Fulminant Viral Hepatit is

Saumya Jayakumar, MD, FRCPCa, Raiyan Chowdhury, MD, FRCSCb,Carrie Ye, MDc, Constantine J. Karvellas, MD, SM, FRCPCb,c,*

KEYWORDS

� Acute liver failure � Cerebral edema � Fulminant viral hepatitis � Hepatitis A� Hepatitis B � Liver transplantation

KEY POINTS

� Fulminant viral hepatitis (FVH) is the predominant cause of acute liver failure (ALF) in devel-oping countries.

� Hepatitis A and B are themost common causes of FVH, whereas other causes (hepatitis E,Epstein-Barr virus, herpes simplex) tend to occur in special patient populations (preg-nancy, immunocompromised patients).

� All patients with FVH-induced ALF should receive N-acetylcysteine because evidencesuggests that this agent improves spontaneous survival.

� Patients with ALF should be transferred to an intensive care unit at an institution withexpertise in liver failure/transplantation.

� Although large studies are lacking, the primary focus of the management of critically ill pa-tients with ALF/FVH is the prevention of cerebral edema and infection, which may greatlyimprove outcomes, either spontaneous recovery or a bridge to successful liver transplan-tation.

BACKGROUND

Fulminant hepatic failure or acute liver failure (ALF) is a condition wherein the previ-ously healthy liver rapidly deteriorates, resulting in jaundice, encephalopathy, and coa-gulopathy. There are approximately 2000 cases per year of ALF in the United States,1,2

averaging approximately 1 in 6 cases per million annually throughout the world.3–5

Funding Sources: S. Jayakumar, R. Chowdhury, C. Ye: None. C.J. Karvellas: Alberta TransplantFund, Shering-Merck, Gambro.Conflict of Interest: None.a Faculty of Medicine and Dentistry, Division of Gastroenterology, University of Calgary, TRWBuilding, 3280 Hospital Drive NW, Calgary, Alberta T2N 4Z6, Canada; b Division of CriticalCare Medicine, University of Alberta, 130 University Campus NW, Edmonton, Alberta T6G2X8, Canada; c Division of Gastroenterology (Liver Unit), University of Alberta, 1-40 ZeidlerLedcor Building, Edmonton, Alberta T6G 2X8, Canada* Corresponding author. Division of Critical Care Medicine, University of Alberta, 1-40 ZeidlerLedcor Building, Edmonton, Alberta T6G-2X8, Canada.E-mail address: dean.karvellas@ualberta.ca

Crit Care Clin 29 (2013) 677–697http://dx.doi.org/10.1016/j.ccc.2013.03.013 criticalcare.theclinics.com0749-0704/13/$ – see front matter � 2013 Elsevier Inc. All rights reserved.

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Although acetaminophen hepatoxicity (APAP) is the most common cause of ALF in theUnited States, viral causes (fulminant viral hepatitis [FVH]) are the predominant causeof ALF in developing countries. Approximately 3% of liver transplants in the UnitedStates are caused by ALF.6 Given the ease of spread of viral hepatitis and the highmorbidity and mortality associated with ALF, a systematic approach to the diagnosisand treatment of FVH is required.

Hepatitis A

The hepatitis A virus (HAV) is an RNA virus that is transmitted through fecal-oral spread(Table 1). It is associated with poor sanitation, cohabitation or sexual contact with aninfected individual, or contaminated food sanitation.7,8 In the developed world, theadvent of HAV vaccines has led to a dramatic decrease in the rates of acute HAV infec-tion.9 HAV has an incubation period of 30 days, after which the prodromal symptomsof fatigue, malaise, vomiting, anorexia, fever, and right upper quadrant abdominal painare present.10 Approximately a week after the onset of these symptoms, patients willexperience jaundice, pruritus, and hepatomegaly. Other physical findings includesplenomegaly, lymphadenopathy, rash, and arthritis.11

Most HAV infections in immunocompetent adults result in self-limited illness, withALF occurring in less than 1% of cases.12 HAV infection accounts for 3.1% of all pa-tientswith ALF in theUnitedStates.13 HAV-inducedALFoften follows a hyperacute (en-cephalopathy within <7 days of jaundice) course. Of 29 patients presenting with ALFfrom HAV over a 7-year period in the United States, 55% made a spontaneous recov-ery, whereas others either died or went on to require an emergency liver transplant(LT).13 In this study by the US Acute Liver Failure Study Group (ALFSG), the presenceof 2 of the following predicted poor survival without transplant: day 1 serum creatinineof 2.0 mg/dL or more, alanine aminotransferase (ALT) less than 2600 IU/mL, and intu-bation status and pressor support (sensitivity 92%, specificity 88%, and positive pre-dictive value of 86%).13 Mortality rates increase with age (0.1% of children, 0.5% inindividuals aged 15–39 years, and 1.1% in those more than 40 years of age).14

The diagnosis of acute HAV infection is made through the presence of anti-HAVimmunoglobulin M (IgM) in the setting of typical symptoms as well as the exclusionof other causes. Anti-HAV is present at the onset of symptoms and remains positivefor 4 to 6 months afterward. Unfortunately, testing for HAV RNA in the setting ofALF is likely to yield false-negative results.15 The treatment of acute HAV infection issupportive (see the intensive care unit [ICU] management section), and there is full re-covery in 3 to 6 months in 85% of cases.14 Patients with severe disease or evidence ofALF should be transferred to an LT center for supportive management and assess-ment for LT.

