intensive management of hepatic failureubccriticalcaremedicine.ca/academic/jc_article/mgt of liver...

Intensive Management of Hepatic FailureMary E. Rinella, M.D.1 and Arun Sanyal, M.D.2

ABSTRACT

A substantial number of patients with liver failure are admitted to the intensivecare unit; thus a thorough understanding of the prevention and treatment of complicationsin such patients is imperative. The management of liver failure is demanding and ofteninvolves the combined efforts of many specialists. Critically ill patients with hepatic failureencompass a broad spectrum of disease, ranging from acute liver failure in a patient with noprior history of liver disease, to acute on chronic liver failure. The initial assessment andmanagement of acute liver failure are reviewed with an emphasis on the prevention andtreatment of brain edema in the pretransplant setting. The current treatment of compli-cations resulting from decompensated chronic liver disease such as portal hypertensivebleeding; infection, renal failure, and hepatic encephalopathy are then discussed.

KEYWORDS: Liver failure, cerebral edema, portal hypertension, management

The management of liver failure is demandingand often involves the combined efforts of many special-ists. Critically ill patients with hepatic failure encompassa broad spectrum of disease, ranging from acute liverfailure in a patient with no prior history of liver disease,to end-stage decompensated cirrhosis. Both sides of thisspectrum present clinical challenges that involve manyorgan systems. Although both sides in acute and chronicliver failure can have a poor prognosis, careful andcomprehensive intensive care can improve outcome andbridge eligible patients to liver transplantation. Becauseacute and chronic liver failure are very distinct clinicalentities, they will be discussed separately.

ACUTE LIVER FAILUREAcute liver failure (ALF) is a rapidly progressive, oftenfatal syndrome characterized by jaundice, encephalop-athy, and coagulopathy leading to multiorgan failure in apatient with no prior history of liver disease.1,2 In recentyears, advancements in supportive care have improvedsurvival and provided a more effective bridge to trans-

plantation. Although ALF remains one of the most acuteserious illnesses, thoughtful intensive management canoptimize the patient’s chances for spontaneous hepaticregeneration or a successful liver transplant.3 Whenpossible, etiology-targeted therapy should be initiated(Table 1). The goal of management should be focusedon the prevention of systemic infection, multiorgan fail-ure, hepatic encephalopathy (HE), and ultimately thedevelopment of brain edema.4–6 At this time liver trans-plantation is the only definitive therapy for those whofulfill criteria for poor prognosis7–9 (Table 2). Thechallenge to the clinician is selection of patients fortransplant that have low likelihood of spontaneous sur-vival but are not too ill to benefit from transplantation.The principles of management of ALF are reviewed here:

INITIAL EVALUATION ANDMANAGEMENTEarly diagnosis and identification of the subject that isunlikely to improve spontaneously constitute a criticalfirst step in the management of ALF. The initial triage

1Division of Hepatology, Northwestern University, Chicago, Illinois;2Division of Gastroenterology, Department of Internal Medicine,Virginia Commonwealth University, Richmond, Virginia.

Address for correspondence and reprint requests: Arun Sanyal,M.D., Division of Gastroenterology, Department of Internal Med-icine, Virginia Commonwealth University, MCV Box 980341,Richmond, VA 23298-0341. E-mail: [email protected].

Non-pulmonary Critical Care: Managing Multisystem Critical Ill-ness; Guest Editor, Curtis N. Sessler, M.D.

Semin Respir Crit Care Med 2006;27:241–261. Copyright# 2006by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York,NY 10001, USA. Tel: +1(212) 584-4662.DOI 10.1055/s-2006-945528. ISSN 1069-3424.

241

of a patient with acute liver injury to an intensive careunit (ICU) is based on the presence of altered mentalstatus and the degree of coagulopathy. It is imperativeto admit most subjects with acute liver injury with aninternational normalized ratio (INR) > 1.5 and allsubjects with mental status changes. Rapid deteriora-tion can occur and is often irreversible in the patientwith ALF. It is therefore imperative that decisionsregarding prognosis and appropriateness for liver trans-plant be made early, and potentially suitable patientsshould be referred to a liver transplant center early inthe evaluation process.

The management of patients in liver failurerequires a multidisciplinary approach involving hepatol-ogists, transplant surgeons, intensivists, and other sub-specialists. The importance of a thorough physical exam

and an accurate history cannot be overemphasized be-cause both treatment and prognosis are significantlyaffected by the underlying etiology. A detailed accountof the psychiatric history, including suicidal ideationand family support, is essential to assess suitabilityfor transplantation. The timing of the psychiatric evalua-tion is of particular importance, given the rapid deterio-ration in mental status that occurs in such patients.

DISEASE-TARGETED THERAPYA thorough discussion of the differential diagnosis ofALF is beyond the scope of this review; however,Table 1 provides a summary of common etiologies ofALF for which potential therapies exist. Only acetami-nophen will be discussed in more detail because it is themost common etiology of liver failure in the UnitedStates and has an effective antidote.

Acetaminophen

Idiopathic and drug-related liver injuries are the mostcommon causes of ALF in the United States.10 Of thedrug-related causes, acetaminophen overdose is the mostcommon cause of ALF in the United Kingdom andUnited States. Overdose can be either intentional orunintentional.11–13 The patient, family, and close contactsmust be questioned about regular alcohol use, dieting, dietpills, medications, or recent illness that may have resultedin poor nutrition. These factors greatly affect toxicityeither through upregulating cytochrome p450 (alcoholand other drugs) promoting the formation of toxic inter-mediates, or through glutathione depletion. Such detailsare important because as little as 2.6 to 4.0 g of acetami-nophen can lead to liver failure in this setting.14–17

It is worth noting that, at the time of presenta-tion, a patient with acetaminophen-induced liver failuremay have undetectable blood levels of acetaminophen.This is particularly true when the toxicity manifests itselfseveral days after ingestion of acetaminophen for ther-apeutic purposes in a susceptible subject. However, inthe majority of cases, detectable acetaminophen levelsare present at the time of presentation. When acetami-nophen overdose is confirmed, N-acetylcysteine (NAC)must be initiated in a timely manner, ideally within16 hours of ingestion, to have a significant impact onsurvival. NAC decreases injury through enhancement ofglutathione synthesis resulting in less formation ofacetaminophen’s hepatotoxic intermediate.18,19 Even ifthe patient is delayed in reaching the hospital or thediagnosis is not forthcoming, there is evidence that lateadministration of NAC can be beneficial.20 NAC mayalso improve outcome through its effects on micro-circulatory function. A large multicenter study (theALF study group) is currently addressing the utility ofNAC in nonacetaminophen-induced ALF.

Table 1 Etiology-Targeted Therapy

Etiology Potential Therapies

TOXIC

Acetaminophen N-acetyl cysteine

Amanita poisoning Penicillin and silibinin

VIRAL

Herpes simplex virus Acyclovir

Acute heptatitis B Antivirals?

