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DOI 10.1378/chest.08-1071 2008;134;1092-1102Chest

R. Todd Stravitz With Acute Liver FailureCritical Management Decisions in Patients

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Critical Management Decisions inPatients With Acute Liver Failure*

R. Todd Stravitz, MD

Few admissions to the ICU present a greater clinical challenge than the patient with acute liverfailure (ALF), the syndrome of abrupt loss of liver function in a previously unaffected individual.Although advances in the intensive care management of patients with ALF have improvedsurvival, the prognosis of ALF remains poor, with a 33% mortality rate and a 25% liver transplantrate in the United States. ALF adversely affects nearly every organ system, with most deathsoccurring from sepsis and subsequent multiorgan system failure, and cerebral edema, resultingin intracranial hypertension (ICH) and brainstem herniation. Unfortunately, the optimal man-agement of ALF remains poorly defined, and practices are often based on local experience andcase reports rather than on randomized, controlled clinical trials. The paramount question in anypatient presenting with ALF remains defining an etiology, since specific antidotes can save livesand spare the liver. This article will consider recent advances in the assignment of an etiology, theadministration of etiology-specific treatment to abate the liver injury, and the management ofcomplications (eg, infection, cerebral edema, and the bleeding diathesis) in patients with ALF.New data on the administration of N-acetylcysteine to patients with non-acetaminophen ALF, thetreatment of ICH, and assessment of the need for liver transplantation will also be presented.

(CHEST 2008; 134:1092–1102)

Key words: hepatitis; liver; liver failure

Abbreviations: ALF � acute liver failure; APACHE � acute physiology and chronic health evaluation;APAP � acetaminophen; CPP � cerebral perfusion pressure; FFP � fresh-frozen plasma; HTS � hypertonic saline;ICH � intracranial hypertension; ICP � intracranial pressure; INR � international normalized ratio; MELD � modelfor end-stage liver disease; MOSF � multiorgan system failure; NAC � N-acetylcysteine; OLT � orthotopic livertransplantation; PT � prothrombin time; rFVIIa � activated recombinant factor VIIa; SIRS � systemic inflammatoryresponse syndrome

A cute liver failure (ALF) may be defined as theabrupt loss of liver function, characterized by he-

patic encephalopathy and coagulopathy, within 26weeks of the onset of symptoms (classically jaundice) ina patient without previous liver disease.1 Many author-

ities2 further subdivide ALF into hyperacute liverfailure (jaundice-to-encephalopathy interval, � 7 days),acute liver failure (jaundice-to-encephalopathy interval,8 to 28 days), and subacute liver failure (jaundice-to-encephalopathy interval, � 28 days), since thetempo of its clinical evolution has important impli-cations about etiology and outcome (Table 1). Ingeneral, patients with hyperacute liver failure have amore favorable rate of spontaneous survival (ie,survival without orthotopic liver transplantation[OLT]), are more likely to have ALF as a result ofacetaminophen (APAP) overdose or acute hepatitisA, and are more likely to have cerebral edemadevelop.2 In contrast, those patients with subacuteliver failure have a dismal rate of spontaneous sur-vival, are more likely to have liver injury due toidiosyncratic drug reactions or indeterminate etiol-

*From the Section of Hepatology, Hume-Lee Transplant Center,Virginia Commonwealth University, Richmond, VA.The author has reported to the ACCP that no significant conflictsof interest exist with any companies/organizations whose productsor services may be discussed in this article.Manuscript received April 23, 2008; revision accepted July 18,2008.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: R. Todd Stravitz, MD, Section of Hepatology,Virginia Commonwealth University Medical Center, PO Box980341, Richmond, VA 23298-0341; e-mail: [email protected]: 10.1378/chest.08-1071

CHEST Postgraduate Education CornerCONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

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ogy, and more frequently exhibit symptoms and signsof chronic liver failure, such as ascites and azotemia(Table 1).2,3

An attempt at defining the “optimal” managementof ALF must begin with the following disclaimer: themanagement of ALF has largely defied systematicstudy. As alluded to above, ALF is a syndrome, not adisease, and may be precipitated by many insults tothe liver (Fig 1), resulting in very different clinicalcourses and complications. Thus, studying a specifictreatment in a homogeneous population of patientswith ALF has been very difficult. Furthermore, thesyndrome is rare, with an estimated incidence of2,000 cases per year in the United States4; indeed,few of even the largest liver transplant centers carefor � 10 cases a year. The need for multicenter trialsspawned the founding of the US Acute Liver FailureStudy Group in 1998, which was composed of 23

centers in an ongoing effort to study all aspects ofALF.4 Finally, ALF generally has a poor prognosiswithout OLT (spontaneous survival rate, � 50%),the application of which interrupts its natural history,rendering the efficacy of a therapeutic maneuverdifficult to interpret.

