: whether to admit the patient to an ICU, whether totransfer the patient to a transplant facility, and (if already Diagnosis and Initial Evaluation
at a transplant center) whether and when to place the All patients with clinical or laboratory evidence of patient on the list for transplantation. For patients in a moderate to severe acute hepatitis should have immediate non-transplant center, the possibility of rapid progression measurement of prothrombin time and careful evaluation of ALF makes early consultation with a transplant facility for subtle alterations in mentation. If the prothrombin critical. Specific prognostic indicators may point toward time is prolonged by Ϸ4-6 seconds or more (INR Ն1.5) the need for transplantation. For patients with acetamin- and there is any evidence of altered sensorium, the diag- ophen-related ALF in particular, an arterial pH of Ͻ7.3 nosis of ALF is established and hospital admission is man- should prompt immediate consideration for transfer to a datory. Since the condition may progress rapidly, with transplant center and placement on a transplant list.9 changes in consciousness occurring hour-by-hour, early Patients with altered mentation should generally be transfer to the intensive care unit (ICU) is preferred once admitted to an ICU. Planning for transfer to a transplant center should begin in patients with grade I or II enceph- History taking should include careful review of possi- alopathy (Table 2) because they may worsen rapidly.
ble exposures to viral infection and drugs or other toxins.
Early transfer is important as the risks involved with pa- If severe encephalopathy is present, the history may be tient transport may increase or even preclude transfer provided entirely by the family or may be unavailable. In once stage III or IV encephalopathy develops. Evaluation this setting, limited information is available, particularly for transplantation should begin as early as possible. In regarding possible toxin/drug ingestions. Physical exami- these critically ill patients with potential for rapid deteri- nation must include careful assessment and documenta-tion of mental status and a search for stigmata of chronic Table 2. Initial Laboratory Analysis
liver disease. Jaundice is often but not always seen at pre- sentation. Right upper quadrant tenderness is variably present. Inability to palpate the liver or even to percuss a sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate significant area of dullness over the liver can be indicative glucoseAST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin of decreased liver volume due to massive hepatocyte loss.
An enlarged liver may be seen early in viral hepatitis or with malignant infiltration, congestive heart failure, or acute Budd-Chiari syndrome. History or signs of cirrhosis Complete blood countBlood type and screen should be absent as such features suggest underlying chronic liver disease, which may have different manage- ment implications. Furthermore, the prognostic criteria anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HEV§, anti-HCV* mentioned below are not applicable to patients with Initial laboratory examination must be extensive in or- Ammonia (arterial if possible)Autoimmune markers der to evaluate both the etiology and severity of ALF (Table 2). In addition to coagulation parameters, early testing should include routine chemistries (especially glu- cose as hypoglycemia may be present and require correc- *Done to recognize potential underlying infection.
tion), arterial blood gas measurements, complete blood #Done only if Wilson disease is a consideration (e.g., in patients less than 40 counts, blood typing, acetaminophen level and screens for years without another obvious explanation for ALF); in this case uric acid level andbilirubin to alkaline phosphatase ratio may be helpful as well.
other drugs and toxins, viral hepatitis serologies (most ‡Implications for potential liver transplantation.
prominently A and B), tests for Wilson disease, autoanti- oration it is necessary to make treatment plans promptly.
antidote for acetaminophen poisoning, has been shown to Social and financial considerations are unavoidably tied to be effective and safe for this purpose in numerous con- the overall clinical assessment where transplantation is trolled trials.15-18 The standard acetaminophen toxicity contemplated. It is important to inform the patient’s fam- nomogram19 may aid in determining the likelihood of ily or other next of kin of the potentially poor prognosis serious liver damage, but cannot be used to exclude pos- and to include them in the decision-making process.
sible toxicity due to multiple doses over time, or alteredmetabolism in the alcoholic or fasting patient.20 Given Recommendations
these considerations, administration of NAC is recom- 1. Patients with ALF should be admitted and
mended in any case of ALF in which acetaminophen over- monitored frequently, preferably in an ICU (III).
dose is a suspected or possible cause. NAC should be given 2. Contact with a transplant center and plans to
as early as possible, but may still be of value 48 hours or transfer appropriate patients with ALF should be ini-
more after ingestion.21 NAC may be given orally (140 tiated early in the evaluation process (III).
mg/kg by mouth or nasogastric tube diluted to 5% solu- 3. The precise etiology of ALF should be sought to
tion, followed by 70 mg//kg by mouth q 4 h ϫ 17 doses) guide further management decisions (III).
and has few side effects (occasional nausea, vomiting, rareurticaria or bronchospasm). In patients with ALF oral Determining Etiologies and Specific
administration may often be precluded (for instance, by Therapies
active gastrointestinal bleeding or worsening mental sta-tus), and NAC may be administered intravenously (load- Etiology of ALF provides one of the best indicators of ing dose is 150 mg/kg in 5% dextrose over 15 minutes; prognosis,5 and also dictates specific management op- maintenance dose is 50 mg/kg given over 4 hours followed by 100 mg/kg administered over 16 hours).
Allergic reactions may be successfully treated with discon- Acetaminophen Hepatotoxicity
tinuation, antihistamines22 and epinephrine for bronch- Acetaminophen hepatotoxicity is suggested by historic evidence for excessive ingestion either as an intended sui-cidal overdose or the inadvertent use of supra-therapeutic Recommendations
quantities of pain medications. Acetaminophen is a dose- 4. For patients with known or suspected acet-
related toxin; most ingestions leading to ALF exceed 10 aminophen overdose within 4 hours of presentation,
gm/day. However, severe liver injury can occur rarely give activated charcoal just prior to starting NAC (I).
when doses as low as 3-4 gm/day are taken.10 Very high 5. Begin NAC promptly in all patients where the
aminotransferases may be seen; serum levels exceeding quantity of acetaminophen ingested, serum drug level
3,500 IU/L are highly correlated with acetaminophen or rising aminotransferases indicate impending or
poisoning11 and should prompt consideration of this eti- evolving liver injury (II-1).
ology even when historic evidence is lacking. Because 6. NAC may be used in cases of acute liver failure
acetaminophen is the leading cause of ALF (at least in the in which acetaminophen ingestion is possible or when
United States and Europe) and there is an available anti- knowledge of circumstances surrounding admission is
dote, acetaminophen levels should be drawn in all pa- inadequate (III).
acetaminophen levels do not rule out acetaminophen poi- Mushroom Poisoning
soning since the time of ingestion may be remote or un- Mushroom Poisoning (usually Amanita phalloides) known, especially when overdose may have been may cause ALF, and the initial history should always in- unintentional and/or occurred over several days. If acet- clude inquiry concerning recent mushroom ingestion.