METABOLIC

Wilson’s disease Transplant

Autoimmune hepatitis Corticosteroids

VASCULAR

Acute Budd-Chiari syndrome Directed thrombolysis,

transjugular intrahepatic

portosystemic shunt

PREGNANCY

Acute fatty liver of

pregnancy/HELLP

Urgent delivery

HELLP, hemolysis elevated liver enzymes low platelets.

Table 2 King’s College Criteria for Acute Liver Failure

Acetaminophen induced

� Arterial blood pH < 7.3 (regardless of degree of

encephalopathy)

If no acidosis then all three of the below criteria:

� Prothrombin time > 100 seconds

� Serum Creatinine >2.5 mg/dL

� Grade 3 or 4 encephalopathy

Nonacetaminophen induced

� Prothrombin time > 100 seconds

If prothrombin time <100 seconds, then any of the below

criteria (regardless of degree of encephalopathy):

� Drug-induced, non-A, non-B, halothane hepatitis

� Time from jaundice to encephalopathy > 7 days

� Age < 10 or >40 years

� Prothrombin > 50 seconds

� Bilirubin >17.5 mg/dL

242 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006

MONITORING AND GENERAL GUIDELINESAcute hepatic dysfunction has profound effects on manyorgans. Therefore, one must remain cognizant of theramifications of specific therapies on other systems. Themental status must be documented several times daily, inaddition to frequent assessment of hepatic syntheticfunction and blood glucose (Table 3). Although a liverbiopsy may be helpful if the diagnosis is in question, it canbe unreliable in predicting outcome and is risky given thepresence of underlying coagulopathy.21 Low serum phos-phate and elevated a fetoprotein can be encouraging signsof hepatic regeneration.22,23 In a retrospective analysis ofALF patients, 74% of patients with phosphate levels< 2.5 were alive at 1 week, in contrast to none in thosewith a serum phosphate > 5.24

Coagulopathy in ALF does not usually requirecorrection unless an invasive procedure is planned orovert bleeding is present because the use of fresh frozenplasma (FFP) can mask deterioration of liver function. Acommon indication for the correction of coagulopathyis placement of a central line. Traditionally, FFP andcryoprecipitates have been used for the correction ofcoagulopathy in subjects with ALF. This is only partiallyeffective in correcting coagulopathy and its effects areshort-lived. It is also associated with a risk of transmittingcytomegalovirus infection and may contribute to volume

overload and pulmonary edema, especially when renalfunction begins to deteriorate. Alternate approaches in-clude the use of plasmapheresis where a volume of plasmaequal to the amount infused is removed to preventvolume overload. Recently, recombinant factor VII(40 mg/kg) has been used in conjunction with FFP torapidly correct coagulopathy prior to either intracranialpressure monitor or central line placement in patientswith ALF.25

MECHANICAL VENTILATIONMechanical ventilation should be initiated once ence-

phalopathy deteriorates to � grade 3 (West Haven cri-

teria) to protect the airway.26,27 In addition to preventingaspiration in the patient with compromisedmental status,intubation and sedatives help control agitation, which canlead to surges in intracranial pressure. Patients withencephalopathy beyond grade 3 are very difficult tomanage without intubation and sedation.28

Sedation is best achieved with a short-actingsedative alone or in combination with a short-actingnarcotic. Recent evidence supports the use of propofolfor this purpose. In a small study, propofol was given toseven patients with ALF and profound encephalopathy.Intracranial pressure (ICP) remained normal in six of

Table 3 Acute Liver Failure: General Management Guidelines

On Admission Daily Tid Hourly If Indicated

Monitoring IV access, CVP and arterial

line, Foley catheter

Blood sugar Mental status Mechanical intubation,

ICP monitoring

Thorough history

and physical

Interview family members

Laboratories Liver panel, renal panel,

CBC, PT, Hep A,B,C

serologies, HSV, CMV,

EBV, ceruloplasmin, ANA,

anti-sm Ab, SPEP,

HIV, acetaminophen

level, toxicology screen,

cosyntropin stimulation

test, TSH, blood type,

blood cultures

Basic laboratories, AFP,

arterial ammonia

(or more if mental

status deteriorating

phosphate,

factor V level

Blood gas Changes in

ICP monitor

Imaging US with Doppler Head CT for neurological

changes or suspected

edema

Directed therapy where indicated Drugs, cooling for

cerebral edema

AFP, alpha feta protein; ANA, antinuclear antibody; anti-sm Ab, antismooth muscle antibody; CBC, complete blood count; CMV, cytomegalo-virus; CT, computed tomography; CVP, central venous pressure; EBV, Epstein-Barr virus; HSV, herpes simplex virus; HIV, human immunode-ficiency virus; ICP, intracranial pressure; IV, intravenous; PT, prothrombin time; SPEP, serum protein electrophoresis; TSH, thyroid stimulatinghormone; US, ultrasound.

INTENSIVEMANAGEMENTOFHEPATICFAILURE/RINELLA, SANYAL 243

seven patients with ALF given propofol at 50 mg/kg/min, suggesting propofol may have independent benefi-cial effects on ICP.29 Paralytics are usually avoidedbecause they can mask seizure activity. However, theymay be used in specific cases to facilitate managementwhen the subject does not respond appropriately tosedation. In such cases, it is imperative to consider thepossibility of seizure activity if the clinical picturecontinues to deteriorate. H2 antagonists or protonpump inhibitors may decrease the incidence of ulcerdisease in mechanically ventilated patients30; however,the theoretical risk of increasing the incidence ofpneumonia has not been studied in this population.

PREVENTION AND MANAGEMENTOF COMPLICATIONS

Circulatory Dysfunction

Derangements in circulatory function manifest early inALF and are often progressive. They are characterized bygeneralized vasodilation, increased cardiac output, de-creased systemic vascular resistance, and a low meanarterial pressure (MAP).31–33 It is challenging to distin-guish this clinical picture from the hemodynamics ofsepsis, particularly given that infection is common andoften a fatal complication.34 Factors such as adrenalinsufficiency also complicate management by makingthe vasculature less responsive to vasopressive agents.35,36

In general terms, fluids and vasopressors shouldbe used to maintain adequate cerebral perfusion pressure(CPP) (50 mm Hg to 65 mm Hg) while avoidingcerebral hyperemia from hyperperfusion.37,38 Becausethe circulatory disturbance in ALF is characterized byvasodilation and increased cardiac output, norepinephr-ine is frequently the vasopressor of choice.

