1. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 9 HEPATIC FAILURE — 1
9 HEPATIC FAILURE
Juan R. Sanabria, M.D., M.Sc., F.A.C.S., and Achilles A. Demetriou, M.D., Ph.D., F.A.C.S.
Approach to the Patient with Liver Failure
Hepatic failure continues to be a frequent and major cause of and assessment of renal function. In addition, a toxicology screen
morbidity and mortality in critically ill patients. In the past decade, should be ordered and a sepsis workup initiated. Detection of one
new approaches to hepatic failure have been developed. Advances or more drugs in the urine or blood may help establish the diag-
in critical care, the increasing use of sophisticated diagnostic nosis and direct treatment. Specific tests to detect other conditions
modalities, and the adoption of a team approach to patient care (e.g., metabolic or autoimmune disorders) are ordered as needed.
(with active collaboration among intensivists, hepatologists, anes- Blood and urine cultures are done to look for a concomitant or
thesiologists, transplant surgeons, and other specialists) have causative infectious agent; if ascites is present, analysis of the
resulted in improved overall outcomes. ascitic fluid (including a cell count with differential, Gram stain-
Hepatic failure may be encountered as an instance of primary ing, and culture) is recommended. Serologic testing for hepatitis
organ failure caused by a liver-specific disease process or as part of viruses and other viruses (e.g., herpesvirus, cytomegalovirus
the multiple organ dysfunction syndrome (MODS). Typically, [CMV], and Epstein-Barr virus [EBV]) is indicated. In addition,
patients with secondary liver failure have no preexisting liver dis- a chest x-ray must be obtained, and additional imaging studies
ease: their liver dysfunction is simply a reflection of their overall should be performed as indicated. At times, a liver biopsy is
critical condition, and management usually involves treatment of required to establish or confirm the diagnosis of liver disease.
underlying nonhepatic disorders. In what follows, we outline gen- Most patients with primary hepatic failure have a history of pre-
eral management guidelines for primary hepatic failure and its existing liver disease and possibly of cirrhosis, generally presenting
complications. with one or more complications of chronic liver disease (e.g., GI
bleeding, hepatic encephalopathy, spontaneous bacterial peritoni-
tis [SBP], or renal failure). In one subgroup of patients, hepatic
Clinical Evaluation and failure occurs as a result of an acute exacerbation of preexisting
Investigative Studies liver disease (e.g., acute reactivation of hepatitis B, acute decom-
Evaluation of patients pensated Wilson disease, or autoimmune hepatitis). In another
with suspected liver disease subgroup, primary hepatic failure develops acutely in the absence
is often complex and typi- of any preexisting liver disease or known risk factors; this condi-
cally requires extensive pa- tion is known as fulminant hepatic failure (FHF). These patients
tient workup—including a present with massive liver necrosis, jaundice, and profound coag-
detailed history and physical ulopathy and often go on to experience deep coma and cerebral
examination, as well as various diagnostic studies—to establish the edema, which may lead to irreversible brain damage and death.
diagnosis and confirm the underlying cause of the disease. The distinction between an acute liver process and a chronic one
Common risk factors include a history of alcohol or I.V. drug is important. Acute liver failure (ALF) may be associated with
abuse, previous transfusion of blood or blood products,1 the use of severe multisystem organ involvement, as in the acute respiratory
certain medications, tattoos, sexual promiscuity, and incarcera- distress syndrome (ARDS) or MODS. The etiology of ALF in-
tion. Less common risk factors include a family history of liver dis- cludes the use of medications (in particular, acetaminophen), infec-
ease and exposure to various toxins and chemicals. tion (specifically, viral hepatitis), miscellaneous conditions, and
indeterminate causes. ALF may also develop after liver transplan-
CHARACTERISTIC FINDINGS
tation secondary to primary graft nonfunction (PNF) or hepatic
Liver disease gives rise to several easily recognizable manifesta- artery thrombosis (HAT). It is manifested mainly by encephalop-
tions. Jaundice and encephalopathy are common symptoms. In athy, progressive coagulopathy, poor urinary output, and elevated
the early stages of liver disease, increasing fatigue, changes in sleep liver enzyme levels. Cerebral edema is uncommon in patients with
patterns, loss of short-term memory, inability to concentrate, and PNF.