aminophen ingestion is known or suspected to have oc- There is no available blood test to confirm the presence of curred within a few hours of presentation, activated these toxins, but this diagnosis should be suspected in charcoal may be useful for gastrointestinal decontamina- patients with a history of severe gastrointestinal symp- tion. While it is most effective if given within one hour of toms (nausea, vomiting, diarrhea, abdominal cramping), ingestion,12 it may be of benefit as long as 3 to 4 hours which occur within hours to a day of ingestion. If these after ingestion.13 Administration of activated charcoal effects are present, it may be early enough to treat patients (standard dose 1g/kg orally, in a slurry) just prior to ad- with gastric lavage and activated charcoal via naso-gastric ministration of N-acetylcysteine does not reduce the ef- tube. Fluid resuscitation is also important. Traditionally, fect of N-acetylcysteine.13 N-acetylcysteine (NAC), the very low rates of survival have been reported without transplantation,23 but more recently complete recovery Table 3. Some Drugs Which May Cause Idiosyncratic Liver
has been described with supportive care and medical Injury Leading to ALF
treatment.24 Penicillin G and silibinin (silymarin or milk thistle) are the accepted antidotes despite no controlled have not found penicillin G to be helpful,27 enough effi- cacy has been reported to warrant consideration of the drug (given intravenously in doses of 300,000 to 1 million units/kg/day) in patients with known or suspected mush- room poisoning.28 Silibinin has generally been reported to be more successful than penicillin G, although penicil- lin G has been used more frequently in the United States.27,28 Silibinin/silymarin is not available as a licensed drug in the United States, although it is widely available in Europe and South America. In the United States, it is commercially available as milk thistle extracts, tablets, capsules or tincture. These products usually contain Combination agents with enhanced toxicity: 70%-80% silymarin, although there is no governmental regulation of such herbal supplements; silymarin concen- trations may vary considerably between preparations and manufacturers.29 When used for treatment of mushroom *Some Herbal products/dietary supplements that have been associated with poisoning, silymarin has been given in average doses of 30-40 mg/kg/day (either intravenously or orally) for an average duration of 3 to 4 days.26 N-acetylcysteine is often combined with these other therapies, but has not been shown to be effective in animal studies30; nevertheless, case reports have described its use as a part of overall Recommendation
7. In ALF patients with known or suspected
mushroom poisoning, consider administration of pen-
tory. There are no specific antidotes for idiosyncratic drug icillin G and silymarin (III).
reactions; corticosteroids are not indicated unless a drug 8. Patients with acute liver failure secondary to
hypersensitivity reaction is suspected. Determination of a mushroom poisoning should be listed for transplanta-
particular medication as the cause of ALF is a diagnosis of tion, as this procedure is often the only lifesaving
exclusion. Other causes of ALF should still be ruled out option (III).
even if a drug is suspected. Any presumed or possibleoffending agent should be stopped immediately where Drug Induced Hepatotoxicity
possible. Classes of drugs commonly implicated include A variety of medications have been associated with antibiotics, non-steroidal anti-inflammatory agents and acute liver injury. Before implicating a particular sub- stance, history should include careful listing of all agentstaken, the time period involved, and the quantity in- Recommendations
gested. Drugs other than acetaminophen rarely cause 9. Obtain details (including onset of ingestion,
dose-related toxicity. Most examples of idiosyncratic drug amount and timing of last dose) concerning all pre-
hepatotoxicity occur within the first 6 months after drug scription and non-prescription drugs, herbs and di-
initiation. A potentially hepatotoxic medication that has etary supplements taken over the past year (III).
been used continually for more than 1 to 2 years is un- 10. Determine ingredients of non-prescription
likely to cause de novo liver damage. Certain herbal prep- medications whenever possible (III).
arations and other nutritional supplements have been 11. In the setting of acute liver failure due to
found to cause liver injury,32 so inquiry about such sub- possible drug hepatotoxicity, discontinue all but essen-
stances should be included in a complete medication his- tial medications (III).
Viral Hepatitis
Wilson disease
Hepatitis serological testing should be done for identi- Wilson disease is an uncommon cause of ALF (2%-3% fication of acute viral infection (Table 2) even when an- of cases in the US ALFSG). Early identification is critical other putative etiology is identified. Viral hepatitis has because the fulminant presentation of Wilson disease is become a relatively infrequent cause of ALF (United considered to be uniformly fatal without transplantation.
States: 12%; hepatitis B – 8%, hepatitis A – 4%).5 Acute The disease typically occurs in young patients, accompa- hepatitis D may occasionally be diagnosed in a hepatitis B nied by the abrupt onset of hemolytic anemia with serum positive individual. Although controversial, hepatitis C bilirubin levels Ͼ20 mg/dL. Due to the presence of he- alone does not appear to cause ALF.5,33 Hepatitis E is a molysis, the indirect-reacting bilirubin is often markedly significant cause of liver failure in countries where it is elevated along with the total bilirubin. Kayser-Fleischer endemic, and tends to be more severe in pregnant rings are present in about 50% of patients presenting with women.33,34 This virus should be considered in anyone ALF due to Wilson disease.40 Serum ceruloplasmin is typ- with recent travel to an endemic area such as Russia, Pa- ically low, but may be normal in up to 15% of cases and is kistan, Mexico, or India. With acute viral hepatitis, as often reduced in other forms of ALF; high serum and with many other etiologies of ALF, care is mainly support- urinary copper levels as well as hepatic copper measure- ive. Of note, the nucleoside analog lamivudine (and pos- ment may confirm the diagnosis. Very low serum alkaline sibly adefovir), used widely in the treatment of chronichepatitis B, may be considered in patients with acute hep- phosphatase or uric acid levels are hints to suggest Wilson atitis B, although these drugs have not been subjected to a disease in the absence of other indicators. A high bilirubin controlled trial35 in acute disease. Acute liver failure due (mg/dL) to alkaline phosphatase (IU/L) ratio (Ͼ2.0) is a to reactivation of hepatitis B may occur in the setting of reliable albeit indirect indicator of Wilson disease in this chemotherapy or immunosuppression. Recent evidence setting.40,41 Renal function is often impaired as the re- suggests that patients found to be positive for HBsAg who leased copper can cause renal tubular damage. Treatment are to begin such therapy should be treated prophylacti- to acutely lower serum copper and to limit further hemo- cally with a nucleoside analog, and that such treatment lysis should include albumin dialysis, continuous hemo- should be continued for 6 months after completion of filtration, plasmapheresis or plasma exchange. Initiation immunosuppressive therapy (please refer to the AASLD of treatment with penicillamine is not recommended in Practice Guideline on Management of Chronic Hepatitis ALF as there is a risk of hypersensitivity to this agent; B, Update of Recommendations36). Herpes virus infec- acute lowering of the copper is more effectively accom- tion rarely causes ALF. Immunosuppressed patients or plished using direct plasma copper reduction techniques, pregnant women (usually in the third trimester) are at especially when renal function is impaired.40 Although increased risk, but occurrences of herpes virus ALF have such copper lowering measures should be considered, re- been reported in healthy individuals.33,37,38 Skin lesions covery is infrequent without transplantation.40,42 Wilson are present in only about 50% of cases. Liver biopsy is disease is one of the special circumstances in which pa- helpful in making the diagnosis. Treatment should be tients may already have evidence of cirrhosis and still be initiated with acyclovir for suspected or documented considered to have a diagnosis of ALF when rapid deteri- cases.37,38 Other viruses such as varicella zoster39 have oc- oration occurs. Please refer to the AASLD Practice Guide- casionally been implicated in causing hepatic failure.
line on Wilson Disease for more detailed informationregarding the diagnosis and management of patients with Recommendations
12. Viral hepatitis A- and B- (and E-) related acute
liver failure must be treated with supportive care as
no virus-specific treatment has been proven effective

15. Diagnostic tests for Wilson disease should
13. Nucleoside analogs should be given prior to
include ceruloplasmin, serum and urinary copper
and continued for 6 months after completion of che-
levels, total bilirubin/alkaline phosphatase ratio,
motherapy in patients with Hepatitis B surface anti-
slit lamp examination for Kayser-Fleischer rings,
gen positivity to prevent reactivation/acute flare of
and hepatic copper levels when liver biopsy is fea-
disease (III).
sible (III).