Hepatitis B

Hepatitis B (HBV) is a DNA virus transmitted through exposure (both vertical and hor-izontal) to infected blood or other bodily fluids. The incubation period is 1 to 4 months.During the prodromal phase, patients may experience a serum sicknesslike reaction,which is then followed by anorexia, nausea, right upper quadrant abdominal pain, andjaundice. Hepatocyte damage occurs mostly through a host immune-mediatedresponse, and ALF develops when there is an immune-mediated lysis of infected he-patocytes.16 Acute HBV accounts for nearly 30% of ALF cases in parts of Europe andis the main cause of ALF in Asia, sub-Saharan Africa, and the Amazon basin,17,18

although only 0.1% to 4.0% of acute HBV infections lead to ALF.16 The advent ofHBV vaccination has led to dramatically decreased rates of HBV infection and asso-ciated morbidity and mortality.19 In patients who do develop ALF, both ALT and

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aspartate aminotransferase (AST) may be more than 1000 IU/mL (ALT higher thanAST), with the prothrombin time or international normalized ratio (INR) acting as thebest markers of prognosis. Mortality in the setting of HBV ALF is higher (0.4%) thanthat seen with HAV (0.01%) or HCV (0.1%).12 ALF associated with HBV can occurwith both a new infection with HBV and also in the setting of chronic infection, transi-tion of the virus from stable viral replication or inactive carrier status to viral clearance,reactivation, or with superinfection with hepatitis D virus (HDV). Reactivation mostoften occurs in the setting of immunosuppression (eg, chemotherapy). The rate of pro-gression to ALF and death is much higher in the setting of reactivation than is seen withde novo infection.20

Diagnosis of ALF secondary to HBV may be difficult owing to the various mutationsassociated with the HBV. Precore or pre-S mutants that do not produce hepatitis Bsurface antigen (HBsAg) or hepatitis B e antigen (HBeAg) may lead to false negativeswhen testing for HBV.2,16 Patients with a negative HBsAg at the time of presentationhave been shown to have higher survival rates than those who are HBsAg positive.20

Thus, it is recommended that patients be initially tested for HBsAg, HBV DNA. Thetreatment of acute HBV is primarily supportive (see the ICU management section). Pa-tients who have coagulopathy, jaundice, or encephalopathy should be hospitalizedand transferred to an LT center. In the setting of hepatic dysfunction or ALF, evidenceexists for empiric treatment with nucleoside/nucleotide therapy because it may pred-icate the need for transplant (eg, tenofovir, entecavir) and prevent recurrence aftertransplant.21,22 Interferon should be avoided ALF due to HBV because it may resultin increased hepatic necroinflammation.20 Treatment should be continued after2 consecutive negative tests for HBsAg or, if patients proceed to liver transplant,should be continued indefinitely.

Hepatitis C

The hepatitis C virus (HCV) is an RNA virus that is transmitted through contact withbodily fluids, especially blood. Most infected patients are initially asymptomatic. AcuteHCV infection develops 2 to 26 weeks after exposure, and, if symptomatic, symptomscan last for 2 to 12 weeks. Patients with a symptomatic, acute infection have a similarpresentation to other acute viral hepatitidies: jaundice, right upper quadrant (RUQ)abdominal pain, fever, anorexia, arthralgias, and pruritus.23 ALF caused by HCV infec-tion is rare but has been reported, usually in the setting of preexisting liver disease(often HBV),24 although there are reports of ALF from HCV occurring in isolation.25

There are no other specific factors (virus genotype/strains/load, demographics, andso forth) that predispose to the development of HCV-induced ALF.24 When acuteHCV infection is a consideration, testing for an HCV antibody and HCV RNA shouldbe performed. The HCV antibody may not register as positive for a few weeks tomonths after infection.25 Because there are no specific treatments for acute HCV,the treatment is mainly supportive (see ICU management section).

HDV

HDV virus is an incomplete RNA virus that requires HBsAg to transmit its genome.Thus, HDV infection can occur either as a superinfection or a coinfection with HBV.The modes of transmission of HDV are similar to HBV (percutaneous exposure, sexualcontact). HDV infection is endemic in the Mediterranean Basin and Far East Asia. InWestern countries, HDV infection is mostly seen in high-risk groups (injection druguse and individuals receiving multiple transfusions), with rates decreasing of latewith the advent of the HBV vaccination.26 Acute hepatitis D has an incubation periodof 3 to 7 weeks.