Infection

Patients with ALF are particularly susceptible to severeinfection due to many immunological defects such asdefective phagocytic function and decreased comple-ment levels.39–42 Bacterial or fungal sepsis is a frequentcause of death in this population. Much like otherimmunocompromised hosts, their response to infectionis atypical in that signs such as fever or leukocytosis areabsent in 30% of cases.43 Thus sepsis is both frequentand difficult to diagnose in subjects with ALF. In aprospective study of 887 patients with ALF, one or morebacterial infections occurred in 37.8%; however, anincidence of up to 80% has been reported.44 Of these,gram-positive cocci were the most common organismsisolated, although Escherichia coli and Klebsiella were alsofrequent pathogens.45 Overall, pneumonias make up50% of bacterial infections in ALF with bacteremiaand urinary tract infections occurring in 20 and 25%,

respectively. These infections presented at a median of5, 3, and 2 days after the onset of ALF.44

Given the frequency of both gram-negative andgram-positive infections in this population, broad spec-trum antibiotic coverage should be administered avoid-ing aminoglycosides due to their nephrotoxicity.34

Although no randomized controlled trials have demon-strated improved survival with prophylactic antibiotics,parenteral antibiotics are associated with a lower inci-dence of infection46 (Fig. 1).47 Given these data, pro-phylactic broad-spectrum antibiotics seem justifiablegiven that uncontrolled infection in such patients isoften catastrophic.48,49

Systemic Inflammatory Response Syndrome

Even in the absence of documented infection, systemicinflammatory response syndrome (SIRS) is common inthose with ALF and is likely due to a surge of cytokinerelease.50 In a study from King’s College, 57% of 887patients with ALF developed SIRS. The presence ofSIRS on admission was independently associated withmore severe illness, worsening of encephalopathy, andsubsequent death. In those patients that were infected(54%), mortality increased with each additional compo-nent of SIRS. At this point it remains unclear howadditional infection contributes or which component ofthe observed inflammatory response originates fromhumoral factors released by the necrotic liver.34,46,51

Adrenocortical Insufficiency

Adrenocortical insufficiency can worsen hyperdynamiccardiovascular collapse typical of ALF or septic shock.52

This should be considered when the patient fails

Figure 1 The effect of antibiotic prophylaxis on the prevalenceof documented infection patients with acute liver failure.(Adapted from Salmeron et al.47)


to respond to volume resuscitation.35 In sepsis, supra-physiological doses of steroids in patients with adrenalinsufficiency have been shown to reduce vasopressorrequirements and improve outcome.36,53 Adrenaldysfunction appears to also be prevalent in patientswith ALF; 62% of patients with ALF were found tohave an abnormal response to high-dose corticotrophinstimulation. The patients with pronounced hemody-namic instability had more marked evidence of adrenalinsufficiency, suggesting that it may contribute to thepattern of cardiovascular collapse seen in liver failure.54

The benefit of stress-dose steroids in this populationneeds to be tested in a randomized-controlled trial;however, given these data, it is reasonable to look forand consider treating adrenal insufficiency in patientswith ALF.

Renal Failure

Renal failure is common in those with advanced liverfailure and is multifactorial in etiology. Common causesof renal failure in this population include prerenalazotemia, renal ischemia, acute tubular necrosis, andhepatorenal syndrome. A majority of patients withALF complicated by profound hypotension and cerebraledema will require renal replacement therapy.31 Due tothe marked vasodilation that characterizes such patients,continuous venovenous hemofiltration (CVVH) tends tobe better tolerated and may have more beneficial effects

on ICP.55,56 Moreover, intermittent hemodialysis hasbeen associated with increases in ICP and decreases inCPP, whereas the opposite has been shown in patientsreceiving CVVH.55,57

Hepatic Encephalopathy and the Development

of Intracranial Hypertension

The development of HE and subsequent cerebral edemaand intracranial hypertension (ICH) define prognosis inpatients with ALF.2,7,58 Treatment options for suchpatients are limited. As a result, �30% of patientswith ALF and cerebral edema succumb to cerebralherniation while awaiting an organ.7,31 Without urgenttransplantation, mortality can exceed 90% in those whohave uncontrolled ICH.

The pathogenesis of cerebral edema is complex(Fig. 2). ALF leads to many hemodynamic changes,including impairment of cerebrovascular autoregulationand blood flow. This impairment makes the standardassumption that CPP¼MAP� ICP less reliable.38

Other factors such as high arterial ammonia levelscontribute to brain edema through the accumulationof glutamine and alanine in astrocytes. In response toswelling, a vasodilating factor is released that leads toincreased CBF and thus increased ICP.59

Arterial ammonia levels > 200 mmol/L in thesetting of ALF have been shown to herald impendingcerebral herniation and poor outcome.60,61 Other

Figure 2 Factors leading to the development of brain edema and potential therapeutic interventions.


markers of brain cell dysfunction and damage such ass100-b and neuron-specific enolase (NSE) have alsobeen evaluated as potential predictors of impendingherniation in the setting of ALF and acute on chronicliver failure with negative results.62 Currently, no serummarkers of brain cell dysfunction reliably demonstrateneurological injury and poor outcome.

Unfortunately, it can be difficult to predict whichpatients are likely to develop elevated ICP. Clinical signssuch as arterial hypertension, fever, and agitation canprecede episodes of severe ICH; however, these are notreliable predictors because elevated ICP is often clin-ically silent.63 Although a computed tomographic (CT)scan is usually used to look for cerebral edema, a normalscan does not exclude the presence of edema because itsappearance on imaging may be delayed.

INTRACRANIAL PRESSURE MONITORINGA significant clinical challenge in the management ofALF is the decision to place an ICP monitor. There areno strict guidelines related to the use of these monitorsand experience across institutions is highly variable.Noninvasive techniques have not proven to be benefi-cial and direct ICP monitoring is the only reliablemodality for the measurement of ICP. The benefitthat can be derived from ICP monitoring is twofold.First, it allows for the early detection and treatment ofICH because it can be clinically silent.63 Second, it canprovide invaluable information about the likelihood ofneurological recovery when deciding whether to pro-ceed with liver transplantation, such as when CPP ispersistently low. Sustained CPP < 40 mm Hg predictsa high likelihood of ischemic brain injury that typicallyresults in a poor neurological outcome after transplan-tation.64,65 Figure 3 proposes an algorithm for the useof ICP monitors in ALF.

Although treatments aimed at reducing ICP canbe used without an ICP monitor, an accurate ICPreading permits targeted therapy to optimize CPP anddetect abrupt surges in pressure that necessitate addi-tional therapy. Concomitant measurement of jugularbulb oxygen saturation,32,66 which allows measurementof brain oxygen utilization, can also be useful in themanagement of these patients.32 Jugular bulb oxygensaturation > 80% or < 60% predicts elevation in ICPwith good sensitivity and specificity.31 Jugulovenous O2

saturations < 50% may herald an increase in anaerobiccerebral glycolysis, increased lactate:pyruvate ratio, andworsening cerebral edema.67

When and in Whom to Insert an Intracranial

Pressure Monitor

To justify the risks of ICP monitor placement, themonitor needs to be placed under controlled circum-stances, when increased ICP is likely to rise but beforeuncontrolled ICH and herniation occur. ICP monitor-ing should be considered for mechanically ventilatedpatients with grade 3 or 4 encephalopathy with poorprognosis (Table 2) but who are otherwise good candi-dates for liver transplant (Fig. 3). Other predictors ofincreased ICP such as arterial ammonia > 150 mmol/Lcould be used to time monitor placement. In those withpoor prognosis without orthopedic liver transplant(OLT), ICP monitoring can guide therapy and preventsurges in ICH before and during OLT.