14. Patients with known or suspected herpes virus
16. Patients in whom Wilson disease is the likely
or varicella zoster as the cause of acute liver failure
cause of acute liver failure must be immediately
should be treated with acyclovir (III).
placed on the liver transplant list (III).
Autoimmune hepatitis
appears to increase the risk of ALF due to herpes virus, With autoimmune hepatitis as with Wilson disease, which should be treated with acyclovir (see section on patients may have unrecognized preexisting chronic dis- acute viral infection).37 It is important to keep in mind ease and yet still be considered as having ALF. Such pa- that ALF in pregnant women may also be caused by en- tients represent the most severe form of the disease, and tities not necessarily related to the pregnant state.
would generally fall into the category of patients recom-mended for corticosteroid therapy as outlined by the Recommendation
AASLD Practice Guidelines for the Diagnosis and Treat- 20. For acute fatty liver of pregnancy or the
ment of Autoimmune Hepatitis (although ALF is not HELLP syndrome, consultation with obstetrical ser-
specifically discussed in that document).43 Although some vices and expeditious delivery are recommended (III).
patients may be responsive to steroid therapy, others re-quire transplantation.44,45 Autoantibodies may be absent Acute Ischemic Injury
making a definitive diagnosis difficult. Liver biopsy may A syndrome often referred to as “shock liver” occurs be helpful if findings include presence of severe hepatic after cardiac arrest, a period of significant hypovolemia/ necrosis accompanied by interface hepatitis, plasma cell hypotension, or in the setting of severe congestive heart infiltration and hepatocyte rosettes. Initiation of steroid failure.51 Documented hypotension is not always found.
therapy may constitute a therapeutic trial for some pa- Drug-induced hypotension or hypoperfusion may be ob- tients (prednisone starting at 40-60 mg/day),43 although served with long-acting niacin,52 or with cocaine,53 or placement on the transplant list is indicated.
methamphetamine.54 Other physical findings may belacking, but evidence of cardiac dysfunction may be elic- Recommendations
ited via echocardiogram.55 Aminotransferase levels will be 17. When autoimmune hepatitis is suspected as the
markedly elevated and respond rapidly to stabilization of cause of acute liver failure, liver biopsy should be
the circulatory problem. Simultaneous onset of renal dys- considered to establish this diagnosis (III).
function and muscle necrosis may be noted. The ability to 18. Patients with acute liver failure due to auto-
manage heart failure or other causes of ischemia success- immune hepatitis should be treated with corticoste-
fully will determine outcome for these patients, and trans- roids (prednisone, 40-60 mg/day) (I).
19. Patients should be placed on the list for trans-
plantation even while corticosteroids are being ad-
ministered (III).

21. In ALF patients with evidence of ischemic in-
jury cardiovascular support is the treatment of choice
Acute Fatty Liver of Pregnancy/HELLP (Hemolysis,
Elevated Liver Enzymes, Low Platelets) Syndrome
A small number of women near the end of pregnancy will develop rapidly progressive hepatocyte failure that Budd-Chiari Syndrome
has been well characterized46-49 and associated with in- The Budd-Chiari syndrome (acute hepatic vein creased fetal or maternal mortality. A variety of presenta- thrombosis) can also present as ALF. Abdominal pain, tions may be seen, generally confined to the last trimester.
ascites and striking hepatomegaly are often present. The The triad of jaundice, coagulopathy, and low platelets diagnosis should be confirmed with hepatic imaging stud- may occasionally be associated with hypoglycemia. Fea- ies (computed tomography, doppler ultrasonography, tures of pre-eclampsia such as hypertension and protein- venography, magnetic resonance venography). In the uria are common. Steatosis documented by imaging presence of significant liver failure, transplantation may studies supports the diagnosis. The Oil-red O staining be required as opposed to venous decompression.56 As technique best demonstrates hepatic steatosis on biopsy.
malignancy-associated hypercoagulability is one of the Intrahepatic hemorrhage and/or hepatic rupture consti- causes of Budd-Chiari syndrome, it is important to rule tute rare emergent situations requiring rapid resuscitation out underlying cancer prior to transplantation of these and intervention. Early recognition of these syndromes and prompt delivery are critical in achieving good out-comes. Recovery is typically rapid after delivery, and sup- Recommendation
portive care is the only other treatment required. Post- 22. Hepatic vein thrombosis with hepatic failure is
partum transplantation has occasionally been necessary, an indication for liver transplantation, provided un-
however.50 Pregnancy (especially in the third trimester) derlying malignancy is excluded (II-3).
Malignant Infiltration
of intravenous NAC versus placebo for non-acetamino- Malignant infiltration of the liver may cause ALF.
phen ALF is currently under way. Because there is no
Massive hepatic enlargement may be seen. Diagnosis proven therapy for ALF in general, management consists should be made by imaging and biopsy, and treatment of intensive care support once treatments for specific eti- appropriate for the underlying malignant condition is in- ologies have been initiated. While some patients with ev- dicated. Transplantation is not an option for such pa- idence of acute liver injury but without significant tients.57,58 Acute severe hepatic infiltration occurs with coagulopathy or encephalopathy may be monitored on a breast cancer,59,60 small cell lung cancers,61 lymphoma58 medicine ward, any patient with altered mental status warrants admission to an ICU as the condition may de-teriorate quickly. Careful attention must be paid to fluid Recommendations
management, hemodynamics and metabolic parameters 23. In patients with acute liver failure who have a
as well as surveillance for and treatment of infection.
previous cancer history or massive hepatomegaly, con-
Maintenance of nutrition and prompt recognition and sider underlying malignancy and obtain imaging and
resuscitation of gastrointestinal bleeding are crucial as liver biopsy to confirm or exclude the diagnosis (III).
well. Coagulation parameters, complete blood counts,metabolic panels (including glucose) and arterial blood Indeterminate Etiology
gas should be checked frequently. Serum aminotrans- When the etiology of ALF cannot be determined after ferases and bilirubin are generally measured daily to fol- routine evaluation, biopsy using a transjugular approach low the course of the condition, however changes in may be helpful in diagnosing malignant infiltration, au- aminotransferase levels correlate poorly with prognosis.
toimmune hepatitis, certain viral infections and Wilson Specific Issues. See Table 4.
disease. Lack of a clear diagnosis suggests that the historymay have been inadequate regarding toxin or drug expo- Central Nervous System
Cerebral edema and intracranial hypertension (ICH) have long been recognized as the most serious complica- Recommendation
tions of ALF.72 Uncal herniation may result and is uni- 24. If the etiological diagnosis remains elusive after
formly fatal. Cerebral edema may also contribute to extensive initial evaluation, liver biopsy may be ap-
ischemic and hypoxic brain injury, which may result in propriate to attempt to identify a specific etiology that
long-term neurological deficits in survivors.73 The patho- might influence treatment strategy (III).