reduced libido may be noted. In the later stages, portal hyperten-
PROGNOSTIC FACTORS
sion (PHT) is signaled by the development of ascites and upper or
lower gastrointestinal bleeding. In addition, hypersplenism and A thorough initial physical examination is important for estab-
abdominal wall collateral vessels may be detected on physical ex- lishing a baseline for comparison, so that trends toward improve-
amination. Changes that occur primarily as a consequence of altered ment or deterioration can be detected during clinical evaluations
liver metabolism include palmar erythema, spider angiomata, gyn- subsequently conducted at 4- to 6-hour intervals. Worsening en-
ecomastia, testicular atrophy, and encephalopathy. Many patients cephalopathy with rapidly deteriorating mental status is an indica-
exhibit a degree of protein-calorie malnutrition, with muscle wast- tion for early endotracheal intubation. Reduced urine output in a
ing and reduced physical activity. euvolemic patient is a sign of impending renal failure. Elevated
Initial laboratory evaluation should include a complete blood liver enzyme concentrations and an elevated international normal-
count, a platelet count, liver function tests, a coagulation profile, ized ratio (INR) suggest that spontaneous liver recovery is unlike-

2. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 9 HEPATIC FAILURE — 2
Approach to the Patient Patient has signs of liver disease or known risk factors
with Liver Failure Perform extensive workup: history, physical examination,
laboratory tests, and imaging studies as needed. Liver
biopsy is occasionally required.
Distinguish primary from secondary hepatic failure.
Primary hepatic failure
Acute liver failure
Determine etiology—infectious (viral), substance-induced,
or other—and treat accordingly.
Begin medical management of complications.
Concurrently, assess prognosis by means of King's
College criteria.
Cerebral edema Extrahepatic complications
Initiate invasive ICP monitoring. Treat fluid, electrolyte, and nutritional
Manage elevated ICP. abnormalities; renal failure; hemodynamic
and pulmonary complications; infectious
complications; and coagulopathy and bleeding.
Good prognosis with
Poor prognosis with
medical management
medical management
Continue medical therapy.
Medical management Medical management fails Transplantation is No contraindications
succeeds contraindicated to transplantation are
Consider emergency OLT if not present
contraindicated. Manage medically.
Treat toxic liver syndrome with
total hepatectomy and end-to-side
portacaval shunt, followed by OLT.
Consider use of BAL support
system.

3. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 9 HEPATIC FAILURE — 3
Secondary hepatic failure
Treat underlying nonhepatic cause.
Chronic liver disease
Determine etiology [see Table 4], and treat accordingly.
Begin medical management of complications.
Portal hypertension Hepatic Renal failure Malnutrition Coagulopathy and
encephalopathy nonvariceal bleeding
Treat complications of PHT: Treat HRS, ATN, RTA, GIve glucose
• Variceal bleeding Control precipitating and drug-induced with fat emulsion. Identify hemostatic
• Ascites: restrict sodium factors, and control interstitial nephritis. Use enteral feeding defect.
and give diuretics. If ammonia levels with Correct underlying unless contraindicated. Give FFP,
medical management lactulose or causes. Manage cryoprecipitate,
fails, perform LVP or use antibiotics. fluids and electrolytes prothrombin complex
a shunt (peritoneovenous carefully. concentrates, platelets,
or TIPS). AT-III concentrate, or
antifibrinolytic agents
as appropriate.
Medical management is unsatisfactory, Medical management is satisfactory,
and no contraindications to transplantation or transplantation is contraindicated
are present
Manage medically.
Perform OLT when donor organ is available.
Consider use of BAL support system while
awaiting organ.

4. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 9 HEPATIC FAILURE — 4
ly. The development of hypoglycemia is a sign that only a limited Management of Acute
amount of functional liver tissue remains. Metabolic acidosis may Liver Failure
also reflect lack of functional liver reserve in a euvolemic patient In the United States,
setting. In addition, factor V levels and the degree of hepatocyte ALF affects 2,300 to 2,800
necrosis observed at liver biopsy may help guide further therapy. patients each year.2 How
Increasing levels of α-fetoprotein (AFP) have been associated liver failure is defined
with liver regeneration and liver recovery. Finally, the patient’s depends largely on the tem-
overall medical status (e.g., the presence of severe coronary artery poral relation between the
disease or a history of recent myocardial infarction) may deter- onset of illness and the
mine the final outcome. appearance of jaundice, encephalopathy, and coagulopathy. For
example, some define FHF as ALF in which the interval between
disease onset and the appearance of major symptoms is 8 weeks
Initial Management or less.3 In most cases, however, it is difficult to establish the pre-
Initial management of a patient with hepatic failure includes cise time of onset of the disease process and thus hard to deter-
the following components: mine precisely how much time elapsed before hepatic failure
developed. Recognizing that clinical findings and prognosis vary
1. Airway protection. Airway management and maintenance
depending on the interval between the onset of jaundice and the
should be established early in the course of the disease to pre- appearance of encephalopathy, some authorities distinguish
vent hypoxia with worsening brain edema or bronchial aspira- between FHF and subfulminant hepatic failure (SHF). Bernuau
tion with pneumonitis, decreased gas exchange, and sepsis. and coworkers defined FHF as an episode of ALF that was com-
Patients with cerebral edema require hyperventilation to lower plicated by encephalopathy developing within 2 weeks of the
the carbon dioxide tension (PCO2) and reduce cerebral vasodi- onset of jaundice and defined SHF as ALF that was complicated
latation; however, the effect on PCO2 is transient. by encephalopathy developing 2 to 12 weeks after the onset of
2. Monitoring of serum glucose levels. In patients who have jaundice.4 We use the term ALF for cases in which there is no evi-
experienced an acute loss of functional liver tissue, the lack of dence of chronic liver disease and in which liver disease develops
gluconeogenic pathways leads to decreased metabolism of lac- within 8 weeks after the initial onset of illness.