Table 1Causes of FVH

ViralType

Mode ofTransmission Endemic Areas Symptoms Prevalence of ALF Diagnosis Treatment

HAV RNA Fecal-oral Developing countries,areas with poorhygiene/sanitation

Fever, RUQ pain, thenfollowed by jaundice,pruritus, andhepatomegaly

Common 1 Anti-HAV IgM SupportiveLiver transplant if

progressivedeterioration

HBV DNA Blood andbodily fluids,verticaltransmission

Asia, sub-SaharanAfrica, AmazonBasin

Serum-sicknesslikereaction, icterichepatitis, fatigue

Common in endemicareas (30% of ALF)

HBsAg AND HBV DNAPrecore and pre-Smutants may notproduce HBsAg orHBeAg

SupportiveNucleotide/sidemolecules

Liver transplant

HCV RNA Blood andbodily fluids

Worldwide Jaundice, fatigue Very rare (only insetting of otherunderlying liverdisease)

HCV RNAHCV Ab of limited use(high rate falsenegative)

SupportiveLiver transplant

HDV RNA Blood (patientsmust beHBsAg 1)

South AmericaFar East Asia

Jaundice to ALF Common in countriesendemic for HBV andHDV

HBsAg and anti-HBcAg(IgM) MUST bepresent

Anti-HDV (IgG and IgM)

Supportive careLiver transplant

HEV RNA Fecal-oral AsiaMiddle EastNorth Africa

Jaundice, hemolysis Uncommon in generalpopulace

Slightly more commonin pregnancy

Anti-HEV IgMHEV RNA in serum orstool

Gold standard: comboof qualitative andquantitative HEV RNAPCR

SupportiveLiver transplantIncreased maternal andfetal mortality

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EBV HHV,DNA

Bodily fluids Worldwide Jaundice,lymphadenopathy,fatigue

Very highmortality withALF

Very rare Positive heterophile AbAnti-EBV viral capsid

antigen (IgG and IgM)High serum EBV DNA

levels

SupportiveCase reports of

ganciclovir for acutehepatitis

HSV HHV,DNA

Bodily fluids,verticaltransmission

Worldwide Fever, anorexia,abdominal pain

LeukopeniaMucocutaneous lesionsJaundiceAST>ALT with mild-no

elevation in bilirubin

Rare inimmunocompetentpatients

Mucocutaneous lesionsHSV IgM and IgG (often

negative acutely)HSV DNA through PCRLiver biopsy

AcyclovirLiver transplantVery high mortality

(90%) in ALF

VZV HHV,DNA

Worldwide Cutaneous lesions (rash)Acute abdominal or

back painFever

Rare Positive viral culturePCR for VZV DNADirect IF on liver biopsy

AcyclovirVaricella

immunoglobulinwithin 72 h ofexposure

Vaccine in high-riskpatients

Abbreviations: Ab, antibody; ALT, alanine transaminase; AST, aspartate transaminase; combo, combination; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HBcAg,hepatitis B core antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; HHV,human herpes virus; HSV, herpes simplex virus; IgG, immunoglobulin G; IgM, immunoglobulin M; PCR, polymerase chain reaction; VZV, Varicella-zoster virus.

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Coinfection with both viruses results in acute HBV and HDV and can range in pre-sentation from a mild jaundice to ALF. Superinfection with HDV occurs when an indi-vidual with chronic HBV infection becomes infected with the delta virus and can leadto more severe disease than with coinfection. In patients with advanced HBV disease,HDV superinfection can lead to hepatic decompensation. Patients presenting withALF caused by HDV infection often have a rapid deterioration (hyperacute presenta-tion), often dying within 2 to 10 days of presentation.27

Patients with HBV presenting with ALF should be tested for the presence of HDVinfection. Some studies suggest that HDV coinfection/superinfection resulting in ALFranges from 16% to 36%,28,29 with poorer outcomes and higher mortality than thosepatients with HBV infection alone.28 In Western countries, the predominant genotypecausing both acute hepatitis and ALF is genotype I.30 The diagnosis of coinfectionrequires the presence of HBsAg and IgMantibody to hepatitis B core antigen. The diag-nosis of HDV ismade through a positive anti-HDVantibody (both IgMand IgG), althougha negative test does not rule out a diagnosis of acute coinfection. Unfortunately, serumHepatitis D Antigen (HDAg) is short lived in immunocompetent individuals31 and, there-fore, is not an appropriate screening or diagnostic test. HDV RNA can be measuredthrough either molecular hybridization or reverse-transcriptase polymerase chain reac-tion (RT-PCR). Currently, there is no specific treatment of acute HDV-induced ALF. Theonly accepted method of treatment is supportive care and possible LT.