The current synopsis will highlight important prac-tical developments in the management of patientswith ALF including the accurate identification ofetiology, the administration of agents to treat theliver injury, and the management of the three majorcomplications of ALF (ie, infection, cerebral edema,and the bleeding diathesis). Specific details of allaspects of the management of patients with ALF arealso available in a recent ALF Study Group consen-sus report.5 The reader is also referred to two recentstate-of-the-art treatises on artificial and bioartificialliver support devices,6,7 which will not be discussed

Table 1—Characteristics of ALF According to the Tempo of Evolution (Jaundice-to-Encephalopathy Interval)*

Liver FailureSubcategory

Jaundice-to-EncephalopathyInterval Common Etiologies

Spontaneous Survival,% Clinical Presentation

Hyperacute 0–7 d APAP, Hep A, ischemia(�shock liver�)

80–90 Cerebral edema most common

Acute 8–28 d Hep B, drugs 50–60 Cerebral edema less commonSubacute 5–26 wk Drugs, indeterminate 15–20 Ascites, peripheral edema, renal failure

*Hep A � acute hepatitis A; Hep B � acute hepatitis B; drugs � idiosyncratic drug reactions; indeterminate � no etiology identifiable;spontaneous survival � survival without liver transplantation. It should be noted that these observations are generalizations based upon largepopulation studies and do not apply to individual patients.2–4,77

0

30

60

90

120

150

180

210

240

270

300

330

360

390

420

450

480

APAP

Drug

HepB

HepA

Autoimm

Ischemic

Wilson's

Budd-Chiari

Pregnancy

Other

Indeter

Etiology

Num

berofPatientsenrolled

46%

12% 7.4%

3.0% 5.3% 4.2%

1.7% 0.9% 0.8% 4.8%

14.6%

N=1,033

Figure 1. Etiologies of acute liver failure in the United States: data from the Acute Liver Failure StudyGroup Registry, from 1998 to 2007. Percentages of the total number of patients enrolled are shownabove each etiology (unpublished data courtesy of W.M. Lee, Principal Investigator, the Acute LiverFailure Study Group). See Table 1 footnote for expansion of abbreviations.

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here due to their experimental nature, unavailability,and disappointing preliminary results.8

Advances in Diagnosis and Management ofthe Liver Injury

The first steps in managing a patient with ALFmust include an attempt to identify an etiology sothat specific treatment of the liver injury may beinitiated. No question is more important thanwhether an APAP overdose is either the sole etiologyor a significant contributor to the liver injury. APAPoverdose constitutes nearly 50% of the cases of ALFin the United States (Fig 1) and in many westernEuropean nations.4,9 The prompt recognition ofAPAP-induced ALF is critical, since a specific anti-dote, N-acetylcysteine (NAC), effectively limits hep-atocellular injury by replenishing glutathione, theputative scavenger of the reactive APAP metabolite[N-acetyl-p-benzoquinoneimine]), thereby prevent-ing its binding to hepatocellular proteins.10 Whilestudies11 have documented the efficacy of NAC inameliorating APAP-induced liver injury, the recog-nition of APAP as the etiology of the liver injuryremains challenging. While an estimate of the risk ofliver injury has been made by using a nomogram ofserum concentration of APAP vs time after inges-tion,12 estimates of time from ingestion often cannotbe reliably determined, and up to 50% of ingestionsoccur as “therapeutic misadventures” after repeatedingestions of APAP-containing drugs.13 It should beobvious that the nomogram applies to patients withnormal transaminase levels. Moreover, in circum-stances of uncertain timing or dose of APAP inges-tion, NAC therapy should not be withheld regardlessof whether a low likelihood of injury has beenestimated by the nomogram.