tic acid.The result is a high–anion gap metabolic acidosis with
hypoglycemia, a state that is exaggerated in cases of sepsis with CLASSIFICATION
poor tissue perfusion. ALF may be classified into three major categories on the basis
3. Monitoring of cerebral perfusion pressure (CPP).The mental of the underlying cause of the disease: infectious, substance-induced,
status of a patient with ALF should be followed by means of and miscellaneous. In two multicenter studies, acetaminophen-
serial neurologic examinations, serial computed tomograms induced toxicity was found to be the most common cause (20%
of the brain as indicated, and monitoring of intracranial pres- and 39%) of ALF, followed by cryptogenic or indeterminate caus-
sure (ICP) and CPP.The signs detected by physical examina- es (15%).5,6
tion are not reliable, and changes in cerebral CT scans may
Infectious (Viral Hepatitis)
develop late after the establishment of cerebral edema.
Measuring CPP is the most reliable means of monitoring the Infectious ALF can be caused by several different viruses. Most
degree of cerebral edema and can help guide early therapy. cases are attributable to hepatitis viruses (types A through G), though
4. Hemodynamic monitoring. Continuous assessment of central herpesviruses (e.g., herpes simplex virus, varicella-zoster virus, CMV,
venous pressure is desirable in ALF patients to optimize fluid and EBV), coxsackieviruses, echoviruses, adenoviruses, and parvo-
administration. Every effort should be made to establish ade- virus B19 are also capable of causing ALF.
quate perfusion pressure without significantly increasing
right-side cardiac pressures, diminishing venous return from Hepatitis A The incidence of FHF and SHF in patients
the brain, and subsequently aggravating cerebral edema. with hepatitis A virus (HAV) infection is very low (< 0.01%).4 The
virus is transmitted orally. HAV infection usually occurs in chil-
Placement of a pulmonary artery catheter may be indicated in
dren and typically gives rise to minimal manifestations that resolve
severely ill patients who may be hemodynamically unstable.
uneventfully, resulting in detectable levels of antibodies. About 10%
5. Correction of coagulopathy. The platelet count and the INR
of patients experience a relapse, usually within 2 to 3 months after
are the main variables monitored for assessment of coagula-
an initial clinical improvement. Relapse is signaled by increased
tion. Because ALF patients typically are subjected to multiple serum transaminase and bilirubin levels and the reappearance of
interventions, invasive monitoring, and other procedures, fresh the virus in the stool. If encephalopathy develops during this peri-
frozen plasma (FFP) and platelets are frequently administered. od, the prognosis is poor.7 The clinical course of the disease tends
6. Diagnostic workup. A rapid diagnostic workup is undertaken to be more severe in older patients. Immunoglobulin therapy may
to allow appropriate disease management. Specific treatment reduce infection rates among young family members and HAV-
should be instituted promptly to enhance liver recovery (e.g., naive health care workers.
administration of N-acetylcysteine to treat acetaminophen
toxicity). It is of particular importance to identify any condi- Hepatitis B ALF related to hepatitis B virus (HBV) occurs
tions that may rule out liver transplantation as a therapeutic in fewer than 1% of HBV infections but is the most common form
option; such conditions include active infection, cancer, irre- of virus-induced FHF.4,5,8 Like HAV infection, HBV infection
versible brain damage, and MODS. Evaluation of the patient leads to FHF more often than to SHF. HBV is transmitted by con-
for potential liver transplantation should begin early. To this tact with blood or body fluids and by intercourse. Detection of
end, it is important that the liver transplant team take part in hepatitis B surface antigen (HBsAg) and a quantitative polymerase
the initial assessment and management of ALF patients. chain reaction (PCR) for HBV DNA establish the diagnosis. In

5. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 9 HEPATIC FAILURE — 5
some cases of FHF secondary to HBV infection, however, these by cooking.19 Liver damage from mushroom toxins is delayed and
markers may be absent,9 which indicates that in certain FHF is usually preceded by several days of vomiting and diarrhea.