Risks of Intracranial Pressure Monitoring

As with all interventions, the risks of ICP monitorplacement need to be balanced against the accuracy andusefulness of the information to be gained. No random-ized, controlled trial is available to compare different

Figure 3 Proposed algorithm for the use of an intracranial pressure monitor.


catheters in the setting of ALF. Types of catheters includeepidural, subdural, parenchymal, and intraventricularcatheters. Blei et al performed a survey of transplantcenters across the United States. They estimated that20% of ICP monitoring resulted in intracranial bleeding.Epidural catheters had the lowest rate of bleeding com-plications (3.8%) and subdural and parenchymal cathetersthe highest; 20% and 22%, respectively.68 A recent multi-center study from the ALF study group showed that ICPmonitors were only used in 92/332 patients (28%) withALF and severe encephalopathy; however, the frequencyof monitoring differed between centers. Ten percent hadintracranial bleeding as a result of the ICP monitor. Intwo of these patients, ICP monitoring was directlyassociated with the patient’s death.69 Although the riskof complications is greater,70 subdural catheters give amore reliable estimate of ICP than epidural catheters.68

Bleeding complications can be decreased signifi-cantly with the use of recombinant factor rVIIa givenimmediately before the procedure.25 The frequency offactor VII dosing was variable in this study; however, as agroup all patients that received factor VII normalizedtheir prothrombin time (PT) and were able to have ICPmonitors placed (compared with 38% in the FFP alonegroup). The ideal initial dose and subsequent doses offactor VII necessitates further study.71 The data showthat ICP monitoring can be an effective tool for manag-ing elevated intracranial pressure; however, ICP mon-itors have not been shown to improve survival. Currentlythere is no consensus about the use of ICP monitoring orwhether the more accurate but higher-risk subduralcatheters or the less accurate but safer epidural cathetershould be used. Individual centers will continue to usewhat they are comfortable with; however, their decisionmay be influenced by the decreased availability of epi-dural catheters.

Prevention and Treatment of Increased

Intracranial Pressure

Routine measures such as elevation of the head of thebed to 30 degrees,55 sedation, minimal stimulation, andmechanical ventilation to minimize cerebral stimulationshould be adhered to whenever possible. The manage-ment should be focused on maintaining an adequateCPP (> 50 mmHg) while minimizing elevations in ICP(< 20 mm Hg). Blood pressure should be maintained toachieve a CPP between 50 and 65 mm Hg. ProlongedCPP below 50 mm Hg in the setting of ICH or an ICPgreater than 40 mm Hg is associated with poor out-come.65

HYPERTONIC SALINE

The use of hypertonic saline is thought to help restorethe osmotic gradient across the astrocyte membrane. Arandomized, controlled trial recently demonstrated that

induction and maintenance of hypernatremia (145 to155 mmol/L) in patients with grade 3 or 4 encephalop-athy resulted in a decreased incidence and severity ofICH.72 Other techniques to reduce brain water accu-mulation through the reduction of arterial ammoniaremain under investigation.73–75

MANNITOL

Mannitol administration leads to increased plasma os-molality in brain capillaries, resulting in movement ofwater out of the brain according to Starling’s law. It hasbeen shown to decrease episodes of cerebral edema andresult in improved survival in a cohort of patients withALF (47.1 and 5.9%, respectively, p¼ .008).76 Its use,however, is limited in renal failure and can lead to aparadoxical increase in brain swelling if osmolality is notcontrolled. If more than two doses are to be used, plasmaosmolality must be checked to assure that it remains< 320 Osm/L.

HYPERVENTILATION

Hyperventilation is an effective technique to decreasecerebral blood flow (CBF) and ICP. It does so throughprecapillary hypocapnic vasoconstriction and helps re-store CBF autoregulation.61,77–79 Although prophylactichyperventilation appears to be ineffective in preventingthe development of ICH,77 it can be useful in controllingacute surges in ICP.

INDOMETHACIN

Indomethacin leads to cerebral vasoconstriction effectsvia altering cerebral temperature and extracellular pHand inhibition of the endothelial cyclooxygenase path-way.80 Its effectiveness has been proven in an animalmodel81 and in a small cohort of patients with ALF.82

However, due to its multiple systemic side effects inpatients with ALF, its routine use cannot be supported.

THIOPENTAL SODIUM

In a small, uncontrolled study, thiopental sodium waseffective in reducing ICP.83 Unfortunately, its use isassociated with significant hemodynamic derangementsthat may necessitate escalation of vasopressor or inotropicsupport. Thus thiopental use should be reserved forsurges of ICH unresponsive to standard medical therapy.

HYPOTHERMIA

Moderate hypothermia (32 to 33�C) in animal models ofALF has been effective in improving encephalopathyand reducing brain water.84,85 Clinical studies of hypo-thermia have also shown significant reduction in ICP.Jalan et al were able to demonstrate that cooling patientswith refractory ICH to 32�C decreased ICP to< 20 mmHg. Subsequently they demonstrated a reciprocal in-crease in ICP with rewarming.86 Since this study, thesame and other groups have also shown that moderate


hypothermia is effective in the prevention of ICH inALF, as a bridge to transplant,87 and during liver trans-plantation88 to prevent surges in ICP. The mechanismof action is presumed to be multifactorial but includesreduction of CBF, cerebrospinal fluid (CSF) ammonia,and extracellular glutamate concentrations. Althoughhypothermia may be beneficial to the brain in decreasingICP, it also impacts coagulation and may promoteinfection and cardiac rhythm disturbances. It is difficultto know, however, if hypothermia exacerbates suchfactors because these are well-known complications ofliver failure per se. Some have raised concern thathypothermia may impair hepatic regeneration and ‘‘com-mit’’ patients to transplant.89,90 The degree to whichhypothermia influences such factors needs to be ad-dressed in a well-designed randomized, controlled trialbefore its use in routine practice can be justified.

LIVER ASSIST DEVICESLiver assist devices are of two general types: biologicaldevices and artificial devices. Biological devices use livinghepatocytes to replace liver function, whereas artificialdevices such as the molecular absorbent recirculatingsystem (MARS) aim to remove injurious substancesfrom the circulation. Most of the trials in ALF haveused either porcine hepatocytes [bioartificial liver (BAL)device]91 or humanHepG2 cells (ELAD [extracorporealliver assist device]).92 A large multicenter study of BALin ALF resulted in no survival advantage.93 In a smallrandomized controlled trial, ELAD resulted in lessseverity of encephalopathy without improvement insurvival.94 Overall, the data on bioartificial liver devicesare disappointing in that they are quite costly and havenot resulted in improved synthetic function or survival.95

MARS removes free and albumin-bound toxinsvia a polysulfone membrane.96,97 In contrast to bioartifi-cial devices, MARS has mainly been tested in acute onchronic liver failure (AoCLF). Two small randomizedclinical trials have shown improvement in encephalop-athy and increased survival.98,99 MARS also appears to beeffective in ameliorating renal function in hepatorenalsyndrome and hemodynamics through increasing sys-temic vascular resistance (SVR).100 Although not aprimary end point, survival was improved in a prospec-tive, randomized, controlled trial of MARS in liver fail-ure.99 The study was terminated prematurely due toperceived ethical considerations. Unfortunately, had aslittle as one or two deaths occurred in the MARS groupthe difference in survival would have no longer beenstatistically significant. The results of this trial wouldhave had a more profound impact if the study hadachieved its targeted enrollment. A recent meta-analysisfound that MARS offered no significant survival benefitover standard medical therapy.101 MARS appears to bewell tolerated; however, a fair number of patients devel-

oped thrombocytopenia; thus its use should be restrictedin patients with DIC.102

LIVER TRANSPLANTATION FOR ACUTELIVER FAILUREBecause the mortality of patients with ALF is almostuniversal once they meet criteria for poor prognosis(Table 2), they receive the utmost priority. The Status1 classification has remained from the former process oforgan allocation. To receive this listing, the patient musthave no prior history of liver disease and fulfill criteria forALF with poor prognosis.