In order to improve the detection of an APAPoverdose, an assay of APAP-protein adducts hasbeen tested in a large group of patients with ALF.14

Such APAP-protein adducts represent the irrevers-ible step in the development of liver toxicity andhave relatively long half-lives in serum compared toAPAP concentrations. APAP-protein adducts weredetected in 100% of sera samples from patients withknown APAP overdose, and in none of those patientswith other well-defined etiologies.14 Moreover,APAP-protein adducts were also observed in nearly20% of those patients with indeterminate ALF,indicating that these patients had surreptitiouslyingested APAP and may have benefited from NACtherapy had the ingestion been recognized. Otherpreliminary studies15 in children have reported sim-ilar rates of APAP-protein adducts in patients withALF of indeterminate etiology and in nearly 10% of

patients with ALF attributed to other causes (eg,acute viral hepatitis). The APAP-protein adduct as-say may also improve the specificity of serum APAPtests in ALF patients with total bilirubin concentra-tions of � 10 mg/dL, in whom false-positive testresults occur frequently using standard colorimetricassays.16 Once the APAP-protein adduct assay hasbeen refined for rapid turnaround, it will likelybecome an important tool for the evaluation of allpatients presenting with ALF.

The US Acute Liver Failure Study Group has alsorecently completed a randomized, controlled trial17

of NAC therapy in patients with ALF not due toAPAP overdose (available in abstract form only). Thehypothesis that NAC therapy would improve out-comes in patients with non-APAP ALF extends fromobservations that NAC therapy improves microcir-culatory abnormalities and systemic inflammatoryresponse syndrome (SIRS) in addition to its effectson glutathione repletion.18 One hundred seventy-three patients were randomized to receive IV NAC orplacebo, and patients were stratified a priori for thedegree of hepatic encephalopathy (mild-to-moderate[grade 1–2] vs severe [grade 3–4]) on admission tothe trial. Spontaneous survival in subjects with grade1 or 2 hepatic encephalopathy at randomization wassignificantly better in subjects who received NACcompared to those who received placebo (52% vs30%, respectively; p � 0.02) [Table 2]. However, theprimary end point of the study, overall survival at 3weeks, was not significantly better in patients whoreceived NAC than in those who received placebo(70% vs 67%, respectively; p � 0.57). Furthermore,spontaneous survival was not improved in NACrecipients with grade 3–4 hepatic encephalopathy

Table 2—Randomized, Blinded, Placebo-ControlledTrial of NAC for the Treatment of ALF Not Due to

APAP Overdose*

Encephalopathy Gradeat Admission

Spontaneous Survival

p ValuePlacebo NAC

1–2 17/56 (30%) 30/58 (52%) 0.0213–4 8/36 (22%) 2/23 (9%) 0.177Total 25/92 (27%) 32/81 (45%) 0.09

*Secondary outcome: spontaneous survival. Patients who were ran-domized to receive NAC received a loading dose of 150 mg/kg IV in250 mL of 5% dextrose in water (D5W) over 1 h, followed by 50mg/kg in 500 mL of D5W over 4 h, 125 mg/kg in 1,000 mL of D5Wover 19 h, and 150 mg/kg in 1,000 mL of D5W over 24 h for anadditional 48 h (72 h total). Patients who were randomized toreceive placebo received the same volume of D5W. The primaryoutcome of the trial, overall survival rate (ie, spontaneoussurvival � survival after OLT), was 61 of 92 patients (67%) in theplacebo group, and 57 of 81 patients (70%) in the NAC group(p � 0.57).17




compared to those who received placebo (9% vs22%, respectively; p � 0.18), although the numberof patients with high-grade encephalopathy was rel-atively small (Table 2). The significance of the appar-ent benefit of NAC therapy in patients with early-stageencephalopathy, therefore, remains somewhat uncer-tain, since the data were gleaned from a subgroupanalysis. A nonrandomized, retrospective review19 ofchildren with non-APAP ALF has also recentlysuggested that NAC administration improved spon-taneous survival over children treated with standardcare without NAC. However, these results must alsobe interpreted cautiously, since the two groups werenoncontemporaneous, with the NAC group seen in amore recent era undoubtedly benefiting from ad-vances in critical care management of ALF. It isdoubtful that more definitive studies of NAC innon-APAP ALF will be performed in the UnitedStates. Consequently, and considering its relativesafety, the administration of NAC may become thestandard of care for ALF patients with mild-to-moderate hepatic encephalopathy without a moreconclusive demonstration of efficacy.