patients, an enhanced immune response prevents further HBV Mortality is high: up to 22% in one series. Emergency liver trans-
replication and results in more rapid clearance of HBsAg.The sur- plantation is sometimes successful.20 Industrial hydrocarbons
vival rate is much lower for patients who are HBsAg-positive on (e.g., carbon tetrachloride, trichloroethylene) are rare causes of
presentation (17%) than for patients who are HBsAg-negative FHF. In developing nations, aflatoxin and herbal medicines have
(47%).4 Clearance of HBsAg and HBV DNA results in better sur- been implicated as causes of FHF.
vival, as well as lower recurrence rates after emergency liver trans- Acute, severe ethanol intoxication may result in the develop-
plantation.10 Protocols based on antiviral therapy with lamividine ment of acute alcoholic hepatitis (AAH), a condition associated
and anti-HBV immunoglobulin yield low rates of HBV recurrence with high mortality. Treatment with steroids improves survival in
after successful liver transplantation. AAH patients; other measures are instituted to treat complications
and associated conditions (e.g., withdrawal syndrome and malnu-
Hepatitis D Hepatitis D virus (HDV, also referred to as the trition). Liver transplantation has not been advocated for treat-
delta agent) is a defective virus that uses HBsAg as its envelope ment of acute AAH.
protein. HDV RNA is detected in only 10% of patients with ful-
minant hepatitis D.11 HDV infection can be either a coinfection Miscellaneous
(in conjunction with HBV infection) or a superinfection (in pa- ALF may be caused by any of a number of miscellaneous
tients with previous HBV infection).12 In FHF patients, HDV processes, including metabolic, vascular, and autoimmune condi-
coinfection is more common than HDV superinfection; however, tions. The most frequent metabolic cause of ALF is Wilson dis-
the latter is associated with a higher mortality than the former ease, which may present as FHF or SHF with intravascular
(72% versus 52%), as well as a stronger predisposition to subse- hemolysis and renal failure.21,22 A family history of hepatic and
quent chronic liver disease (54% versus 31%).13 neurologic disease, the presence of Kayser-Fleischer rings, and
low serum ceruloplasmin levels help establish the diagnosis. Acute
Hepatitis C and indeterminate hepatitis Previously, FHF decompensated Wilson disease carries a high mortality and is an
of indeterminate etiology was attributed to non-A, non-B viral indication for emergency liver transplantation.23
hepatitis. It is now clear that some such cases are caused by hepati- Acute fatty liver of pregnancy is a rare cause of FHF associated
tis C virus (HCV) infection, though the precise extent to which with high mortality for both mother and infant. Delivery of the fetus
HCV infection contributes to this indeterminate group is unclear. results in regression of the microvesicular steatosis and improve-
Unlike HAV and HBV infection, HCV infection is more likely to ment in liver function for the mother.The risk of FHF is increased
cause SHF than FHF. Despite the availability of advanced sero- with misdiagnosis and continuation of pregnancy. Liver transplan-
logic testing, there are still many cases of FHF and SHF whose tation has been successfully performed to treat this condition.24
cause cannot be determined.14,15 These cases may be attributable An unusual cause of ALF is the Budd-Chiari syndrome (acute
to other, more recently described types of hepatitis viruses (e.g., hepatic vein thrombosis). The typical patient is a young woman
hepatitis E virus [HEV], hepatitis F virus [HFV], and hepatitis G who presents with right upper quadrant pain of acute onset,
virus [HGV]). ALF caused by HEV infection, though rare in hepatomegaly, and ascites. The clinical course is usually benign,
Western countries, is the most common form of FHF in India.16 and liver enzyme levels normalize promptly. Occasionally, howev-
er, the syndrome progresses to FHF. Portal decompression some-
Substance-Induced times treats this type of ALF successfully if done before massive
Drugs Drug toxicity accounts for 35% of all cases of FHF hepatic necrosis occurs; once FHF develops, liver transplantation
and SHF and usually runs a subfulminant course.5 Drug ingestion is the only option.
causes hepatic injury in fewer than 1% of patients, about 20% of Acute autoimmune hepatitis can cause FHF. It is typically seen
whom manifest FHF or SHF. In most cases of drug-induced in female patients and may occur either with or without known
hepatoxicity, the degree of the toxicity correlates with the dose autoimmune disorders. A panel of reactive antibodies confirms the
ingested and the serum drug level, but in others (e.g., certain cases diagnosis. High-dose steroid therapy usually arrests the process,
of valproic acid–induced toxicity), patients manifest an idiosyn- resulting in rapid normalization of liver enzyme levels. In 10% to
cratic reaction with massive liver necrosis after exposure to the 20% of cases, urgent liver transplantation is necessary.