genic mechanisms leading to the development of cerebraledema and ICH in ALF are not entirely understood. It is Therapy: General Considerations
likely that multiple factors are involved, including os- Background
motic disturbances in the brain and heightened cerebral While patients with ALF represent a heterogeneous blood flow due to loss of cerebrovascular autoregulation.
group, they have consistent clinical features, and share the Inflammation and/or infection, as well as factors yet un- common disease process of acute hepatocyte loss and its identified may also contribute to the phenomenon.74 Sev- sequelae. Despite decades of research, however, no agent eral measures have been proposed and used with varying or therapy that is beneficial to all patients with ALF has success to tackle the problem of cerebral edema and the been found. Systemic corticosteroids are ineffective in this associated ICH in patients with ALF. Some interventions are supported by more evidence than others; no uniform Because most patients with ALF tend to develop some degree of circulatory dysfunction, agents that may im- Prevention/Management of Elevated Intracranial
prove hemodynamics have been of particular interest.
Pressure (ICP). The occurrence of cerebral edema and
While prostacyclin and other prostaglandins have ap- ICH in ALF is related to severity of encephalopathy (Ta- peared promising in some reports,66,67 others have not ble 5). Cerebral edema is seldom observed in patients with supported their efficacy in ALF.68 NAC may improve grade I-II encephalopathy. The risk of edema increases to systemic circulation parameters in patients with ALF,69 25% to 35% with progression to grade III, and 65% to but this was not observed in all studies.70 NAC has been 75% or more in patients reaching grade IV coma.75 A shown to improve liver blood flow and function in pa- stepwise approach to management is therefore advised.76 tients with septic shock.71 Use of NAC in all forms of ALF Grades I-II. Depending on the overall clinical pic-
cannot be justified based on current evidence. A large, ture, patients with only grade I encephalopathy may multi-center, randomized, double-blind controlled trial sometimes be safely managed on a medicine ward with Table 4. Intensive Care of Acute Liver Failure
with cirrhosis, it has been suggested that reducing elevated Cerebral Edema/Intracranial Hypertension ammonia levels with enteral administration of lactulose might help prevent or treat cerebral edema in ALF. A Consider transfer to liver transplant facility and listing for transplantation preliminary report from the United States Acute Liver Brain CT: rule out other causes of decreased mental status; little utility to Failure Study Group (US ALFSG), retrospectively com- Avoid stimulation, avoid sedation if possible paring patients who received lactulose to a well-matched Antibiotics: surveillance and treatment of infection required; prophylaxis group of patients who did not, found that lactulose ther- apy was associated with a small increase in survival time, but with no difference in severity of encephalopathy or in Continue management strategies listed above overall outcome.78 One concern regarding the use of lac- tulose in this setting is the potential for gaseous abdomi- Elevate head of bedConsider placement of ICP monitoring device nal distension that could present technical difficulties in a Immediate treatment of seizures required; prophylaxis of unclear value subsequent transplantation procedure.
Mannitol: use for severe elevation of ICP or first clinical signs of herniation Grades III-IV. As patients progress to grade III or IV
Hyperventilation: effects short-lived; may use for impending herniation encephalopathy it is advisable to intubate the trachea for airway protection. Choice of sedation in this instance will Surveillance for and prompt antimicrobial treatment of infection requiredAntibiotic prophylaxis possibly helpful but not proven vary according to clinician preference: propofol is often used because it may reduce cerebral blood flow79; how- ever, its effectiveness in this regard has not been shown in FFP: give only for invasive procedures or active bleeding controlled studies. Small doses of propofol may be ade- Platelets: give for platelet counts Ͻ10,000/mm3 or invasive procedures quate, given its long half-life in patients with hepatic fail- Recombinant activated factor VII: possibly effective for invasive proceduresProphylaxis for stress ulceration: give H2 blocker or PPI ure. Patients in advanced stages of encephalopathy require close follow-up. Monitoring and management of hemo- dynamic and renal parameters as well as glucose, electro- lytes and acid/base status becomes critical, and frequent Pressor support (dopamine, epinephrine, norepinephrine) as needed to neurological evaluation for signs of elevated intracranial pressure should be conducted. Patients should be posi- Continuous modes of hemodialysis if needed tioned with head elevated at 30 degrees.80 Efforts should be made to avoid patient stimulation. Maneuvers that Vasopressin: not helpful in ALF; potentially harmful.
cause straining or Valsalva-like movements in particular Follow closely: glucose, potassium, magnesium, phosphate may increase ICP; it may be advisable to use endotracheal Consider nutrition: enteral feedings if possible or total parenteral nutrition lidocaine prior to endotracheal suctioning.
Seizures. Seizures, which may be seen as a manifesta-
tion of the process that leads to hepatic coma and ICH, skilled nursing in a quiet environment to minimize agita- should be controlled with phenytoin. Use of any sedative tion, although management in an ICU is preferable. Fre- is discouraged in light of its effects on the evaluation of quent mental status checks should be performed with mental status. Only minimal doses of benzodiazepines transfer to an ICU if level of consciousness declines. With should be used given their delayed clearance by the failing progression to grade II encephalopathy, an ICU setting is liver. Seizure activity may acutely elevate ICP81 and may indicated. Head imaging with computerized tomography also cause cerebral hypoxia and thus contribute to cerebral (CT) is used to exclude other causes of decline in mentalstatus such as intracranial hemorrhage. Sedation is to beavoided if possible; unmanageable agitation may be Table 5. Grades of Encephalopathy
treated with short-acting benzodiazepines in small doses.