In the last few years, the administration of com-pounds to treat other specific etiologies of ALF has alsobeen examined for acute hepatitis B and autoimmunehepatitis. Although one retrospective study20 of lami-vudine in patients with severe and fulminant acutehepatitis B suggested an improvement in spontaneoussurvival compared to historical control subjects, alarger, randomized, placebo-controlled study21 foundno benefit, although it may have been underpow-ered. Similarly, a small retrospective series22 ofpatients with autoimmune hepatitis presenting asALF found no improvement in outcomes with theadministration of corticosteroids, and suggested anincrease in septic complications.

Advances in Management of theComplications of ALF

Management of Infection

Infection remains one of the most common causes ofdeath in patients with ALF and commonly precipitatesmultiorgan system failure (MOSF), the most commoncause of death.23,24 Furthermore, sepsis with SIRS isa major risk factor for developing cerebral edemaand intracranial hypertension (ICH).25 Therefore,the prevention and rapid recognition of infection inthe patient with ALF is a problem of paramountimportance, especially considering that signs of in-fection are often absent.

Rolando and colleagues23,24,26 have best describedthe incidence of infections in ALF patients. Pneu-monia (50%), urosepsis (22%), IV catheter-induced

bacteremia (12%), and spontaneous bacteremia (16%)account for the majority of infections in patients withALF,27 as they do in non-ALF ICU patients; how-ever, their high incidence (up to 90% of patients)emphasizes the fact that ALF patients are immuno-compromised. The most common offending organ-isms include Gram-negative enteric bacilli, Gram-positive cocci, and Candida species.23,28 Theseobservations have led to randomized trials of prophy-lactic antibiotics in patients with ALF. The sponta-neous seeding of blood by enteric organisms hasbeen suggested in the pathogenesis of sepsis inpatients with ALF27,29; consequently, these studieshave included the administration of both nonabsorb-able, orally administered agents as well as IV antibi-otics. Unfortunately, the primary end point of thefirst study,27 improved survival, was not achieved(possibly due to type 2 error) by prophylactic admin-istration of antibiotics, although the incidence ofinfections was decreased. The second study29 con-cluded that enteral decontamination provided noadditional benefit over prophylactic therapy withparenteral antibiotics.

Based on these limited data, prophylactic therapywith antibiotics cannot be advocated for all patientswith ALF. Several guidelines, however, should beobserved. As with all critically ill patients, IV linesshould be minimized, and their placement and main-tenance performed with the strictest aseptic tech-nique. In severely ill patients (ie, those with high-grade encephalopathy, mechanical ventilation, renalfailure, and severe coagulopathy), chest radiographsand surveillance cultures of blood, urine, and sputumshould be performed daily. Indeed, the study refer-enced above27 reported earlier recognition and treat-ment of infection in patients receiving surveillancecultures. Finally, patients with ALF should be em-pirically administered broad-spectrum antibioticswithout culture results in the following situationswhere infection has been reported frequently in thefollowing patients: those with progression to high-grade encephalopathy; those with renal failure;and/or those with any of the components of theSIRS.24,25 Most programs would also administerprophylactic antibacterial and antifungal agents topatients with ALF awaiting OLT, since posttrans-plant infection after immunosuppression has direconsequences.

Cerebral Edema and ICH

Cerebral edema remains a dramatic and numeri-cally important cause of death in patients with ALF(22% of deaths at the King’s College Liver Unit),although its incidence may be decreasing.30 Thepathogenesis of cerebral edema in ALF patients is




multifactorial and incompletely understood, but theprimary mechanism includes the uptake of ammoniaby astrocytes, resulting in an accumulation of osmot-ically active glutamine, followed by the passive influxof water.31 In patients with cirrhosis and hyperam-monemia, a slower rate of glutamine accumulation maybe offset by the export of organic osmolytes fromastrocytes to maintain osmotic balance, accounting forthe fact that ICH occurs rarely in such patients.However, the rapid development of hyperammonemia inALF patients does not allow the time for this compensa-tion to occur, and likely explains the observation that theincidence of cerebral edema in patients with ALF isproportional to the rapidity of its clinical evolution asestimated by the jaundice-to-encephalopathy interval.2