drug. As a general rule, however, increasing the total drug dose, Several other conditions and disease processes are also known
simultaneously ingesting other drugs that induce or inhibit hepat- to cause ALF in both adults and children [see Table 1].
ic enzymes (synergistic toxicity), and continuing drug adminis-
ASSESSMENT OF PROGNOSIS
tration after the onset of liver disease all increase the risk of hepat-
ic failure.4 Several prognostic criteria and indicators have been developed
Acetaminophen toxicity is the most common cause of drug- for predicting outcome after optimal medical management of FHF.
induced hepatic failure. The prognosis for patients with FHF The two main factors determining likelihood of survival are (1) the
caused by acetaminophen is usually better than that for patients extent of liver necrosis and (2) the potential for hepatocyte regen-
with FHF caused by other drugs (e.g., isoniazid, psychotropic eration. In a 1989 study, investigators at King’s College Hospital in
drugs, antihistamines, and nonsteroidal anti-inflammatory London compiled a set of indicators for predicting a poor outcome
drugs).17 Halothane-induced FHF occurs within 2 weeks after after medical therapy and hence the need for emergency liver trans-
general anesthesia and carries a high mortality.18 plantation.25 The underlying cause of FHF was the single most
important predictive variable. Accordingly, patients were divided
Toxins Most cases of toxin-induced FHF involve mushroom into two groups, one comprising all cases of acetaminophen-
poisoning or exposure to industrial hydrocarbons. In mushroom induced FHF and the other all cases of FHF from other causes.
poisoning, the active agents are heat-stable and are not destroyed Age, degree of encephalopathy, serum pH, prothrombin time (PT),

6. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 9 HEPATIC FAILURE — 6
tive of survival when measured within 6 hours after admission.27
Assessment of the residual functional reserve of the liver has been
Table 1 Etiology of Acute Liver Failure studied as an indicator of prognosis.The ratio of acetoacetate to β-
Infectious hydroxybutyrate in an arterial blood sample (also known as the
Viral: hepatitis A, B, C, D, E, F, and G and hepatitis of indeterminate arterial ketone body ratio [AKBR]) is thought to reflect hepatic
etiology; infection by herpes simplex virus, cytomegalovirus, energy status.28 Galactose clearance reflects both residual liver
Epstein-Barr virus, or adenovirus
mass and hepatic blood flow.29 This test has long been considered
Bacterial: Q fever
a standard test of hepatic functional reserve, and newer tests are
Parasitic: amebiasis
routinely compared to it. At present, functional assessment tools
Drugs
are not widely used.
Toxins At our center, we apply the King’s College criteria on admission
Mushrooms: Amanita phalloides, verna, and virosa; Lepiota species
to predict the likely outcome with medical therapy. Once the ini-
Bacillus cereus
tial assessment is completed, the decision to proceed with emer-
Hydrocarbons: carbon tetrachloride, trichloroethylene, 2-nitropropane,
chloroform gency evaluation for liver transplantation is made. Evaluation, if
Copper indicated, is usually completed within 12 to 24 hours. The evalu-
Aflatoxin ation is similar to that of patients with chronic liver disease [see
Yellow phosphorus Chronic Liver Disease, below], with a few exceptions. Patients with
Miscellaneous conditions FHF usually do not have preexisting liver disease; thus, it is vital
Wilson disease that the evaluation [see Table 3] reveal the probable cause of liver
Acute fatty liver of pregnancy failure. Unlike chronic liver disease, FHF is associated with cere-
Reye syndrome bral edema and elevated ICP, which is the leading cause of death
Hypoxic liver cell necrosis in these patients. Therefore, an extensive neurologic evaluation
Hypothermia or hyperthermia should be completed before a patient is listed for transplantation.
Budd-Chiari syndrome Serial neurologic assessment is necessary to rule out irreversible
Veno-occlusive disease of the liver brain damage and brain-stem herniation; use of short-acting seda-
Autoimmune hepatitis tives make this evaluation less difficult.