Intensive medical supportive care is geared towardthe avoidance of complications that could precludetransplant. The decision to proceed with transplantationis a difficult one not only from a medical managementperspective but also due to the limited time available toassess the patient’s social support network, mental stabil-ity, compliance, and wishes. Psychiatric stability andstrong social support are essential to a successful trans-plant. It is imperative to accurately document activedrug or alcohol abuse, suicidal ideation, or history of aprevious suicide attempt because these are examples ofpotential contraindications to transplant.

ACUTE OR CHRONIC LIVERFAILURE—GENERAL CONSIDERATIONSCritically ill patients with cirrhosis admitted to the ICUhave poor survival even if they survive the initial ICUstay. Mortality can reach 100% in cases complicated byseptic shock.103–106 Acute hepatic decompensation in apatient with chronic liver disease (AoCLF) is mostcommonly precipitated by gastrointestinal bleeding orinfection. As a result of this, major functions of the liversuch as the synthesis of key proteins, detoxification, andmetabolic regulation are impaired to various degrees.The imbalance created by the physiological needs of thecritically ill patient and the liver’s limited ability toperform key functions leads to life-threatening compli-cations such as renal failure, infection, HE, cholestasis,ascites, and bleeding.

An important step in the initial management ofpatients with AoCLF is the identification and treatmentof the precipitating factor that led to acute decompen-sation. Patients admitted to the ICU with AoCLFshould be managed with a simultaneous multifacetedapproach that will bridge eligible patients to transplan-tation and improve short-term survival in nontransplantcandidates.

PORTAL HYPERTENSIVE BLEEDINGPortal hypertensive hemorrhage is a serious and frequentcomplication of advanced cirrhosis.107–109 Bleeding can


originate from gastroesophageal varices, portal hyper-tensive gastropathy, or less commonly from portal col-opathy, duodenal or rectal varices. A successful outcomedepends on accurate diagnosis, prompt resuscitation,hemodynamic support, management of complications,and control of active bleeding. Clinical factors associatedwith bleeding include deterioration of liver function,portal vein thrombosis, hepatocellular carcinoma, andongoing alcohol use.110

In cirrhosis, portal hypertension is the result ofthe combined effects of increased portal venous inflowand an increased resistance to that flow.111 The correctedsinusoidal pressure gradient is inversely associated withrisk of bleeding as well as outcome after bleeding.112–114

A hepatic venous pressure gradient (HVPG) of 12 mmHg is a threshold value, with variceal hemorrhageoccurring above this level112 and therapeutic interven-tion aiming at a reduction below this value.115,116 How-ever, many studies have shown that if portal pressure isreduced in a sustained manner by � 20%, the risk ofbleeding is low (10% at 2 years), even if the HVPGremains above 12 mm Hg.109,117

Acute variceal hemorrhage (AVH) occurs in 30 to35% of patients with cirrhosis and is associated withsignificant mortality. A recent retrospective analysis re-ported in-hospital, 6-week, and overall mortality rates of14.2%, 17.5%, and 33.5%, respectively, suggesting im-proved therapy of AVH has impacted survival.118 One-year survival following a variceal bleed greatly depends onthe severity of liver disease assessed by the Child-Pughclassification (Table 4). Mortality after a variceal hemor-rhage is 5% and 50% in Child-Pugh A and C cirrhoticpatients, respectively,119 and 70% of those that survivewill rebleed.110,120 A hepatic venous pressure gradient> 20 mm Hg after an acute bleed is an independentpredictor of poor outcome. Such measurements may beuseful to assess prognosis and tailor therapy.114

The management of patients with gastroesopha-geal varices involves (1) prevention of the initial bleed(primary prophylaxis is beyond the scope of this review),(2) management of the acute bleed, and (3) prevention ofrebleeding (secondary prophylaxis).

Variceal Hemorrhage—General Considerations

Acute hemorrhage typically presents with hematemesiswith or without melena or hematochezia. Hemody-

namic instability is often present and needs to beaddressed with continuous cardiac monitoring andgood intravenous access. Knowledge of the centralvenous pressure is helpful to gauge the adequacy ofvolume administration without overresuscitating thepatient because this can provoke more bleeding frompreviously decompressed varices or lead to other com-plications such as acute pulmonary edema.121,122 Pro-phylactic endotracheal intubation should be consideredin the setting of significant upper gastrointestinalhemorrhage prior to endoscopic intervention for airwayprotection. Figure 4 proposes an algorithm for themanagement of AVH.

Esophageal Variceal Hemorrhage

Mortality associated with AVH has improved in thepast decade.123 Based on data comparing patientspresenting with AVH from 1981–82 to 1988–91, thelate cohort experienced a significant decline in mortal-ity at 30 days (20.8% vs 29.6%, p¼ .0001) and at 6 years(69.7% vs 74.5%, p¼ .0001). For patients who survivedthe first 30 days, survival was slightly better in the latecohort on multivariate analysis (p¼ .01).124 Spontane-ous cessation of bleeding occurs in 50% of patients;however, 60% of these patients will rebleed if there is nointervention.120 Therapeutic options for the manage-ment of variceal hemorrhage include pharmacologicaltherapy (somatostatin, octreotide, vasopressin, or terli-pressin), endoscopic therapy (endoscopic band ligationor sclerotherapy), balloon tamponade, transjugular in-trahepatic portosystemic shunt (TIPS) or surgicalshunts (Fig. 4). Pharmacological treatment is effectiveand should be initiated on admission to the ICU.Although studies have shown some drugs to be aseffective as endoscopic therapy,125,126 this is controver-sial; thus we recommend endoscopic intervention inaddition to pharmacotherapy for the control of varicealhemorrhage.