Hepatitis E

Hepatitis E virus (HEV) is an RNA virus transmitted through fecal contamination of wa-ter resources, although perinatal transmission32 and transmission through bloodtransfusion have been reported.33 Most cases of HEV infection in Western countriesarise from travel to an endemic area (Asia, Middle East, Central America) or throughzoonotic transmission.34

HEV causes an acute infection that does not progress to chronic hepatitis, except inthe setting of immunosuppression. The standard incubation period for HEV is 15 to60 days, with symptoms being similar to other forms of acute viral hepatitis.35

HEV-induced ALF is uncommon, except in pregnant women. In this setting, the inci-dence of ALF can be as high as 15% to 25%,with the highestmortality seenwhen infec-tion occurs in the third trimester.36 Maternal mortality rates in the setting of HEV-induced ALF range from 60% to 70%,37 compared with mortality rates of 0.5% to3.0% in the nonpregnant population.38 The cause of this more severe infection is notfully understood but is thought to be related, at least in part, to the altered T-helper1/T-helper 2 balance in pregnancy.39 HEV-ALF in pregnancy may resemble severalother hepatobiliary diseases of pregnancy, such as acute fatty liver of pregnancy, he-molysis, elevated liver enzymes, low platelets (HELLP), or herpes simplex hepatitis.40

The gold standard for the diagnosis of acute HEV infection is the combination ofboth qualitative and quantitative HEV RNA through PCR assays because this has ahigher sensitivity while maintaining a high specificity for diagnosis than anti-HEVIgM antibodies.41 Unfortunately, the only treatment of HEV is supportive. Patients pre-senting with jaundice in pregnancy should be tested for HEV and, in the event of he-patic synthetic dysfunction, should be transferred to a transplant center and referredto a high-risk obstetrician.

Epstein Barr Virus

Epstein-Barr virus (EBV) is a herpesvirus, which is often spread through contactwith bodily fluids of an infected individual or an asymptomatic carrier, and is foundworldwide. Most patients with EBV infection will have mild elevations in their

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aminotransferase levels42; but severe liver disease is rare, with jaundice occurring inonly 1.8% to 5.0% of patients.43 ALF from EBV is uncommon, with only a few casesreported in the literature. It is thought to be secondary to either an intense hostresponse to the infection or a primary B-cell hepatic infiltrate.44 Although there is ahigh fatality rate among patients reported to have ALF from EBV infection, most ofthese patients were also immunocompromised (either inherited or acquired immuno-deficiency)45 or, in the pediatric population, had X-linked lymphoproliferative syn-drome.42 ALF can be seen in both the primary infection and in viral reactivation.46

The diagnosis of acute EBV infection is made through a positive heterophile anti-body test, the presence of anti-EBV viral capsid antigen (IgG and IgM), or serum mea-surement of EBV DNA through PCR (most sensitive). The treatment of ALF secondaryto EBV infection is mainly supportive (see ICU management section).

Herpes Simplex Virus

Herpes simplex virus (HSV) is endemic worldwide. In most cases, infection with eitherHSV-1 or HSV-2 presents as a self-limiting disease with mucocutaneous lesions andmild viremia. However, in immunocompromised, pregnant, or elderly patients, ALFmay occur. Patients with HSV hepatitis can present in a heterogeneous fashion,frommild constitutional symptoms to ALF. The most common signs/symptoms are fe-ver, anorexia, abdominal pain, leukopenia, and coagulopathy. Patients may also pre-sent with rash and a history of mucocutaneous lesions, with the latter being present inless than one-third of patients.47 Although rare, there are reports of ALF from HSVinfection occurring in immunocompetent individuals.48 In HSV hepatitis, the serumAST is often greater than the ALT. Often an elevation in bilirubin is mild or absentresulting in anicteric hepatitis. The course is rapid, and once patients develop mentalstatus changes, progression to hepatic necrosis and coma (ALF) is often imminent49;therefore, it is imperative that HSV be considered when patients with either acute se-vere hepatitis or ALF present.Diagnosis of HSV hepatitis is made through physical examination (oral or genital

mucocutaneous vesicular lesions) and serologic testing (HSV IgM and IgG), althoughthe latter may be falsely negative in the acute setting. HSV DNA levels can also bemeasured by PCR.50 The most accurate method of diagnosis is through a liver biopsy,with special attention paid to the presence of viral inclusions and special immunoper-oxidase stains.The mortality rate for patients with untreated HSV-ALF is extremely high (up to

90%),51 so prompt treatment is necessary in suspected cases. Treatment shouldnot be initiated until after diagnostic testing has been performed, although one neednot wait for a positive result to start acyclovir. High-dose acyclovir has been used his-torically for the treatment of HSV hepatitis, including in pregnancy.52 Rapid initiation ofacyclovir increases rates of transplant-free survival. Consider transfer to an LT centerin severe disease.