Massive malignant infiltration of the liver
Partial hepatectomy TREATMENT OF
Liver transplantation COMPLICATIONS
Postjejunoileal bypass
Galactosemia Cerebral Edema
Hereditary fructose intolerance
Cerebral edema develops
Tyrosinemia
in most patients with FHF,
Erythropoietic protoporphyria
and its presence significantly
Irradiation
α 1-Antitrypsin deficiency
influences management and
Niemann-Pick disease
outcome. Autopsy studies
Neonatal hemochromatosis indicate that cerebral edema
Cardiac tamponade is present in 80% of patients who die of FHF.30,31 It occurs in
Right ventricular failure advanced stages of FHF and can be recognized by clinical, radio-
Circulatory shock logic, or invasive means. Clinical findings include decerebrate pos-
Tuberculosis turing, myoclonus, spastic rigidity, seizure activity, systemic hyper-
tension, bradycardia, hyperventilation, and mydriasis with dimin-
ished pupillary response.These findings initially are paroxysmal but
later become persistent. Papilledema is a late finding and often does
time of onset of encephalopathy, and admission serum creatinine not occur at all, even in advanced stages of the disease.32 Nonin-
and bilirubin levels also proved to be significant variables [see Table vasive diagnostic modalities (e.g., CT scanning, electroencephalo-
2]. Patients who met the criteria in either group had a 95% chance graphic monitoring, and transcranial Doppler flow measurement)
of dying with medical therapy alone and were identified as candi- have not proved helpful for early detection and management of
dates for emergency liver transplantation.The major strength of the cerebral edema.33,34 CT scanning of the brain is not a sensitive test
King’s College study is that it based patient assessment on parame- for detecting early cerebral edema: 25% to 30% of patients with
ters that are easily obtained within a few hours of admission to the elevated ICP exhibit no radiographic changes.35 It is, however, use-
emergency department. This approach to assessment facilitates ful for ruling out intracranial bleeding.
early transfer of patients with a poor prognosis to a specialized liver Currently, ICP monitoring is the best means of monitoring
unit for evaluation for transplantation. intracranial hypertension and is recommended for guiding treat-
In another study, plasma factor V level and age were found to ment in patients with stage III or IV encephalopathy. ICP can be
be independent predictors of survival.26 The criteria for liver trans- measured by using epidural, subdural, or intraventricular cathe-
plantation were the presence of hepatic encephalopathy (stage III ters. Although epidural catheters are slightly less sensitive to ICP
or IV) and a factor V level either less than 20% of normal in changes, they have the lowest complication rate (3.8%) and the
patients younger than 30 years or less than 30% of normal in lowest rate of fatal hemorrhage (1%).36 Despite a slightly higher
patients older than 30 years. complication rate, we prefer subdural catheters: in our view, they
Other predictive models have been developed. A study of 59 offer more reliable ICP monitoring. Institution of ICP monitoring
patients with non–acetaminophen-induced FHF showed that is followed by aggressive treatment of any concomitant coagulopa-
plasma levels of albumin, lactate, valine, and pyruvate were predic- thy. FFP infusions are given to bring the PT below 25 seconds,

7. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 9 HEPATIC FAILURE — 7
and platelet transfusions are given if the patient has severe throm-
bocytopenia (platelet count < 50,000/mm3). Once ICP monitor-
Table 3 Liver Transplant Evaluation
ing is established, bolus administration of FFP is repeated as need-
ed to keep the INR below 5 so as to reduce the risk of intracranial and Workup for FHF Patients
bleeding. To minimize the need for ICP monitoring, it has been Laboratory workup
suggested that patient selection should be based on reverse jugu- CBC and differential count
lar oxygen saturation; saturations lower than 65% or higher than Chemistry panel
80% are associated with a high likelihood of elevated ICP.37 Coagulation profile
The goal of invasive monitoring is to keep the ICP below 15 24-hr creatinine clearance
mm Hg while keeping CPP, which is a better predictor of out- Urinalysis
come, above 50 mm Hg. CPP is calculated by subtracting the ICP Arterial blood gases
from the mean arterial pressure (MAP). ICP monitoring allows ANA, AMA, ceruloplasmin, urinary copper, α 1-antitrypsin
early detection of cerebral edema and hence earlier introduction of AFP
aggressive management.To date, no randomized, controlled trials RPR
have addressed the effect of high ICP and low CPP on outcome Thyroid function tests
after liver transplantation; however, it appears that persistence of Alcohol and drug toxicology screen
either an ICP higher than 25 mm Hg or a CPP lower than 40 mm Viral serologies
Hg for more than 2 hours is associated with an increased risk of Hepatitis A virus (IgM, IgG)
irreversible brain damage and a poor outcome.38,39 Hepatitis B virus (HBsAg, HBcAb, HBeAg, HBV DNA)
Hepatitis C virus (HCV antibody, HCV RNA-PCR)
Management of elevated ICP involves hyperventilation, mini-
Cytomegalovirus
mization of external stimuli, deep sedation, elevation of the head,
Epstein-Barr virus
maintenance of hemodynamic stability, and infusion of mannitol.