Changes in behavior with minimal change in level of consciousness Gross disorientation, drowsiness, possibly asterixis, inappropriate Lactulose. There is increasing evidence that ammonia
may play a pathogenic role in the development of cerebral Marked confusion, incoherent speech, sleeping most of the time but edema/ICH; ammonia infusion has been shown to cause brain edema in animal models.77 Some human studies Comatose, unresponsive to pain, decorticate or decerebrate posturing have supported these findings, with an arterial ammonia Note: some patients will overlap grades; clinical judgment is required. Adapted level Ͼ200 ug/dL being strongly associated with cerebral from Conn HO, Leevy CM, Vhlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, LevyLL. Comparison of lactulose and neomycin in the treatment of chronic portal- herniation.7 Based on such evidence and on prior experi- systemic encephalopathy. A double blind controlled trial. Gastroenterology 1977; ence with treatment of hepatic encephalopathy in patients edema. Some experts have advocated prophylactic use of surgery. There are documented studies and reports of ex- phenytoin, especially as seizure activity may be inappar- perience which indicate ICP monitoring devices can ent. A small randomized controlled trial of prophylactic safely provide helpful information,76,90,93 and may even phenytoin in ALF showed no difference in overall sur- lengthen survival time,94 but there are no controlled trials vival, but a striking diminution in cerebral edema at au- available to demonstrate an overall survival benefit. There topsy in the treated group.82 A recent clinical trial did not is understandable concern over the risks (mainly infection show beneficial effects on the prevention of seizures, brain and bleeding) involved in placing invasive intracranial edema or survival.83 Further studies may clarify the value devices in critically ill, coagulopathic patients, based on of this treatment, but it cannot be recommended as a data on 262 patients at U.S. transplant centers that ob- served a complication rate of 3.8% (1% fatal hemorrhage)with epidural catheters. Reliability was improved but the Intracranial Pressure Monitoring
risk of complications increased with the use of subdural or The use of ICP monitoring devices in ALF is a subject intraparenchymal instrumentation.95 It is not known of ongoing debate. ICP monitoring is used variably across whether newer, smaller monitoring devices have de- the United States, with some centers not considering it creased the risk of complications. More aggressive correc- useful and others using it regularly. A survey of the initial tion of coagulation parameters, perhaps with addition of 14 transplant centers in the US ALFSG found ICP mon- recombinant activated factor VII, may further reduce itoring devices were used in 13 of these sites from 1998- bleeding risk, allowing wider use of ICP monitoring de- 200084; a more recent informal review of more than 20 vices.96 Indeed, preliminary results indicate a considerable sites found ICP monitors used in a little more than half reduction in the prevalence of bleeding complications (unpublished). Without the use of these monitoring de- (2/58 cases with the majority being subdural monitors).97 vices, early recognition of cerebral edema cannot reliably Recent data did not show improved outcomes when ICP be made. The clinical signs of elevated ICP including hypertension, bradycardia and irregular respirations Specific Treatment of Elevated Intracranial Pres-
(Cushing’s triad) are not uniformly present; these and sure. If patients develop increased ICP it may be neces-
other neurological changes such as pupillary dilatation or sary to perform immediate interventions beyond the signs of decerebration are typically evident only late in the general strategies outlined above. If an ICP monitor is course. CT of the brain does not reliably demonstrate placed, key parameters to follow are both ICP and CPP.
evidence of edema especially at early stages.85 Other ICP should be maintained below 20-25 mm Hg if possi- methods of monitoring (such as transcranial doppler ul- ble, with CPP maintained above 50-60 mm Hg.4,98 Evi- trasonography, near-infrared spectrophotometry, and dence from trauma patients with cerebral edema suggests measurement of serum S-100 beta and neuronal specific that maintaining CPP above 70 mm Hg may further im- enolase) that are in various stages of evaluation have thus prove neurological outcomes, if this level can be far not been proven reliable in estimatingICP.86-89 A pri- achieved.99 Support of systemic blood pressure may be mary purpose of ICP monitoring is to detect elevations in ICP and reductions in cerebral perfusion pressure (CPP; Mannitol. If ICH develops, either as seen on ICP
calculated as mean arterial pressure minus ICP) so that monitoring or by obvious neurological signs (decerebrate interventions can be made to prevent herniation while posturing, pupillary abnormalities), osmotic diuresis with preserving brain perfusion. The ultimate goal of such intravenous mannitol is effective in the short term in de- measures is to maintain neurological integrity and pro- creasing cerebral edema.100 Mannitol has been shown in long survival while awaiting receipt of a donor organ or controlled trials to correct episodes of elevated ICP in recovery of sufficient functioning hepatocyte mass. ICP ALF patients; its use has also been associated with im- monitoring is particularly important during orthotopic proved survival.101 Administration of intravenous manni- liver transplantation, when shifts in hemodynamics can tol (in a bolus dose of 0.5-1g/kg) is therefore cause large fluctuations in cerebral pressure parameters.90 recommended to treat ICH in ALF. The dose may be Additionally, refractory ICH and/or decreased CPP is repeated once or twice as needed, provided serum osmo- considered a contraindication to liver transplantation in lality has not exceeded 320 mosm/L. Volume overload is many centers.90,91 Case reports of ALF patients demon- a risk with mannitol use in patients with renal impair- strating spontaneous and complete recovery after pro- ment, and may necessitate use of dialysis to remove excess longed ICH and decreased CPP may call this practice into fluid. Hyperosmolarity or hypernatremia also may result question,92 but there is no way of knowing whether these from overzealous use. Prophylactic administration of patients would have survived the rigors of transplantation Hyperventilation. Hyperventilation to reduce PaCO2
has supported a beneficial effect of hypothermia in pa- to 25-30 mm Hg is known to quickly lower ICP via vaso- tients with ALF as well,111,112 but hypothermia has not constriction causing decreased cerebral blood flow (CBF), been subjected to a controlled trial. Potential deleterious but this effect is short-lived.102 In a small series of patients effects of hypothermia include increased risk of infection, with ALF, loss of auto-regulation of CBF appeared to be coagulation disturbance, and cardiac arrhythmias.113 restored after several minutes of hyperventilation.103 Resto-ration of CBF auto-regulation should theoretically be bene- Recommendations
ficial if cerebral hyperemia is contributing to cerebral edema 25. In early stages of encephalopathy, sedation
and ICH; this study did not evaluate effect on ICP or sur- should be avoided if possible. Lactulose may be used,
vival, however. A randomized controlled trial of prophylactic but concern has been raised about increasing bowel
continuous hyperventilation in ALF patients showed no re- distention during the subsequent transplant procedure
duction in incidence of cerebral edema/ICH and no survival (II-2, III).
benefit, although onset of cerebral herniation did appear de- 26. In patients progressing to grade III or IV en-
layed in the hyperventilated group.104 There has been some cephalopathy, the head should be elevated to 30 de-
concern that cerebral vasoconstriction with hyperventilation grees, and endotracheal intubation should be
could potentially worsen cerebral edema by causing cerebral performed (III).
hypoxia.105 Based on available evidence, there is no role for 27. Seizure activity should be treated with phenyt-
prophylactic hyperventilation in patients with ALF. If life- oin and low-dose benzodiazepines. (III).
threatening ICH is not controlled with mannitol infusion 28. Although there is no consensus among the cen-
and other general management outlined above, hyperventi- ters and experts, intracranial pressure monitoring is
lation may be instituted temporarily in an attempt to acutely mainly considered for patients who are listed for
lower ICP and prevent impending herniation; beyond this transplantation (III).
acute situation it cannot be recommended as routine man- 29. In the absence of ICP monitoring, frequent
evaluation for signs of intracranial hypertension are
Hypertonic Sodium Chloride. A recent controlled
needed to identify early evidence of uncal herniation
trial of administration of 30% hypertonic saline to main- (III).
tain serum sodium levels of 145-155 in patients with ALF 30. In the event of intracranial hypertension, man-
and severe encephalopathy suggests that induction and nitol should be given and hyperventilation may be
maintenance of hypernatremia may be used to prevent the considered in order to temporarily reduce the ICP, but
rise in ICP values.106 Survival benefit could not be dem- prophylactic use of these interventions is not helpful
onstrated in this small trial. The role of hypertonic saline and therefore not recommended (I).
as a prophylactic measure requires confirmation in larger 31. Short-acting barbiturates may be considered
for refractory intracranial hypertension (III).