Gastric Variceal Hemorrhage

Gastric varices represent a less frequent, but importantsource of bleeding in patients with portal hypertension.They are present in up to 57% of patients with esoph-ageal varices secondary to portal hypertension.127 Lesscommonly, they are found in the absence of esophageal

Table 4 Child-Pugh Score

Score Bilirubin/mmol/L Albumin/g/L INR Ascites Encephalopathy

1 < 2 >3.5 < 1.3 Absent 0

2 2.1–3 2.8–3.5 1.3–1.5 Mild I/II

3 > 3 <2.7 > 1.5 >Moderate III/IV

The Child-Pugh score is derived from the sum of the assigned points in each category. Child-Pugh A,B, and C are defined as <6, 7–9, and > 10, respectively. INR, international normalized ratio.


varices.128 If isolated gastric varices are noted imagingmust be performed to exclude splenic vein thrombosisbecause this is managed with splenectomy. In 117patients with fundal varices, the size of the vessels, thepresence of red spots, and the degree of liver decom-pensation were predictors of bleeding.129 Althoughbleeding from gastric varices is less common than bleed-ing from esophageal varices, bleeding episodes are oftenmore severe and carry a higher mortality.128,130–132

The management of bleeding from gastric vari-ces differs from that of esophageal varices. Althoughgastric varices in continuity with esophageal varices canbe managed by endoscopic band ligation, isolatedvarices in the fundus of the stomach are not amenableto either sclerotherapy or band ligation.133 However,numerous reports have documented the efficacy ofcyanoacrylate injections (tissue glue) in achieving he-mostasis in bleeding fundic varices.134,135 Cyanoacry-late glue leads to more rapid variceal obliteration andmore effective hemostasis than alcohol injection.134

Severe complications associated with intravariceal cya-noacrylate glue injection include mediastinitis, CVA,

and cardiac and pulmonary vascular glue emboli.136–138

Recently, pilot studies have found thrombin injectionsto be another promising approach.139 Yet another wayto control bleeding gastric varices is with special de-tachable endoscopically placed snares.140,141 Althoughthere is limited experience with the technique in theUnited States, the Japanese report success with balloon-occluded retrograde transvenous obliteration (B-RTO)of isolated gastric varices.142,143 Unfortunately, most ofthese modalities are not routinely available in theUnited States.

The first-line approach to the control of activelybleeding fundic varices is balloon tamponade. The air-way must be protected when this approach is taken. Thisis, however, a temporizing measure and such varices havea great propensity to rebleed over time. It is thereforereasonable to decompress the portal vein with a TIPS asthe definitive procedure of choice in most patients beforedischarge from the hospital.144,145 It is often necessary toembolize prominent portosystemic collaterals at the timeof TIPS to reduce the risk of bleeding. When this is notdone, nonselective b-blockers may be used to reduce the

Figure 4 Proposed algorithm for the management of acute variceal bleeding.


risks of rebleeding, although the data to support such anapproach are weak at best. In those with well-preservedliver function, a surgical shunt can also provide long-term relief from bleeding.146

Portal Hypertensive Gastropathy

Portal hypertensive gastropathy (PHG) is a manifes-tation of portal hypertension. Endoscopically it ischaracterized by a mosaic mucosal pattern with varyingdegrees of submucosal hemorrhage. It is often asymp-tomatic but may lead to chronic transfusion–requiringblood loss or acute bleeding (rarely). Although portalgastropathy is more often seen in the setting of gastro-esophageal varices, its severity does not correlate withportal pressure. Nevertheless, bleeding is often amelio-rated by reduction of portal pressure. Both octreotideand nonselective b-blockade can be helpful in decreas-ing acute bleeding and the degree of rebleeding fromPHG via reduction of portal blood flow.147–149 Inrefractory cases, TIPS can be effective at reducingtransfusion requirements.150

THERAPIES TO ACHIEVE HEMOSTASIS

Drug Therapy

Drug therapy is an integral component of the manage-ment of acute portal hypertensive hemorrhage andshould be started on presentation. To optimize theeffectiveness of drug or endoscopic therapy, clottingabnormalities must be corrected. Target INR andplatelet count should be 1.5 and 75, respectively. Inthe setting of renal failure platelets may be dysfunc-tional and DDAVP (Desamino-D-Arginine Vasopres-sin) should be considered. FFP alone or in combinationwith rFVIIa can be given to rapidly correct coagulop-athy. A recent randomized, clinical trial showed thatwhen given in addition to standard therapy, 100 mg/kgof rFVIIa may improve control of bleeding in patientswith advanced cirrhosis.151

Somatostatin or octreotide, its synthetic analogue,stops acute bleeding from varices in 80% of cases.152 Itdoes so through a reduction of portal pressure via effectson vasoactive peptides or through the prevention ofpostprandial hyperemia (blood meal). Octreotide hasan excellent safety profile and can be given initially as asubcutaneous bolus of 50 to 100 mg followed by acontinuous infusion of 50 mg/h for 3 to 5 days. Althoughit does decrease portal pressure acutely, these effectsappear to be short lived due to rapid tachyphylaxis.153

Nevertheless, studies have shown a significant decreasein rebleeding after endoscopic therapy in those receivingoctreotide infusion.154,155

Vasopressin reduces splanchnic blood flow inaddition to portal pressure. It is effective in controlling

variceal hemorrhage; however, its use is limited due tosystemic effects such as coronary and mesenteric ische-mia.156 If vasopressin is used in conjunction with nitro-glycerin, these effects can be minimized.157,158

Terlipressin is a synthetic analogue of vasopressinwith a longer half-life and fewer side effects. It iseffective in the treatment of acute variceal bleedingwith or without endoscopic therapy and has been shownto reduce mortality.125,159 It appears to be as effective asvasopressin or endoscopic treatment126,160 in controllingacute variceal hemorrhage, but is not yet available in theUnited States.

Endoscopic Therapy

Endoscopic variceal band ligation (EBL) is currently thepreferred endoscopic technique for the management ofesophageal varices. It is at least as effective as endoscopicsclerotherapy (EST) but has a superior safety profile andlower complication rate.133,161,162 EBL also decreasesthe incidence of bleeding, when given as primary pro-phylaxis,163,164 and death165 from variceal bleeding.Band ligation leads to strangulation and subsequentobliteration of the banded varix.

EST involves the injection of a sclerosant (sodiummorrhuate, ethanolamine, or polidocanol) into or arounda varix. This leads to coagulative necrosis and obliter-ation of varices in the vicinity of the injection. Compli-cations related to EST tend to occur more frequently andbe more severe than with EBL and include esophagealulceration, stricturing, esophageal perforation, pleuraleffusion, and sepsis. Despite a higher complicationrate, a role still exists for EST. It can be a useful adjunctto EBL in the setting of massive hemorrhage with poorvisibility because the location of injection need not be asprecise to achieve hemostasis.

Regardless of the choice of endoscopic manage-ment for acute bleeding, follow-up endoscopy within1 to 2 weeks for further banding is essential to decreasethe risk of rebleeding. EBL should then be continued inthe future until variceal obliteration is achieved.