HIV
Patients are usually sedated with a short-acting agent (e.g., propo-
Cultures
fol) in small boluses before a procedure, nasotracheal suction,
Bacterial, fungal, and viral cultures
venipuncture, or line placement. Mechanical hyperventilation re-
Blood
duces ICP by lowering arterial carbon dioxide tension (PaCO2) to
Sputum
25 to 30 mm Hg, thereby maximizing cerebral vascular constric- Urine
tion and reducing blood flow.This vascular effect diminishes pro- Ascites
gressively after 6 hours of therapy, though a clinical response is
12-lead ECG
apparent for days. As many as 80% of patients without renal fail-
Chest x-ray
ure respond to mannitol infusions.40 Serum osmolality should be
Pulmonary function tests
measured frequently and maintained at 300 to 320 mOsm/L.
Mannitol should be withheld if osmolality reaches or exceeds 320 Abdominal Doppler ultrasonography
mOsm/L, if renal failure occurs, or if oliguria and rising serum CT scans of head
osmolality develop simultaneously. Repeated administration of man- AFP—α-fetoprotein AMA—antimitochondrial antibody ANA—antinuclear anti-
nitol may reverse the osmotic gradient. Mannitol should be dis- body RPR—rapid plasma reagent
continued if the ICP does not respond after the first few boluses.
Acute renal failure is a frequent complication. Fluid management
Table 2 King’s College Hospital Prognostic is very difficult in this setting. Continuous hemofiltration or con-
Criteria Predicting Poor Outcome tinuous venovenous hemodialysis (CVVHD) can be beneficial.
for Patients with FHF Continuous hemofiltration is less deleterious than intermittent
therapy in the management of patients with brain edema and renal
pH < 7.30 (irrespective of grade of dysfunction,16 probably because it does not cause the large fluid
encephalopathy) shifts that can occur with the intermittent technique.
or Patients who do not respond to conventional therapy may be
Acetaminophen-induced All of the following: placed in a barbiturate coma. Thiopental infusion decreases cere-
FHF PT > 100 sec (INR > 6.5) bral metabolic activity, lowers CNS oxygen demand, and protects
Serum creatinine > 3.4 g/dl the brain from ischemic injury secondary to decreased cerebral
Stage III or IV hepatic encephalopathy
blood flow. In a retrospective, nonrandomized study, it lowered
PT > 100 sec (INR > 6.5) (irrespective of grade ICP and reduced mortality from FHF.41 In our experience, how-
of encephalopathy) ever, the effect of thiopental infusion on ICP is transient and
or unpredictable. Subclinical seizure activity has been detected in as
Any three of the following (irrespective of grade many as 24% of ALF patients, but in a 2004 study, administration
of encephalopathy):
of phenytoin with control of the abnormal electrical activity did
Non–acetaminophen- Age < 10 or > 40 yr
induced FHF Etiology: non-A, non-B hepatitis, halothane
not affect overall outcome in ALF patients with seizures.42 In a
hepatitis, drug toxicity study of 30 patients with ALF, the use of hypertonic saline led to
Duration of jaundice to encephalopathy significantly decreased ICP levels.43 Administration of indometha-
> 7 days cin or dexamethasone has led to modest reductions of ICP.
PT 50 sec (INR > 3.5) Studies evaluating the use of mild hypothermia (32° to 33° C
Serum bilirubin > 17.5 g/dl [89.6° to 91.4° F) in managing ALF reported significant decreases
FHF—fulminant hepatic failure INR—international normalized ratio in ICP in all patients, some of whom were cooled for as long as
PT—prothrombin time 5 days.44,45 Bleeding and other coagulation disorders were not

8. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 9 HEPATIC FAILURE — 8
observed; however, upon rewarming, a rebound effect was noted albumin solutions may be preferable to carbohydrate-based vol-
with an increase in ICP. In view of these findings, the authors sug- ume expanders. If oliguria is present, especially if mannitol is
gested caution and recommended gradual, gentle rewarming. In administered to treat ICP, hemodialysis or hemofiltration may be
addition, they found that liver implantation could be successfully needed to maintain optimal fluid volume.
performed under hypothermic conditions. Moderate hypothermia
appears to be a promising experimental technique in ALF patients, Hemodynamic and pulmonary complications Circula-
but its utility in clinical practice remains to be determined. tory disturbances tend to occur at an early stage of ALF and to
worsen over the course of the illness; they are characterized by gen-
Other Complications eralized vasodilatation, resulting in increased cardiac output and
In addition to cerebral reduced systemic vascular resistance and MAP.47-49 The mech-
edema and increased ICP, anisms of these hemodynamic disturbances are unclear, but
MODS and a variety of life- increased levels of nitric oxide and cyclic guanosine monophos-
threatening complications phate (cGMP) have been demonstrated during the later stages of
are associated with FHF. the disease.50 Fluids are managed so as to achieve euvolemia (see
Most of these complications above). A particular problem in managing hypotension related to
are similar to those seen in ALF is that autoregulation of cerebral blood flow is typically lost.51
chronic liver disease [see Terlipressin (a vasopressin analogue) is widely used in patients
Chronic Liver Disease, Treatment of Complications, below]; how- with end-stage liver disease (ESLD) and hepatorenal syndrome
ever, the following complications are seen with particular frequen- (HRS). This agent acts through both V1 receptors, which are dis-
cy in FHF. tributed in the systemic circulation and mediate vasoconstriction,
and V2 receptors, which are distributed in the cerebral vasculature
Fluid, electrolyte, and nutritional abnormalities Euvo- and mediate cerebral vasodilatation. The role of terlipressin in the
lemia must be maintained to prevent fluid overload, pulmonary hemodynamic management of patients with ALF remains unclear.