Barbiturate. Barbiturate agents (thiopental or pento-
32. Corticosteroids should not be used to control
barbital) may also be considered when severe ICH does elevated ICP in patients with acute liver failure (I).
not respond to other measures; administration has beenshown to effectively decrease ICP. Significant systemic Infection
hypotension frequently limits their use, and may necessi- All patients with ALF are at risk for acquisition of tate additional measures to maintain adequate mean arte- bacterial114 or fungal115 infection or sepsis, which may preclude transplantation or complicate the post-operative Corticosteroids. Corticosteroids, which are often
course. Prophylactic antimicrobial therapy reduces the in- used in the prevention and management of ICH caused cidence of infection in certain groups of patients with by brain tumors and some infections of the central ner- ALF, but no actual survival benefit has been shown,116,117 vous system, have been shown in a controlled trial to making it difficult to recommend antibiotic prophylaxis confer no benefit in patients with ALF with respect to uniformly. Although often given, poorly absorbable anti- controlling cerebral edema or improving survival.101 biotics for selective bowel decontamination have not been Hypothermia. Moderate hypothermia (32-34°C)
shown to impact survival either.116 Deterioration of men- may prevent or control ICH in patients with ALF. It has tal status in hospital, particularly in patients with acet- been shown in experimental animal models to prevent aminophen toxicity, may represent the onset of infection.
development of brain edema,108-110 possibly by prevent- If antibiotics are not given prophylactically, surveillance ing hyperemia, altering brain ammonia or glucose metab- for infection (including chest radiography and periodic olism, or by a combined effect. Some limited experience cultures of sputum, urine and blood for fungal and bac- terial organisms) should be undertaken, while maintain- mend more conservative levels of 15-20,000/mm3 espe- ing a low threshold for starting appropriate anti-bacterial cially in patients with infection or sepsis,121 Experience in or anti-fungal therapy. There are no controlled trials other conditions of thrombocytopenia suggests that val- available to confirm whether the use of prophylactic an- ues Ն10,000/mm3 are generally well tolerated.122 When timicrobials decreases the likelihood of progression of en- invasive procedures must be perfomed, platelet counts of cephalopathy and/or development of cerebral edema in 50-70,000/mm3 are usually considered adequate.121 Pa- ALF. Recent studies have suggested an association be- tients who develop significant bleeding with platelet levels tween infection and/or the systemic inflammatory re- below approximately 50,000/mm3 should generally be sponse syndrome (SIRS) and progression to deeper stages transfused with platelets provided no contraindication ex- of encephalopathy.117,118 Given that prophylactic antibi- ists. Likewise, bleeding in the setting of a prolonged pro- otics have been shown to reduce the risk of infection, that thrombin time (INR Ն1.5) warrants administration of later stages of encephalopathy are associated with in- FFP. Recombinant activated factor VII (rFVIIa) may be creased incidence of cerebral edema, and that fever may used in treating coagulopathy in patients with liver dis- worsen ICH,119 it is possible that antibiotic and anti- ease. A recent small nonrandomized trial of fifteen pa- fungal prophylaxis may decrease the risk of cerebral tients with ALF found that administration of rFVIIa in edema and ICH. This hypothesis is yet to be proven, combination with FFP produced more effective tempo- rary correction of coagulopathy and thus might be usefulin facilitating performance of invasive procedures in these Recommendations
patients particularly in the setting of renal insufficiency in 33. Periodic surveillance cultures should be per-
which volume overload is a concern.96 This agent will formed to detect bacterial and fungal infections as
require further study and analysis of cost-benefit ratio early as possible and prompt treatment should be
(current cost for one dose is approximately $4,000) before initiated accordingly (II-2, III).
it can be broadly recommended, however.
34. Prophylactic antibiotics and anti-fungals may
be considered but have not been shown to improve
overall outcomes (II-2, III).
35. Replacement therapy for thrombocytopenia
and/or prolonged prothrombin time is recommended
only in the setting of hemorrhage or prior to invasive
Clotting abnormalities are uniform in patients with procedures (III).
ALF as previously discussed, leaving patients at increasedrisk for bleeding complications. While synthesis of coag- Gastrointestinal Bleeding
ulation factors is decreased, consumption of clotting fac- Gastrointestinal (GI) bleeding is a recognized compli- tors and platelets also may occur, so that platelet levels are cation of ALF. A large prospective multi-center cohort often Յ100,000/mm.3 In the absence of bleeding it is not study found that mechanical ventilation for more than 48 necessary to correct clotting abnormalities with fresh fro- hours and coagulopathy were the only significant risk fac- zen plasma (FFP).120 An exception is when an invasive tors for bleeding in critically ill patients of all types.123 procedure is planned and perhaps in the setting of pro- Additional risk factors for bleeding reported in smaller found coagulopathy (e.g., INR Ͼ7). In addition to the studies have included hepatic and renal failure, sepsis, risks associated with transfusion of blood products, use of shock and others.124 Patients with acute liver failure are plasma supplementation limits the value of coagulation thus at high risk for gastrointestinal hemorrhage. Hista- parameters as a means of following the progress of ALF mine-2 receptor (H2) blocking agents such as ranitidine patients and can also lead to volume overload which may have long been used in the prophylaxis of GI bleeding in exacerbate ICH. Vitamin K is routinely given in a dose of critically ill patients; their efficacy has been supported in 5-10 mg subcutaneously, regardless of whether poor nu- several trials.125-128 Sucralfate has also been found to be tritional status appears to be contributing to the coagu- effective in many studies, and there have been smaller randomized trials and a meta-analysis which suggested Experts differ regarding prophylactic use of platelets in that sucralfate may be as effective in preventing gastroin- thrombocytopenic patients or use of FFP for evidence of testinal bleeding and might be associated with lower risk severe coagulopathy. Platelet transfusions are not gener- of nosocomial pneumonia than H2 blockers which lower ally used until a low threshold value is observed. In the gastric pH.129,130 More recently, however, a much larger absence of bleeding, it is safe to use a threshold platelet (1,200 patients), well-designed trial comparing ranitidine count of 10,000/mm3, although some experts recom- to sucralfate in mechanically-ventilated patients found that ranitidine but not sucralfate decreased the risk of and vasodilatation associated with ALF will generally re- clinically significant bleeding; the incidence of pneumo- spond to these agents, and they should be used if needed nia was similar for the two groups.128 Limited studies of to maintain perfusion of vital organs. Agents that pro- proton pump inhibitors (PPIs) as bleeding prophylaxis mote vasoconstriction are generally avoided unless signif- have demonstrated their effectiveness in maintaining ele- icant systemic hypotension is present, and therefore vated intragastric pH.131-133 Two trials found no signifi- should not be used in the setting of decreased intracranial cant bleeding in PPI-treated patients on mechanical perfusion with normal systemic blood pressure.
ventilation,131,132 but study size may have precluded de- Acute renal failure is a frequent complication in pa- tection of significant bleeding. H2 blockers have been tients with ALF135 and may be due to dehydration, hepa- proven to be effective and PPIs are almost certainly effec- torenal syndrome or acute tubular necrosis.136 The tive as well. PPIs may provide superior protection but this frequency of renal failure may be even greater with acet- remains to be proven. Sucralfate may be acceptable as aminophen overdose or other toxins, where direct renal toxicity is seen.137 Although few patients die of renal fail-ure alone, it often contributes to mortality and may por- Recommendation
tend a poorer prognosis.9,138 Every effort should be made 36. Patients with ALF in the ICU should receive
to protect renal function by maintaining adequate hemo- prophylaxis with H2 blocking agents or PPIs (or su-
dynamics, avoiding nephrotoxic agents such as aminogly- cralfate as a second-line agent) for acid-related gas-
cosides and non-steroidal anti-inflammatory drugs, and trointestinal bleeding associated with stress (I, III).
by the prompt identification and treatment of infection.