PROGNOSIS IN FVH/ACL

The cause has significant prognostic implications (spontaneous recovery) and impli-cations of severity and rapidity of the progression of ALF secondary to FVH and itscomplications.53 Compared with other causes of ALF, HAV and HBV (acute) portenda better prognosis of spontaneous recovery despite often an initial presentation asso-ciated with multisystem organ failure (MSOF) and a high risk of cerebral edema (hyper-acute liver failure). In contrast, subfulminant liver failure, often caused by drug induced

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liver injury (DILI) or seronegative causes, often necessitates listing for LT with a signif-icantly lower (<25%) chance of spontaneous hepatic recovery.54–57

PROGNOSTIC CRITERIA IN ALF

Application of the King’s College Criteria (KCC) (Table 2) should guide the clinician indetermining who should be listed for LT.58 A recent systematic review of 18 studies ofnonacetaminophen causes of ALF estimated a sensitivity of 68% and specificity of92% of the KCC.59 Despite its limitations (low sensitivity), the KCC remain the mostwidely used criteria to determine a medical need for LT.60–64

The Clichy-Villejuif criteria, using serum factor V levels and age for prognostication,have been previously validated in patients with HBV.65 Based on a French prospectivestudy of patients presenting with FVH, those patients identified as having the lowestsurvival rates without undergoing LT were those with hepatic encephalopathy andlow factor V levels. These criteria predicted mortality with a positive predictive valueof 82% and negative predictive value of 98% in this cohort (see Table 2).The model of end-stage liver disease (MELD) was initially derived in the setting of

patients with cirrhosis and has been adopted widely for organ allocation purposes inthe United States (United Network for Organ Sharing).66 Prospective data from theUS ALFSG revealed in nonacetaminophen ALF causes a MELD score of 30 ormore had a positive predictive value of 81%, yet these values were not more accu-rate than the KCC.67 Serum lactate levels of more than 3.5 mmol/L at presentation(or >3.0 mmol/L after 12 hours) with fluid resuscitation are associated with highmortality in APAP-induced ALF.68,69 Low serum phosphate levels may be a surrogatefor hepatic regeneration and have been associated with a better prognosis.70

ICU MANAGEMENT OF ALF

There are several ICU management challenges associated with patients with FVH/ALF. Early prognostication regarding which patients will require LT, who will

Table 2Prognostic criteria for ALF

Criteria Reference

KCC O’Grady et al,58 1989 INR>6.5 orINR>3.5Bilirubin>300 mmol/LAged<10 y or >40 yPoor prognostic groupa

Non-APAP

Clichy-Villejuif Bernuau et al,65 1986 Factor V level <20% if aged <30 yFactor V level <30% if aged >30 y

(grade III/IV HE)

HBV

MELD Schmidt & Larsen,162 2008 MELD>33 APAPa

Ammonia Bernal et al,76 2007 Arterial ammonia >150 mmol/L Mixed

Lactate Bernal et al,68 2002 Lactate >3.5 mmol/L APAPa

APACHEII Mitchell et al,163 1998 APACHE II >15 APAPa

Liver biopsy Donaldson et al,164 1993 Hepatocyte necrosis >70% Mixed

Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation score; HE, hepatic en-cephalopathy; MELD, modified end-stage liver disease.

a Data from Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liverfailure: recommendations of the U.S. Acute Liver Failure Study Group. Crit Care Med2007;35(11):2498–508.

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spontaneously recover without LT, and for whom recovery is not possible and LT isfutile is essential. Initial investigations and tempo of deterioration often determinethe diagnosis, severity of the illness, and the possible need for LT.71

NEUROLOGIC MANAGEMENT

Cerebral edema (CE) is a major cause of mortality in patients with FVH (ALF), account-ing for 25% of deaths.72 CE occurs as a result of (1) glutamine accumulation (the prod-uct of glutamate amidation) within the astrocytes and (2) the loss of cerebral vascularautoregulation (vasodilatation) caused by the systemic inflammatory response. As he-patic function deteriorates, increased cerebral blood flow (CBF) exacerbates intracra-nial hypertension (ICH) with the clearest clinical surrogate of this pathophysiologybeing worsening hepatic encephalopathy (HE).73,74 CE is more likely to occur in hyper-acute presentations (eg, hepatitis A) because of the rapid accumulation of glutamineoccurring faster than the compensatory loss of organic osmolytes in the astrocytes.73

Other clinical risk factors include high-grade HE (grade III/IV), high serum ammonialevels (>150–200 mmol/l), the presence of sepsis or systemic inflammatory responsesyndrome (SIRS), and the need for renal replacement therapy (RRT) or vasopres-sors.75,76 Although computed tomography (CT) is insensitive in detecting ICH, it re-mains worthwhile to rule out other intracranial pathologic conditions (ie, bleeding).77

Intracranial pressure (ICP) monitoring remains the gold standard for the diagnosisand management of ICH; however, its use has been limited by concerns of intracranialhemorrhage (5%–10%).78 In retrospective studies, ICP monitoring has not beendemonstrated to improve survival.79,80 The US ALFSG recommends the placementof an ICP monitor in patients with high-grade (III/IV) HE.81 Transcranial Doppler ultra-sonography (TCD) is a noninvasive device that can continuously measure CBF veloc-ity. Although studied extensively in the neurosurgical literature, to date, limited dataare available in patients with ALF to guide clinical use.