Basic maneuvers to minimize the risk of ICH inpatients with ALF should be applied universally inpatients with high-grade hepatic encephalopathy.These maneuvers include elevation of the head ofthe bed to 30°, maintenance of a neutral neckposition, avoidance or minimization of painful stim-uli (including suctioning), and facilitation of a state ofmild respiratory alkalosis (eg, to a Pco2 of 30 to 35mm Hg), which usually occurs spontaneously. Thedecision to place an intracranial pressure (ICP)monitor remains one of the most contentious issuesin the management of the patient with ALF. Someauthorities routinely place ICP monitors in patientswho are at the highest risk of cerebral edema,including those with grade 3–4 hepatic encephalop-athy, elevated arterial ammonia levels (ie, � 150�mol/L), and hyperacute liver failure (eg, APAPetiology), or in those receiving therapy with vaso-

pressors.32,33 Some centers place ICP monitors onlyin patients who are deemed to be OLT candidates,while other centers never use the device, citing anabsence of data showing improved outcome, the riskof intracranial bleeding, and a lack of consensusregarding goal pressures.34,35 Based on limited data,however, the US Acute Liver Failure Study Grouprecently endorsed5 the use of ICP monitors in patientswith ALF who are at high risk of ICH, includingnontransplant candidates with relatively high rates ofspontaneous survival (ie, those who have experiencedan APAP overdose or have acute hepatitis A). De-spite the lack of consensus, many experts believe thatICP monitors improve the management of ICH inALF patients and that they may also provide infor-mation regarding the likelihood of poor neurologicrecovery after OLT. Specifically, it has been sug-gested that a cerebral perfusion pressure (CPP)[CPP � ICP � mean arterial pressure] of � 40 mmHg for � 2 h was associated with poor neurologicprognosis,36 although four case reports refute thisobservation.37 Most literature38–40 cites an ICP of� 20 to 25 mm Hg as an indication for treatment.Although the goals for CPP are less well defined,most authorities treat hypotension with vasopressors(usually norepinephrine) to maintain a CPP of � 50to 60 mm Hg.41,42

The simplified pathogenesis of cerebral edemaoutlined above forms the rationale for administeringosmotically active agents to patients with ALF andICH (Table 3). IV mannitol osmotically draws waterfrom astrocytes into the intravascular space. Surpris-ingly few published data are available to support the

Table 3—Treatment Strategies for Cerebral Edema and ICH in Patients With ALF

Agent/Maneuver Drug/Dose/Goal Adverse Effects Study/Year

Mannitol 0.25–0.5 g/kg IV; boluses can be repeatedif serum osmolality is � 320 mOsm/L

Dehydration, hyperosmolality,and renal toxicity

Stravitz et al5/2007;Lidofsky et al36/1992;Canalese et al38/1982;Jalan et al39/1999

Hypertonic saline solution Depends upon available stock solutions(to 145–155 mmol/L)

Dehydration andhyperosmolality

Murphy et al40/2004;Horn et al45/1999

Barbiturates Pentobarbital, 3–5 mg/kg load, followedby 1–3 mg/kg/h;

Thiopental, 5–10 mg/kg load, followed by3–5 mg/kg/h

Hypotension, hypokalemia,and prolonged coma

Lidofsky et al36/1992;Forbes et al46/1989

Sedatives Propofol Propofol infusion syndrome Wijdicks and Nyberg47/2002;Cremer et al81/2001

Indomethacin 25-mg IV boluses Renal toxicity? gastricmucosal erosions?

Tofteng and Larsen48/2004;Clemmesen et al82/1997

Hypothermia 32–33°C Infection, dysrhythmias,pancreatitis?

Jalan et al39/1999;Jalan et al41/2004;Polderman58/2004

Vasopressors Norepinephrine titrated to CPP of� 50–60 mmHg*

Decreased hepatic perfusion? Stravitz et al5/2007

*After ensuring euvolemia.




efficacy of mannitol, although the following originalobservations are impressive: mannitol (1 g/kg IVbolus) resolved ICH in � 80% of patients andincreased spontaneous survival compared to notreatment.38 Unfortunately, patients with a very highICP (� 60 mm Hg) do not usually achieve normalICP after receiving mannitol boluses,43 and othertherapies are needed to delay herniation. The ad-ministration of hypertonic saline (HTS) solution,which acts similarly to mannitol, has only been testedas a prophylactic agent to prevent ICH, but not inpatients with established ICH.40 Patients with ALFand high-grade hepatic encephalopathy but normalICP were randomized to receive HTS solution (30%)to achieve a serum sodium concentration of 145 to155 mEq/L or to “normonatremia” (ie, 135 to 145mEq/L). ICH was effectively prevented from devel-oping in patients who were rendered hypernatremiccompared to the control group (p � 0.04). Althoughthe administration of HTS solution as a treatment forestablished ICH has not been tested, it would seemreasonable to raise serum sodium levels to 145 to 155mEq/L in patients with persistent ICH despite ther-apy with mannitol, which is similar to the practice inpatients with other causes of cerebral edema.44,45