When dialysis is needed, continuous rather than intermit- Hemodynamics/Renal Failure
tent modes of renal replacement therapy (e.g., continuous Hemodynamic derangements consistent with multiple venovenous hemodialysis [CVVHD]) should be used, as organ failure occur in ALF; the underlying mechanisms they have been shown in randomized trials to result in are complex and incompletely understood. Management improved stability in cardiovascular and intracranial pa- of hemodynamic balance becomes increasingly important rameters compared with intermittent modes of hemodi- and difficult in the face of elevated ICP and/or compro- alysis.139 Intravenous contrast agents are associated with mised renal function. Preservation of renal function is nephrotoxicity in the setting of compromised hepatic imperative in this setting. In many ways patients with function, and should be used with caution. If contrast ALF resemble physiologically the patient with cirrhosis must be administered, pretreatment with NAC may be of and hepatorenal syndrome. Intravascular volume deficits value, although this remains controversial.140-142 may be present on admission due to decreased oral intake The potential utility of prostaglandins and NAC in resulting from altered mental status, transudation of fluid improving hemodynamics and renal function was dis- into the extravascular space, and possibly GI blood loss.
cussed previously; neither has sufficient evidence to be Most patients will require fluid resuscitation initially.
recommended as part of the management of hemody- Low systemic vascular resistance results in low blood pres- namic derangements in ALF at this time, although NAC sures even in the fluid-resuscitated patient, and placement may have other benefits as discussed above. Evidence that of a pulmonary artery catheter may aid in assessing vol- terlipressin or vasopressin may be useful in patients with ume status and guiding further management. Fluid re- cirrhosis and hepatorenal syndrome has raised the ques- placement with colloid (such as albumin) is preferred tion of whether this agent might benefit patients with rather than crystalloid (such as saline); all solutions should ALF as well. A recent small study of terlipressin in patients contain dextrose to maintain euglycemia.
with ALF found that even in very small doses, the drug While adequate fluid replacement and treatment of was associated with increased cerebral blood flow and potential infection and sepsis may help to correct hypo- ICH.143 Such results indicate that at this time the risks tension, inotropic or pressor support may be required in associated with vasopressin use appear to outweigh its order to maintain mean arterial pressures of at least 50-60 mm Hg. There has been debate over which agents are best The observation that hemodynamic status as well as used to support blood pressure in ALF and whether they ICH tends to improve after removal of the native liver are useful at all. Alpha-adrenergic agents such as epineph- during transplantation for ALF led to a recommendation rine and norepinephrine have been thought to potentially of hepatectomy as a “last resort” means of improving se- worsen peripheral oxygen delivery.66 On the other hand, vere circulatory dysfunction in these patients. This option dopamine has actually been associated with increased sys- is based on uncontrolled studies and case reports, where temic delivery of oxygen.134 In any case, the hypotension successful outcomes have occasionally been reported even with patients who remained anhepatic for more than 48 regeneration of sufficient hepatocyte mass to sustain life.
hours.144-146 Despite these reports, hepatectomy to con- As mentioned previously, the advent of transplantation trol hemodynamics cannot be recommended.
has coincided with improvement in overall survival ratesfrom as low as 15% in the pre-transplant era to Ն60% Recommendations
presently.5 Advances in critical care and changing trends 37. Careful attention must be paid to fluid resus-
toward more benign etiologies such as acetaminophen citation and maintenance of adequate intravascular
(having a better overall outcome) have likely helped.
volume in patients with acute liver failure (III).
Spontaneous survival rates are now around 40%,5 com- 38. If dialysis support is needed for acute renal
pared to 15% in the pre-transplant era. Post-transplant failure, it is recommended that a continuous mode
survival rates for ALF have been reported to be as high as rather than an intermittent mode be used (I).
80% to 90%,5,93 but accurate long-term outcome data are 39. Pulmonary artery catheterization should be
not yet available. In the largest U.S. study, only 29% of considered in a hemodynamically unstable patient to
patients received a liver graft, while 10% of the overall ensure that appropriate volume replacement has oc-
group (1/4 of patients listed for transplantation) died on curred (III).
the waiting list.5 Other series have reported death rates of 40. Systemic vasopressor support with agents such
those listed for transplant as high as 40%,150,151 despite as epinephrine, norepinephrine, or dopamine but not
the fact that ALF remains the one condition for which the vasopressin should be used if fluid replacement fails to
most urgent (UNOS status 1) listing is reserved. Devel- maintain MAP of 50-60 mm Hg (III, II-1).
oping effective methods of liver support or other alterna-tives to transplantation and better prognostic scoring Metabolic Concerns
systems remain key goals to further improve overall sur- A number of metabolic derangements are common in vival rates for the condition. Living-related donor liver ALF. Alkalosis and acidosis may both occur and are best transplantation may help address the shortage of available managed by identifying and treating the underlying organs, but its use has thus far been very limited probably cause. Hypoglycemia should be managed with continu- as a result of time constraints for evaluating donors and ous glucose infusions, because symptoms may be ob- scured in the presence of encephalopathy. Phosphate,magnesium, and potassium levels are frequently low andmay require repeated supplementation throughout the Recommendation
hospital course. Nutrition is also important. Enteral feed- 42. Urgent hepatic transplantation is indicated in
ings should be initiated early. Severe restrictions of pro- acute liver failure where prognostic indicators suggest
tein should be avoided; 60 grams per day of protein is a high likelihood of death (II-3).
reasonable in most cases. Branched-chain amino acidshave not been shown to be superior to other enteral prep- Liver Support Systems
arations.147 If enteral feedings are contraindicated (e.g., A support device to replace the acutely failing liver severe pancreatitis), parenteral nutrition is an option, al- seems a reasonable but elusive goal. The ideal replacement though the risks of infection, particularly with fungal for the failing liver would detoxify, metabolize and syn- pathogens, should be considered. Enteral148 and paren- thesize; in short, perform all the liver’s many functions. A teral nutrition149 may reduce the risk of gastrointestinal variety of systems have been tested to date, with no certain bleeding due to stress ulceration in critically ill patients.
evidence of efficacy. Sorbent systems embody only detox-ification and no hepatocyte replacement. Such systems, Recommendation
employing charcoal or other adherent particles in a cap- 41. Metabolic homeostasis must be carefully main-
sule or column device placed in an extracorporeal circuit, tained in patients with acute liver failure. Overall
may show loss of platelets and worsening of coagulation nutritional status as well as glucose, phosphate, potas-
parameters across the device.152,153 Transient improve- sium and magnesium levels should be monitored fre-
ment of hepatic encephalopathy may be observed but no quently, with expeditious correction of derangements
improvement in hepatic function or long-term benefit has (III).