PREVENTION AND MANAGEMENT OF ICH

In patients with low-grade (I/II) HE (West Have Criteria), it is recommended that patientstimulation (chest physiotherapy) be minimized. In advanced HE (Glasgow ComaScale [GCS] <8), the patients’ head should be kept in the neutral position and elevatedto 30�.82–84 The use of lidocaine before suctioning can be considered.85 Consider-ations for intubation include minimizing responses (straining, coughing, Valsalva)that could worsen ICP. Propofol has the potential benefit of being short active anddecreasing cerebral metabolic rate and ICP.86 For pain, short-acting opiate infusionsare recommended.81,87 Inducing mild hypernatremia of 145 to 150 mmol/L can reducethe incidence and severity of ICH.88,89 The use of continuous RRT (CRRT) may lead toa sudden decrease in sodium levels because of isotonic replacement solutions oftenused (140mmol/L). In these cases, hypertonic saline infusion (5–30mL/h) can be run inthe presence or absence of CRRT.

Hypothermia

Theoretically, the induction of therapeutic hypothermia (33�C–35�C) may be of benefitin patients with ICH.90–95 Despite a paucity of randomized evidence, hyperthermiashould be treated and spontaneous hypothermia in patients with ALF is potentially ad-vantageous.96 Neuroprotective benefits of therapeutic hypothermia include de-creasing splanchnic ammonia production, restoring normal regulation of cerebralhemodynamics, and lowering oxidative metabolism within the brain.97 Theoreticalrisks include derangement of immune function, cardiac dysrhythmias, and bleeding.98

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In patients with documented evidence of elevated ICP by invasive monitoring (ICP>25mm Hg), consider actively cooling patients to 33�C to 35�C.81

Treatment of ICH

Complete neurologic recovery has been reported after LT even with sustained, severeICH (ICP>25 mm Hg for >5 minutes) despite medical therapy.99 However, severe ICH(ICP>40 mm Hg or central perfusion pressure [CPP] <40 mm Hg for >2 hours) is asso-ciated with poor neurologic recovery after LT.100 Vasopressors should be used tomaintain CPP greater than 50 mm Hg depending on markers of CBF (reverse jugularbulb saturations, reverse jugular bulb venous oximetry [SjO2], or TCD). In patients withsustained ICH (ICP>25 mm Hg for 5 minutes), mannitol is recommended as a first-linetherapy.101 Consider doses of 0.25 to 1.0 g/kg IV bolus as long as serum osmolality isless than 320 mOsm/L. Potential complications include increasing ICP if acute kidneyinjury (AKI) is present, volume overload, hypernatremia (>155 mmol/L), and hyperos-molality. Lower doses may reduce the risk of severe osmotic disequilibrium and dehy-dration.102 If patients’ sodium level allows (<155 mmol/L), intravenous (IV) bolus ofhypertonic saline (23.4% saline [30 mL] or 7.5% saline [2.0 mL/kg] boluses) adminis-tered slowly may be as effective or superior to mannitol.88,103 In patients failingosmotic therapy, increasing sedation, paralytics, and moderate hypothermia (33�C–35�C) and hyperventilation may be considered depending on the clinical need andmarkers of cerebral hemodynamics (ie, cerebral hyperperfusion or hypoperfusion:TDC or SjO2 if available). For severe refractory cases, barbiturate coma, (pentobarbital3–5 mg/kg IV bolus 1–3 mg/kg/h infusion or thiopental 5–10 mg/kg IV bolus then 3–5 mg/kg/h), may reduce ICP.104 Nonconvulsive seizure activity has been documentedin several patients with ALF and advanced stages of HE and is associated withincreased ICP.105 Electroencephalogram monitoring is recommended in patientswith grade III or IV HE, sudden unexplained deterioration in neurologic examination,and myoclonus (along with CT if feasible). Prophylaxis with phenytoin has not shownunequivocal benefit.106

RESPIRATORY SUPPORT

More than 30% of the patients with ALF will develop acute lung injury (ALI) or acuterespiratory distress syndrome (ARDS) while in ICU.107,108 The resulting impaired gasexchange further exacerbates the respiratory/metabolic acidosis leading to cerebralvasodilation, increased ICP, and progressive HE.109,110 Intractable hypoxemia con-tributes to increased mortality.108 Endotracheal intubation should be performed forairway protection for all patients with a GCS of less than 8 or high-grade HE (III/IV).81

Intubation for ventilator support is required in hypoxemic or hypercapnic respiratoryfailure. Intubation should also be performed in the setting of increasing agitation orICP monitoring device placement.81

If ICP or CBFmonitoring is unavailable, a target PCO2 of 32 to 38mmHg or that equalto the preintubation PCO2 is desirable, whichever is lower. In patients with concomitantALI, a tidal volume and plateau pressure should be limited to 6 mL/kg of predictedbody weight and 30 cm H2O, respectively.111 Positive end-expiratory pressure(PEEP) may exacerbate ICP and decrease hepatic blood flow.112,113 As such, PEEPshould be the lowest level possible that achieves adequate oxygenation, optimizescompliances, and minimizes the effects on ICP and cardiac output.83

Lowering PCO2 may be useful in cases of increased CBF (SjO2>80%). In casesof low CBF (SjO2<60%), lowering PCO2 could potentially exacerbate cerebralischemia. Accordingly, hyperventilation should only be used in the presence of

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acute neurologic deterioration or ICP greater than 20 mm Hg with evidence ofincreased CBF.