Patients with ALF and ICH despite the use ofosmotic agents present an urgent clinical problem,for most progress to herniation and brain death.Other salvage maneuvers (Table 3) include theinduction of barbiturate coma,46 the use of paralyticagents and deep sedation,47 and therapy with IVindomethacin (25-mg boluses),48 which is not avail-able in the United States. Intractable ICH alsoportends herniation during OLT, as ICP frequentlyincreases with dissection of the native liver andfollowing reperfusion of the transplanted liver.49,50

Spikes of ICP may even occur during OLT inpatients without ICH prior to transplant.50

Therapeutic hypothermia has become a commonlyemployed method to improve neurologic recoveryafter cardiac arrest,51 anoxia,52 and head trauma,53

other conditions in which cerebral edema contrib-utes to brain injury. In experimental models of ALF,the induction of hypothermia has been shown to beneuroprotective, with beneficial effects on numerousphysiologic targets,54 and may also attenuate APAP-induced liver injury.55 Based on these observations,38 patients with ALF and uncontrolled ICH (definedas an ICP of � 25 mm Hg despite two boluses ofmannitol [1 g/kg body weight over 20 min] andultrafiltration [500 mL fluid removed]) were cooledto 32 to 33°C.39,41,50,56 The mean ICP decreasedfrom 37 to 45 mm Hg to 16 mm Hg after theinstitution of hypothermia, cerebral hyperperfusiondecreased, and CPP increased. Furthermore, hypo-thermia prevented relapses of ICH, stabilized ICP to

bridge patients to OLT, and prevented spikes in ICPduring the dissection of the native liver and reper-fusion of the implanted liver during OLT.50 Thesepromising preliminary results require validation in arandomized, controlled trial of hypothermia beforewidespread adoption of the practice,57 especiallyconsidering that the safety of hypothermia in ALFpatients remains poorly defined.58

Management of the Bleeding Diathesis

Despite the fact that an abnormal prothrombintime (PT)/international normalized ratio (INR) com-prises part of the definition of the ALF syndrome,spontaneous, clinically significant bleeding occursrarely (approximately 5% of cases).59 Patients withALF typically have near-normal portal pressure, incontrast to patients with cirrhosis, and bleedinggenerally occurs from superficial mucosal lesions,rather than varices. The most common site of bleed-ing in patients with ALF is from gastric erosions,59,60

but may occur from nasopharyngeal and genitouri-nary sources. The suppression of gastric acid secre-tion with the administration of histamine-2 receptorantagonists (cimetidine) has been shown to decreasethe risk of gastric mucosal bleeding and therebydecrease the transfusion requirements in patientswith ALF61; by inference, prophylaxis with protonpump inhibitors has been advocated.5 Despite thefrequency of ICH, spontaneous intracranial bleedingin ALF patients is exceedingly rare (� 1%) in theabsence of the insertion of an ICP monitor.62

More frequently, concern about coagulopathy inpatients with ALF arises before invasive proce-dures.63 There are few data regarding the risk ofsignificant bleeding after invasive procedures in pa-tients with ALF, such as transjugular liver biopsy, orthe placement of a central venous catheter or ICPmonitor. Furthermore, evidence-based guidelinesregarding the goals of INR do not exist, although ageneral consensus has arisen that the INR should becorrected to � 1.5.5 It must be emphasized, how-ever, that PT/INR poorly reflects the bleeding risk inALF patients since levels of liver-derived anticoagu-lants (eg, protein C/S or antithrombin III) decreasein concert with procoagulant factors.63,64 In a largesurvey of ALF patients who underwent ICP monitorplacement, the risk of bleeding was proportional tothe depth of insertion of the device (epidural loca-tion, 4%; subdural location, 20%; intraparenchymallocations, 22%).34 In the same series, fatal hemor-rhage occurred in only 1%, 5%, and 4%, respectively.A more recent series35 documented intracranialhemorrhage in 10% of subjects, but half were inci-




dental radiologic findings, and bleeding may havecontributed to the demise of the patient in only 3.5%of subjects.