Balloon Occlusion

Balloon tamponade is effective in the 5 to 10% ofpatients in which hemostasis cannot be achieved acutelywith medical or endoscopic therapy. It successfully stopsbleeding from esophagogastric varices through externalcompression of varices, but rebleeding occurs in 50%.166

Many types of tubes exist (Sengsten-Blake Tube, WarneSurgical Products, Ltd., Armagh, Ireland, UK; andLinton Tube, Bard Manufacturing, Covington, Geor-gia, USA) with mild variations; however, in most cases;inflation of the gastric balloon is adequate to stopvariceal hemorrhage. It is quite effective as a bridge tomore definitive therapy (TIPS or surgery) and cannot be


in place for more than 24 hours given the significant riskof esophageal necrosis and rupture.167

Transjugular Intrahepatic Portosystemic

Shunt (TIPS)

TIPS involves placing a stent within the liver thatbridges a branch of the intrahepatic hepatic vein withan intrahepatic branch of the portal vein, allowingdiversion of blood flow away from the cirrhotic liver,decompressing portal pressures, and reducing the im-petus to bleed. In experienced hands TIPS is a veryeffective method for stopping acute hemorrhage fromesophageal varices but can be less effective in gastricvariceal bleeding.168 In the setting of variceal bleeding,TIPS should be reserved for cases that are refractory toendoscopic therapy,169 or in the case of gastric varices,used in conjunction with embolization. If recurrentbleeding occurs in a patient with a TIPS in place, themost important intervention is interrogation of theTIPS to document and treat thrombosis or stenosis.

Until recently, TIPS was complicated by fre-quent stenosis and thrombosis.168 Polytetrafluoroethy-lene (PTFE)-coated stents have significantly improvedstent patency and the need for reintervention.170–172

Although they have not been directly compared withsurgical shunts, these data suggest they offer comparableresults.

Surgery

TIPS has significantly reduced the need for shuntsurgery; however, surgery remains a good option inselected cases when TIPS is not technically feasible orfails or in patients with significant portal hypertension inthe face of preserved hepatic synthetic function. Thelong-term patency rate of shunt surgery is thought to besuperior to that of TIPS; however, newer coated stentsmay challenge this assumption.170–172 Surgical alterna-tives for acute portal hypertensive hemorrhage includetotal or selective shunt surgery, devascularization proce-

dures (Suguira or modification) or liver transplantation.If surgery is necessary, it is best done at a center withextensive experience.

COMPLICATIONS ASSOCIATED WITHVARICEAL BLEEDING

Hepatic Encephalopathy

The initial approach to the patient with HE should focuson the identification and correction of any precipitant inaddition to treatment of the encephalopathy. Commonprecipitants include gastrointestinal (GI) bleeding,medications, infection, dehydration, electrolyte distur-bances, constipation, excessive protein load, portosyste-mic shunting (TIPS or spontaneous), and worseningliver function (Table 5). Potential precipitants such asthese must be individually considered and subsequentlyexcluded. In the case of infection, spontaneous bacterialperitonitis (SBP) is the most common infection in thispopulation and must be ruled out with a diagnosticparacentesis as already discussed. Often, HE is theonly manifestation of SBP.

TREATMENT OF HEPATIC ENCEPHALOPATHY

Nonabsorbable disaccharides and antibiotics have beenshown to modify gut flora and decrease blood ammonialevels, but these are not necessarily related (indicatingnonbacterial sources of ammonia, which may also bedecreased by these compounds). Lactulose is the first-line therapy for HE. It is most effective if given orallyand titrated to a dose that achieves three to four softbowel movements a day. A common mistake in the ICUis continued lactulose despite diarrhea in the encepha-lopathic patient. Not only will this not improve ence-phalopathy, it may worsen it through free waterdepletion. If the patient is having adequate bowel move-ments on lactulose, but continues to be confused, severalagents can be added. Nonabsorbable antibiotics such asneomycin or rifaxamin are effective for the treatment ofHE either alone or in conjunction with lactulose. Met-ronidazole is also efficacious; however, side effects limitprolonged use. Zinc is a cofactor for the urea cycle andcan increase the clearance of ammonia. Zinc levels aredecreased in patients with cirrhosis and HE. Supple-mentation with zinc sulfate 600 mg/d normalizes zinclevels, decreases ammonia, and improves HE.173

Branched-chain amino acids have not convincinglyshown improvement in HE; however, they may beconsidered in patients that are not receiving protein inany form.174,175

When HE is refractory to medical treatmentother possibilities must be entertained. In those with aTIPS, occlusion or narrowing of the stent lumen canimprove mental status.176,177 If no TIPS or surgicalshunt is present, abdominal imaging should be obtained

Table 5 Precipitants of Hepatic Encephalopathy

Infection

Gastrointestinal bleeding

Medical noncompliance

Medication—sedatives, narcotics, other

Electrolyte disturbances

Portosystemic shunting

Transjugular intrahepatic portosystemic shunt

Spontaneous

Dehydration

Excessive protein load

Constipation

Worsening liver function


to look for a prominent portosystemic collateral thatcould be radiographically embolized.178

Infection

Bacterial infections complicate 35 to 66% of cases ofgastrointestinal bleeding in patients with AoCLF.179–184

Not only is infection common after bleeding, it may alsoprovoke rebleeding.179 Furthermore, bacterial infectionand the use of prophylactic antibiotics are independentlyassociated with failure to control variceal hemorrhage inthe first 5 days of admission.180 Many randomized,controlled trials have shown that antibiotic prophylaxistargeted at enteric organisms (such as quinolones orthird-generation cephalosporin) is effective in the pre-vention of postbleeding infection in cirrhotic patients. Inaddition, a meta-analysis of randomized, controlledtrials concluded that antibiotic prophylaxis resulted inless infections and improved short-term survival inbleeding patients with cirrhosis.185 Given these data,prophylactic systemic antibiotics should be given tocirrhotic patients with gastrointestinal hemorrhage.

Spontaneous Bacterial Peritonitis

SBP is a frequent and severe complication in those withcirrhosis and ascites.186 It is associated with significantmorbidity and mortality by precipitating renal failure in30%,187 worsening HE, and causing hemodynamic col-lapse in an already critically ill patient. The deteriorationof renal function is the most sensitive predictor of in-hospital mortality.187,188 Renal failure often results froma reduction in effective circulating blood volume, cyto-kine surges, and activation of the renin-angiotensinsystem precipitated by infection.187,188 Bacterial trans-

location from the gut is thought to be the most commonmode of ascitic fluid inoculation.189,190 Predisposingfactors for the development of SBP include advancedliver disease, gastrointestinal bleeding, ascitic total pro-tein fluid content � 1 g/dL and a previous history ofSBP.181,191–193

INTERPRETATION OF A DIAGNOSTIC PERITONEAL TAP

It is crucial to have a very low threshold to perform adiagnostic paracentesis in the patient with suspectedSBP. Ideally, this should be done prior to the initia-tion of antibiotics. Peritoneal fluid should be sentfor cell count, culture, albumin, total protein, LDH(lactate dehydrogenase) and glucose. Blood culturebottles should be inoculated at the bedside to improveyield.

SBP is defined as an ascitic fluid polymorphonu-clear (PMN) � 250 cells/mm3, in the setting of apositive monomicrobial ascitic fluid culture.194,195 Cul-ture positivity can fluctuate from one tap to the next;thus culture-negative neutrocytic ascites should betreated with antibiotics as previously outlined.196

Monomicrobial non-neutrocytic bacterascites isanother common variant of SBP. It is defined as a fluidcell count < 250 cells/ mm3 with a positive culture.197

Runyon and Hoefs and Chu et al found that 62 to 86%of cases of monomicrobial bacterial ascites resolve spon-taneously, and those that did not resolve were sympto-matic on presentation.197,198 Thus, in a clinically stableasymptomatic patient, one could observe or considerrepeat diagnostic paracentesis. However, in a criticallyill patient with AoCLF in the ICU, antibiotic therapymay be the best course of action.