CARDIOVASCULAR MANAGEMENT

Distributive shock is common in ALF because of the loss of precapillary sphincter toneand the systemic inflammatory response. Euvolemia (avoiding positive fluid balance)is desirable to minimize the risk of CE. Initial resuscitation with 0.9% normal saline witha target central venous pressure of 6 to 10 mm Hg is appropriate. Vasopressorsshould be used to maintain a mean arterial pressure greater than 65 mm Hg and, inthose with ICP monitoring, a CPP greater than 50 mm Hg. Norepinephrine (NE) isthe vasopressor of choice because of its B-adrenergic activity and effect of increasinghepatic blood flow. In the traumatic brain injury population, NE is superior to dopa-mine in maintaining CPP.114 Epinephrine should be avoided because it can reducemesenteric blood flow in sepsis and theoretically reduce hepatic blood flow inALF.115 Although vasopressin has been found to be NE sparing in septic shock, itsrole in ALF is secondary because of theoretical concerns of increasing CBF/ICP.116,117 Echocardiography is useful to assess cardiac filling and may help guidefluid, inotropic, and vasopressor support.83

RENAL SUPPORT

AKI occurs in 50% of patients with ALF and is often polyfactorial.118 AKI early in thecourse of ALF is often consistent with acute tubular necrosis, whereas AKI developinglate may more closely resemble hepatorenal syndrome (HRS).119 HRS is caused byintense renal arterial vasoconstriction caused by a loss of systemic vascular resis-tance and activation of compensatory vasoconstriction systems. All patients withALF should have urinary sodium levels measured and microscopic examination ofurine. A low urinary Na (<10 meq/L) is expected in prerenal azotemia and HRS. A1.5-L crystalloid or colloid IV fluid challenge may be reasonable to rule out HRS andprerenal causes.81,119

Although there are no evidence-based recommendations for timing and modality,RRT in ALF should be considered early for oliguria, volume overload, lactic acidosis,electrolyte disturbances, or enhanced ammonia clearance rather than for usualparameters (eg, azotemia, hyperkalemia). Intermittent hemodialysis may introducehemodynamic instability, fluid shifts, sudden or unpredictable changes in electrolytelevels, and may worsen ICP issues.120 As such, CRRT is recommended for patientswith ALF requiring renal support.121 Although there is no evidence pertaining tomodality, continuous venovenous hemofiltration (CVVH) has the benefit of being runwith minimal or without anticoagulation and can be run at standard (25 mL/kg) orhigh volumes (40–60 mL/kg). Consider using bicarbonate-based (not lactate) replace-ment fluids. Systemic anticoagulation should be used with caution; citrate regionalanticoagulation portends a high risk of citrate toxicity in ALF because of alteredmetabolism.CRRT is often used as an ammonia-lowering modality in patients at high risk for CE,

with hyperammonia being a common indication for initiation of CRRT with levelsgreater than 200 umol/L associated with higher rates of ICH.75,76 CRRT, especially ifusing increased diffusive modalities (continuous venovenous hemodiafiltration[CVVHDF]) or high-volume CVVH, can lower ammonia levels in an attempt to tempo-rize ICH.122 If the initial approach using either CVVHDF or high-volume exchangeCVVH fail to reduce ammonia levels, then consider high-volume plasmapheresis ormolecular adsorbent recirculating system (MARS) (see later discussion).123,124

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Larsen125 recently demonstrated that high-volume plasmapheresis has been associ-ated with improved in-hospital and 90-day survival in patients with ALF.

N-ACETYLCYSTEINE

N-acetylcysteine (NAC) has been studied extensively in APAP hepatotoxicity, and cur-rent evidence supports its benefit in limiting hepatic injury and improving recov-ery.126–128 NAC has demonstrated improvement in hemodynamics and peripheraloxygen delivery in APAP-induced ALF.129–131 Antioxidant properties, decreasedshock state, and decreased incidence of CE have also been demonstrated.132 Leeand colleagues133 also demonstrated in non-APAP ALF improved survival in non-LTpatients treated early and with low-grade HE. NAC infusion should be initiated in allcases of ALF and be continued until LT, resolution of HE, or INR less than 1.5.83,129

NAC therapy should not be withheld regardless of the timing of acetaminophen over-dose or measured acetaminophen level as a result.134 NAC doses of 150 mg/kg IVload for 15 to 60 minutes, followed by a maintenance infusion (12.5 mg/kg/h for4 hours, then 6.25 mg/kg/h) are currently used in most centers.