Strategies for the management of coagulopathy inALF patients have also not been well defined (Table 4).In the absence of clinically significant bleeding, theprophylactic administration of fresh-frozen plasma(FFP) has not been shown to decrease the risk ofbleeding or to improve outcome,65 and most authori-ties66,67 recognize the importance of the spontaneoustrend in PT/INR and factor V in assessing prognosisand the need for OLT. Although significant bleedingprovides a clinical rationale for treating coagulopathywith FFP, normalization of PT/INR without causingvolume overload is usually an unattainable goal. In ALFpatients with severe coagulopathy, isovolumetric plas-mapheresis has been shown to be very effective andwell tolerated.68

Although there are no data to support the prophy-lactic correction of coagulopathy before invasiveprocedures in patients with ALF, the practice isnearly universal. Activated recombinant factor VII(rFVIIa) has been administered before invasive pro-cedures such as ICP monitor placement.69 Modestdoses of rFVIIa dramatically improve PT/INR anddecrease the risk of volume overload compared tothe administration of FFP alone in patients under-going ICP monitor placement; however, FFP shouldalso be given prior to rFVIIa to replenish otherdeficient factors.5,63 Cryoprecipitate should also beadministered before rFVIIa and FFP when patientsare significantly hypofibrinogenemic (ie, fibrinogenconcentrations of less than approximately 100 mg/dL).5Despite promising preliminary observations regardingthe use of rFVIIa, several concerns remain undefined,such as the risk for thrombotic complications,70 theoptimal dosing of rFVIIa, and the follow-up of PT/INRafter its administration.

Fewer data exist regarding the treatment ofthrombocytopenia in patients with ALF. As with

FFP, platelet replacement therapy is not indicated inthe absence of active bleeding; the goals of platelettransfusion have not been defined, although a con-centration of 50,000 platelets/�L has been suggestedas an acceptable threshold before an invasive proce-dure.5 Whether to issue platelet transfusions forpatients with platelet counts of 10,000 to 30,000cells/�L remains controversial, particularly in thosewith indwelling ICP monitors. As above, hypofibrino-genemia (fibrinogen concentration of � 100 mg/dL)should be corrected with cryoprecipitate administra-tion before the patient undergoes invasive proce-dures; but, again, no data exist to support its prophy-lactic use. Severe hypofibrinogenemia may reflectdisseminated intravascular coagulation and hyperfi-brinolysis, which is a relatively common complicationof ALF that adversely affects outcome.71,72 Althoughheparin has not been shown to improve outcome insuch circumstances and may increase bleeding com-plications,73 the administration of epsilon aminocap-roic acid is reasonable.74 Finally, vitamin K (10 mgadministered parenterally) should be considered inall patients with ALF, as � 25% of patients may havevitamin K deficiency as a contributing factor.75

Advances in Assessing Prognosis

There may be no more weighty a managementdecision than whether a patient with ALF should belisted for OLT, since the US organ allocation systemprioritizes ALF patients above all with cirrhosis,often resulting in a rapid offer of an organ andprecluding the option of watchful waiting. Althoughlong-term survival after OLT for the treatment ofALF is comparable to OLT for cirrhosis, periopera-tive mortality is definitively higher, reflecting theacuity of the clinical situation.76 Furthermore, OLTintroduces the need for lifelong immunosuppressiontherapy and the inevitability of long-term metaboliccomplications. These considerations emphasize the

Table 4—Management of the Bleeding Diathesis in ALF*

Blood Product/Maneuver Indication Adverse Effects Study/Year

FFP Overt bleeding; prophylaxis for procedure;before rFVIIa

Volume overload; TRALI Rana et al83/2006;Munoz et al63/2008

Plasmapheresis Volume overload or insufficient correctionof coagulopathy with FFP

TRALI? Munoz et al68/1989

rFVIIa Volume overload or insufficient correctionof coagulopathy with FFP

Thrombosis Shami et al69/2003;Pavese et al70/2005

Cryoprecipitate Fibrinogen � 100 mg/dL Munoz et al63/2008;Stravitz et al5/2007

ε-Aminocaproate Mucosal/puncture site oozing, evidence ofhyperfibrinolytic state

Munoz et al63/2008;Lisman et al74/2002

Platelets Overt bleeding; prophylaxis for procedure Transfusion reactions Stravitz et al5/2007

*TRALI � transfusion-related acute lung injury.




undesirability of performing OLT in a patient who willrecover with medical management, especially consid-ering that successful liver regeneration after ALF gen-erally connotes an excellent long-term prognosis.