been shown. Hepatocytes, whether of human or othermammalian origin, have been used in cartridges in extra- Transplantation and Prognosis
corporeal circuits, either with or without sorbent col- Transplantation
umns. Few controlled trials have been published, and Orthotopic liver transplantation remains the only de- some preliminary reports suggest no benefit to outcome, finitive therapy for patients who are unable to achieve with or without transplantation.154 One recent multi- center trial did report improved short-term survival for a Table 6. Potentially Helpful Indicators* of Poor (Transplant-
subgroup of patients with ALF who were treated with a free) Prognosis in Patients With ALF
porcine hepatocyte-based bioartificial liver,155 but corrob- oration of these results by further studies will likely be required before the true utility of this device can be estab- Acute hepatitis B (and other non-hepatitis A viral infections)Autoimmune hepatitis lished. All such trials are difficult to perform and to con- trol properly due to the rarity of well-characterized patients, the heterogeneity of etiologies, varying levels of disease severity and varying access to transplantation. A recent meta-analysis, considering all forms of devices to- gether, demonstrated no efficacy for bio-artificial liver de- vices for the treatment of ALF.156 A variety of other strategies have been employed including exchange trans- Arterial pH Ͻ7.3 (following adequate volume resuscitation) irrespective of fusion, charcoal hemoperfusion, extracorporeal liver per- fusions, and intra-portal hepatocyte infusions.157-159 To PT Ͼ100 seconds (INR ⅐ 6.5) ϩ serum creatinine Ͼ300 ␮mol/L (3.4 mg/ date, none can be recommended, and their use remains experimental. Efforts to improve hepatocyte regeneration PT Ͼ100 seconds irrespective of coma grade OR have likewise been futile thus far.160 When heterotopic or Any three of the following, irrespective of coma grade: partial replacement transplantations have been performed – Drug toxicity, indeterminate cause of ALF– Age Ͻ10 years or Ͼ40 years‡ it appears that the native liver can recover in some but not – Jaundice to coma interval Ͼ7 days‡ all situations, but this may require weeks or months to occur, underscoring the real challenge to liver replace- – Serum bilirubin Ͼ300 ␮mol/L (17.5 mg/dL) ment devices, that is, that liver assist devices might well be *Please note: None of these factors, with the exception of Wilson disease and possibly mushroom poisoning, are either necessary or sufficient to indicate theneed for immediate liver transplantation.
‡These criteria, in particular, have not been found to be predictive of outcome Recommendation
43. Currently available liver support systems are
not recommended outside of clinical trials; their fu-
ture in the management of acute liver failure remains

subsequent studies in both acetaminophen167 and non- unclear (I, II-1).
acetaminophen ALF165 have shown these criteria to be lessaccurate than King’s College Hospital criteria in predict- Prognosis
In a recent meta-analysis, Bailey et al.168 compared Given limited organ availability, lack of good alterna- various prognostic criteria in patients with ALF due to tives to transplantation, and potential complications of acetaminophen, including King’s College Hospital crite- lifelong immunosuppression, accurate prognosis in ALF ria, various combinations of elevated serum creatinine, is a paramount goal. Prognostic scoring systems, although encephalopathy, and prothrombin time elevations (both derived from data on relatively large numbers of patients, single and serial measurements), decreased factor V levels, still fail to achieve success, given the wide variety of etiol- the Acute Physiology and Chronic Health Evaluation ogies that lead to this end stage syndrome. The traditional (APACHE) II scores169 and Gc globulin (vitamin D bind- King’s College Hospital criteria have been the most com- ing protein, a liver-derived component of the actin-scav- monly utilized and most frequently tested of the numer- enging system170). The analysis found that King’s College ous proposed prognostic criteria for ALF.9 Several studies Hospital criteria and pH Ͻ7.30 alone were both fairly evaluating these criteria have shown positive predictive specific in predicting a poor outcome. While the King’s values ranging from just below 70% to nearly 100% and College Hospital criteria were more sensitive than pH negative predictive values ranging from 25% to alone (69% versus 57% sensitivity), use of both criteria 94%.161-165 Overall, such prognostic scores have proven was still likely to miss many patients who would ulti- to have acceptable specificity but low sensitivity to deter- mately require transplantation. The authors also found mine outcome. Criteria based on decreased levels of factor that an APACHE II score of Ͼ15 on admission had a V in patients with encephalopathy predicted death in specificity of 92% (comparable to King’s College Hospi- acute viral hepatitis cases with a positive predictive value tal criteria) with a much better sensitivity of 81%, but this of 82% and a negative predictive value of 98%,166 but measure was only examined in one limited study.169 Other factors such as age and the length of time be- W. Faust, MD, Steven L. Flamm, MD, Gregory J. Gores, tween onset of illness and onset of encephalopathy have MD, Elizabeth Hespenheide, MSN, ACNP, Maureen M.
previously been proposed as important prognostic indica- Jonas, MD, Michael R. Lucey, MD, David R. Nelson, tors in ALF,9,171 these parameters did not affect outcome MD, F. Fred Poordad, MD, Margaret C. Shuhart, MD, in the largest U.S. multi-center study of ALF to date.5 MS, Brent A. Tetri, MD, Zobair M. Younossi, MD, Patients presenting in grade III or IV encephalopathy were less likely than those patients presenting in grade I or The authors have no conflicts of interest to disclose.
II encephalopathy to survive without receiving a livergraft. The most significant predictor of outcome in this References
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2. Position and policy statement: American Gastroenterological Association related disease showed Ն50% transplant free survival, policy statement on the use of medical practice guidelines by managed while all other etiologies showed Ͻ25% transplant-free care organizations and insurance carriers. Gastroenterology 1995;108: Other prognostic criteria have been proposed includ- 3. Woolf SH, Sox HC. The expert panel on preventive services: continuing the work of the USPSTF. Am J Prev Med 1991;7:326-330.
ing severity of SIRS,117,118 Alpha fetoprotein (AFP) lev- 4. Hoofnagle JH, Carithers RL, Sapiro C, Ascher N. Fulminant hepatic els,172 ratios of factor VIII and factor V,173 liver failure: summary of a workshop. HEPATOLOGY 1995;21:240-252.
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9. O’Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439- Recommendation
44. Currently available prognostic scoring systems
10. Schiodt FV, Rochling FJ, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital N Engl J Med 1997;337:1112-1117.
do not adequately predict outcome and determine
11. Zimmerman JH, Maddrey WC. Acetaminophen (paracetamol) hepato- candidacy for liver transplantation. Reliance entirely
toxicity with regular intake of alcohol: analysis of instances of therapeutic upon these guidelines is thus not recommended. (II-2,
misadventure. HEPATOLOGY 1995;22:767-773.
II-3, III).
12. Green R, Grierson R, Sitar DS, Tenenbein M. How long after drug ingestion is activated charcoal still effective? J Toxicol Clin Toxicol 2001;39:601-605.
13. Sato RL, Wong JJ, Sumida SM, Marn RY, Enoki NR, Yamamoto LG.
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PREFERRED THERAPIES: (additional pediatric-specific formulations appear in blue) Most Common Approx Cost Non-Formulary Approx Cost Drug Class Formulary Agent Per Month‡ Per Month‡ Penicillins Augmentin XR 2gm BID BPA, F3, $165/10days Allergy Drugs Analgesics Antidepressants Hyperlipidemics Hypertensives Infectives Allergy Drugs Analgesics A

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