SEPSIS

Patients with ALF are abnormally susceptible to infection as a result of acquired immu-nologic deficits.107 Delayed antimicrobial therapy in patients with sepsis likely resultsin increased mortality and morbidity. However, studies have failed to show conclu-sively improved survival with prophylactic antibiotics.135 Pneumonia, urosepsis, andcatheter-related infections account for 85% of sepsis in ALF.136,137 The most commonagents are gram-positive cocci (staphylococcus, streptococcus) and enteric gram-negative bacilli.136,138 Serial bacterial surveillance and chest radiographs should beperformed in all patients with ALF.135,136 Although not evidence based, broad-spectrum beta-lactams should be considered where infection already exists or thechance of sepsis is high. Culture-guided therapy can be achieved if specific isolatesare found. Otherwise, empiric treatment should be provided in cases of progressionof or advanced-stage (III/IV) HE, refractory hypotension, or the presence of SIRS,AKI, or listing for LT.81,139 In patients with possible catheter-related bloodstream infec-tion or possible methicillin-resistant Staphylococcus aureus colonization, vancomycinshould be initiated. Antifungal therapy should be considered in patients who do notshow signs of improvement with antibiotics, any patient in the ICU for greater than5 days, and for patients having undergone LT.

HEMATOLOGY

Although coagulopathy (prolonged prothrombin time, elevated INR) is common in ALF,spontaneous clinically significant bleeding is rare (<10%).140 Coagulopathy is second-ary to decreased hepatic synthesis and increased consumption of procoagulant fac-tors.141 Thrombocytopenia is also common in ALF (50%–70%) because of an unclearmechanism.142 Platelet dysfunction is both quantitative and qualitative. Dysfi-brinogenemia often results from decreased hepatic synthesis and increased catabo-lism.143 Low spontaneous bleeding rates in ALFmay be explained by the simultaneousbalanced decrease in both anticoagulant proteins and procoagulant factors.144,145 Inthe absence of bleeding or procedures (ICP monitor insertion), prophylactic correctionof coagulopathy does not reduce the risk of significant bleeding and may exacerbatevolume overload and should be avoided.146 Fresh frozen plasma should be adminis-tered initially in conjunction with cryoprecipitate in patients with dysfibrinogenemia.147

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EXTRACORPOREAL LIVER SUPPORT SYSTEMS

MSOF, HE, and ICH in the setting of ALF are exacerbated by impaired metabolism ofprotein-bound toxins, including ammonia, inflammatory cytokines, protein breakdownproducts, conjugated bilirubin, and nitric oxide/prostanoids.148 Extracorporealalbumin-dialysis (ECAD)–based systems can potentially remove these compoundsthat are not efficiency cleared by conventional RRT techniques.149 Potential goals ofECAD in ALF include improvement in hemodynamics and reversal of HE/ICH byreduction in glutamine production.150 MARS is the most studied of the available liversupport systems in ALF. In a 13-patient pilot study compared with CRRT, Schmidt andcolleagues151 demonstrated improvements in hemodynamics after one 6-hour MARSrun but no mortality benefit. In a prospective randomized study of 102 patients withALF (FULMAR study) performed by Saliba and colleagues,152 there was no significantdifference in 6-month survival, but there was a trend toward increased transplant-freesurvival in the MARS group for APAP causes. A definitive recommendation on MARSin ALF cannot be made at this time. Despite extensive research, there is little evidenceshowing a mortality benefit with an artificial support system in FVH/ALF.

SURGICAL THERAPIES: TOTAL HEPATECTOMY AND LT

Although anecdotal, in patients with refractory ICH, despite all interventions, who havea liver graft donor identified for LT, total hepatectomy can be considered in the short-term (<8 hours) because the failing liver is the primary source of proinflammatory cy-tokines that contribute to CE.153 The 1-year survival of patients with ALF post-LT issimilar to patients with chronic liver disease (70%–80%).154 Given the short windowfor transplant, ABO identical/compatible organs are preferred and have comparablesurvival.155 To date, the use of partial grafts (auxiliary LT and living-donor LT) remainscontroversial with higher rates of complications and retransplantation.156–159 Althoughliving-donor LT improves the ability to rapidly assess the donor, ethical dilemmas arecompounded when donor screening occurs in an expedited time period.156,160,161

SUMMARY

FVH is the predominant cause of ALF in developing countries. Hepatitis A are B andthe most common causes of FVH, whereas other causes (hepatitis E, EBV, herpessimplex) tend to occur in special patient populations (pregnancy, immunocompro-mised patients). All patients with FVH-induced ALF should receive NAC becauseevidence suggests that this agent improves spontaneous survival. Patients with ALFshould be transferred to an ICU at an institution with expertise in liver failure/LT.Although large studies are lacking, the primary focus of the management of criticallyill patients with ALF/FVH is the prevention of CE and infection, which may greatlyimprove outcomes, either spontaneous recovery or a bridge to successful LT.

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