TREATMENT OF SPONTANEOUS BACTERIAL PERITONITIS

Patients should be given a non-nephrotoxic antibioticwith good enteric coverage such as a third-generationcephalosporin. Cefotaxime 2 g (q8h) is the best-studied antibiotic for the treatment of SBP.199,200

Other antibiotics of comparable spectrum can beused and can be tailored if the organism is identified.Once the patient has been on antibiotics for 48 hours,a diagnostic tap must be repeated to assess response totreatment. If there is not a significant decrement in thewhite blood cell (WBC) count, antibiotic coverageshould be broadened. Once treatment efficacy is estab-lished, antibiotics should be given for 5 days.201 Intra-venous albumin is integral to the treatment of SBPand should be used in conjunction with antibiotics. Ithas been shown in a randomized, controlled trial todecrease the incidence of renal failure and subsequentmortality when compared with antibiotics alone.202

Based on these data, albumin should be given at adose of 1.5 mg/kg on day 1 and 1 mg/kg on day 3. Arecent study compared albumin to plasma expansionwith hydroxyethyl starch. Fernandez and colleagues

Table 6 Diagnostic Criteria for Hepatorenal Syndrome

(International Ascites Club)

MAJOR

Chronic or acute liver disease with advanced hepatic failure

and portal hypetension

Creatinine>1.5mg/dLor24-hourcreatinineclearance<40mL/min

Absence of shock, ongoing infection, use of nephrotoxic

drugs, gastrointestinal or renal fluid losses >500 g/d or

> 1000 g/d in the setting of edema

Urine protein < 500 mg/dL

No ultrasonographic evidence of primary renal disease

No sustained improvement in renal function after hydration

MINOR

Urine sodium <10 mEq/L

Urine osmolality > plasma osmolality

Urine red blood cells < 50 per high power field

Urine output <500 mL/d

Serum sodium < 130 mEq/L

For the diagnosis of hepatorenal syndrome, all major criteria must bemet. Minor criteria are supportive but not necessary for the diagnosis.


found that only albumin improved hemodynamics inpatients with SBP, suggesting that it may also havedirect effects on the vascular endothelium.203 Lifelongsecondary antibiotic prophylaxis is mandatory in thepatient with a history of SBP. Oral quinolones aremost commonly used (norfloxacin); however, manyantibiotics are effective for secondary prophylaxis ofSBP.

ASCITESAscites is the result of avid water and sodium retentioncharacteristic of the altered hemodynamics of cirrhosisand portal hypertension. It is associated with a 50%2-year survival. Uncomplicated ascites is managedwith sodium restriction (< 88 mmol/d) and diuretics;potassium sparing (i.e., spironolactone) alone, or incombination with a loop diuretic (i.e., furosemide).Diuretics are advanced until therapeutic efficacy isachieved or limited by worsening renal function orhyponatremia. In diuretic-refractory or resistant casesrepeat large-volume paracentesis (LVP) with albumininfusion, TIPS, or peritonovenous shunts can beeffective in improving the ascites but does not improvesurvival.204,205

Ascites can be a difficult problem to managein the ICU. Copious colloid and crystalloid infusioninevitably worsens ascites and diuretic use is oftenlimited by hyponatremia, hypotension, or renal failure.Massive ascites can also alter respiratory mechanics andmake breathing more labored or mechanical ventilationmore challenging. Occasionally, massive ascites canworsen renal failure through compression of the renalarteries. LVP should be reserved for patient discomfortand improvement of respiratory mechanics when possi-ble to avoid large-volume shifting and activation ofvasoactive neurohumoral systems after paracentesis thatcan worsen renal perfusion. Such changes can be mini-mized with the use of albumin (6 to 8 g/L removed).Albumin administration helps maintain intravascularvolume and minimize postparacentesis circulatory dys-function.205,206

RENAL FAILURETwenty percent of cirrhotic patients with tense ascitesdevelop renal failure characterized by the hepatorenalsyndrome (HRS).207,208 HRS is defined as functionalrenal impairment in a patient with advanced liver diseasein the setting of normal tubular function and renalhistology209 (Table 6). Two types of HRS have beendescribed; HRS I and HRS II, based upon the rapidityand extent of renal failure.210 HRS I is characterized by arapid and severe deterioration of renal function withsurvival measured in days to weeks, and HRS II repre-sents a more indolent and stable renal dysfunction.

Table 6 illustrates the International Ascites Club classi-fication of HRS.

The pathophysiology of HRS is complex.Splanchnic arteriolar vasodilation leads to central vaso-dilation and compensatory activation of systemic andrenal vasoconstrictor systems.107,211 The resultant renalvasoconstriction leads to reduced glomerular filtrationrate and increased water and sodium retention.

Treatment of Hepatorenal Syndrome

Liver transplantation is the ultimate treatment forHRS. After transplantation renal function returns tobaseline in most cases.212,213 Combination drug ther-apy that counteracts renal and systemic vasoconstrictionleading to arterial hypotension and central hypovolemiawith vasoconstrictors and plasma expanders, respec-tively, is the most effective strategy. Terlipressin, along-acting vasopressin analogue that stimulatessplanchnic V1a vasopressin receptors increases bloodpressure, GFR (glomerular filtration rate), and urinevolume in patients with HRS.214,215 Unfortunately,terlipressin is not yet available in the United States.In a small study of patients with HRS I, the combina-tion of the a-agonist midodrine (7.5 mg tid), octreotide(100 g SQ tid), and albumin (25 g/day) was effective inimproving renal function.216 In a more recent study,these findings were confirmed and insertion of a TIPSin a subset of patients led to further improvement inrenal function.217

LIVER TRANSPLANTATION—CHRONICLIVER DISEASEAllocation of organs in chronic liver disease changed onFebruary 27, 2002. The model of end-stage liver disease(MELD) system was adopted to objectify the way inwhich livers were allocated in the United States. It is asurvival model based on a composite of three laboratoryvalues: serum bilirubin, serum creatinine, and INR.The model was originally used to assess short-termmortality in cirrhotic patients undergoing electiveTIPS placement.218 This model was subsequently va-lidated as an independent predictor of survival inpatients with cirrhosis.219,220 Thus priority on the livertransplant waiting list is based on the patient’s bloodgroup and the MELD score without emphasis onwaiting time.

SUMMARYManagement of the patient with acute or chronichepatic failure remains a challenging problem, despiteadvances in intensive care. Liver failure typically hasprofound effects on other organ systems and the effectsof therapeutic interventions on other organs must be


considered. A multidisciplinary approach is most effec-tive and urgent transfer to a transplant center is man-datory in potential transplant candidates. Ideally, good,comprehensive intensive care can support the patientinto spontaneous hepatic recovery; however, oftenthe goal of therapy is to bridge patients to definitivetherapy—liver transplantation.

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