The following two types of approaches have beendeveloped to assess prognosis in patients with ALF:those that estimate the severity of liver injury andMOSF (Table 5); and those that attempt to quantifyliver regeneration (Table 6). Since the extent of liverinjury contributes to the vigor of liver regeneration,the two are not mutually exclusive. The most time-

tested prognostic assessments for estimating theformer are the King’s College Criteria,77 but othersystems such as acute physiology and chronic healthevaluation (APACHE) II score and the model forend-stage liver disease (MELD) have also beenevaluated (Table 5).78,79 Unfortunately, none ofthese schemes is adequately sensitive to predictdeath.80 Similarly, assays which can be determinedserially to predict hepatic regeneration may improveidentification of spontaneous recovery, but generallylack specificity (Table 6).

Table 5—Systems Used To Assess the Severity of Liver and MOSF in ALF Patients

Systems Etiology of ALF Criteria Predicting Death Study/Year

King’s College criteria APAP overdose Arterial pH � 7.30OrAll of the following: PT � 100 s

(INR � 6.5), creatinine level of� 3.4 mg/dL, and grade 3–4encephalopathy

O’Grady et al77/1989

Non-APAP overdose PT � 100 s (INR � 6.5)OrAny three of the following:

NANB/drug/halothane etiology;jaundice to encephalopathytime � 7 d; age � 10 yr or� 40 y; PT � 50 s (INR� 3.5); and bilirubin level of� 17.4 mg/dL

Clichy criteria Viral Age � 30 yr and factor V � 20%OrAny age, factor V � 30%, and

grade 3–4 encephalopathy

Bernuau et al84/1991;Bernuau et al85/1986

APACHE II score APAP overdose Score � 15 Mitchell et al78/1998MELD/�MELD score APAP overdose � 33/� � 0.4 Schmidt and Larsen79/2007

Table 6—In Vivo Assays Used To Estimate Hepatic Regeneration and Predict Death or Spontaneous Recovery inALF Patients*

Assays Method/Sample Criteria Predicting DeathCriteria Predicting

Survival/Regeneration Study/Year

PT/INR ratio Plasma Rising 3 d after APAP OD Declining within 3 d of APAPOD

Harrison et al67/1990

-Fetoprotein Serum � 3.9 ng/dL 1 d after peakALT level

Increasing within 3 d of APAPOD

Schmidt and Dalhoff86/2005

Lactate Serum (arterial) � 3.5 mmol/L Declining within 12 h of hospitaladmission

Bernal et al87/2002;Macquillan et al88/2005

Phosphate Serum (arterial) � 1.2 mmol/L Declining within 1 d of hospitaladmission

Schmidt and Dalhoff89/2002

Factor V Plasma � 10% of normal on hospitaladmission; absence ofincrease within 3 d

Increasing within 3 d of hospitaladmission

Pereira et al66/1992

Galactose eliminationcapacity

Plasma ELISA � 16.5 �mol/kg/min(normal, 25–55 �mol/kg/min)

Increasing elimination within 4 dof APAP OD

Schmidt et al90/2004

13C-Methacetin breathtest

Breath 13CO2 Absence of increase within3 d

Increasing within 3 d of hospitaladmission

Ilan91/2007

*CK-18 � cytokeratin-18; NANB � non-A, non-B viral hepatitis; ELISA � enzyme-linked immunosorbent assay; OD � overdose.




Conclusions

The optimal management of ALF remains poorlydefined and specific to the particular medical center.Nevertheless, the rates of overall and spontaneoussurvival have increased over the last 20 years because ofimproved intensive care management and advances inOLT techniques. The relative frequency of complica-tions of ALF leading to death may be evolving, with adecrease in the number of cerebral deaths, and anincrease in the number of patients with sepsis andMOSF. Unfortunately, patients with ALF continue tohave a dismal prognosis, with an overall mortality rateof 33% and a transplant rate of 25% in the UnitedStates. The importance of the recognition of APAP asthe sole or contributing etiology to a liver injury cannotbe overstated, for the timely administration of NAC canbe lifesaving and organ-saving; the APAP-protein ad-duct assay should improve our diagnostic accuracy.Recent studies in patients with non-APAP ALF havesuggested that the administration of NAC should beconsidered in patients with early-stage hepatic enceph-alopathy regardless of etiology. Multicenter studies tobetter define the optimal management of ALF, as wellas the prediction of outcome, are urgently needed.

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DOI 10.1378/chest.08-1071 2008;134; 1092-1102ChestR. Todd Stravitz

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