edema, and dehydration; extreme fluid shifts should be avoided. Pulmonary complications, especially pulmonary edema, aspira-
The presence of cerebral edema and intracranial hypertension calls tion pneumonia, and ARDS, are common in FHF patients.52
for careful fluid administration so as not to expand the intravascu- Pulmonary edema is seen in as many as 40% of patients. Supple-
lar space or exacerbate the edema. Electrolyte and acid-base mental oxygen and mechanical ventilation are indicated. Sedative
imbalances are frequent in FHF patients and should be managed and paralytic agents may be required to ensure tolerance of venti-
appropriately. Hyperkalemia may be multifactorial; usually it is lation; however, they should be used sparingly because they may
secondary to liver necrosis, massive transfusion, acid-base imbal- hinder neurologic evaluation. Aspiration pneumonia is a potential
ance, and renal failure. Acidosis results from increased lactic acid contraindication to transplantation and should therefore be treat-
production and decreased handling of lactate by the failing liver. ed aggressively.
Compensatory respiratory alkalosis develops initially, but if
encephalopathy progresses, respiratory acidosis may result. Infectious complications Infection poses a serious threat to
Sodium or potassium bicarbonate infusions should be adminis- FHF patients both by placing them at risk for sepsis and by being
tered in cases of severe acidosis. Acetate provides twice the bicar- a contraindication to liver transplantation. Immunologic defects
bonate load and is metabolized outside the liver; thus, if sodium observed in this setting include impaired opsonization, impaired
and potassium intake is severely restricted, continuous infusion of chemotaxis, impaired neutrophil and Kupffer cell function, and
acetate salts may be useful. complement deficiency.53,54 Bacterial translocation through a
Initially, amino acids should be withheld to prevent excessive failed mucosal barrier has been implicated as one of the factors
nitrogen loading; later, limited nitrogen supplementation (70 to 80 responsible for a high incidence of septic episodes in this popula-
g protein/day) may be provided. Most patients present with severe tion. Gram-negative organisms and the lipopolysacharide derived
hypoglycemia that can be fatal and warrants aggressive therapy. from their cell walls promote a systemic inflammatory response
Hypoglycemia should be corrected rapidly by infusion of 50% that aggravates the patient’s overall condition.55 To lower the risk of
dextrose, followed by continuous infusion of a more dilute solution infectious complications, some groups advocate selective gut
at a rate of 4 mg/kg/min. A 10% solution is usually adequate; how- decontamination. This practice appears to have no significant
ever, higher concentrations should be considered in patients whose advantages over systemic antibiotic prophylaxis alone.56
hypoglycemia persists or whose fluid intake is restricted. Caloric Bacterial infection, usually originating from the respiratory or
supplementation has not been extensively studied in FHF. the urinary tract or from a central venous catheter, occurs in more
than 80% of cases. In one study, bacteremia was documented in
Renal failure Renal failure occurs in as many as 55% of 25% of patients, with staphylococci, streptococci, and gram-nega-
FHF patients. Functional renal failure is a common cause of renal tive rods the most common pathogens.57 Because most FHF
failure in this population. However, acute tubular necrosis (ATN) patients have percutaneous lines and indwelling catheters in place,
is more common in these patients than in those with chronic liver iatrogenic sources must always be considered. Fungal infection is
disease and cirrhosis.46 This is especially true in patients who have less common than bacterial infection in this setting; however, one
not been resuscitated adequately, who have experienced prolonged series found a significant incidence of fungal infections, with
hypotension, or who have ingested hepatotoxins that are also Candida albicans cultured in 33% of the patients studied.58 The
nephrotoxic (e.g., acetaminophen). majority of the patients had renal failure and had been treated with
Adequate urine volume can be maintained by judicious volume antibiotics for longer than 5 days.
expansion, administration of loop diuretics, or both, along with The high prevalence of infection notwithstanding, we do not
infusion of low doses of dopamine. Depleted intravascular volume advocate antibiotic prophylaxis in this population unless either
may be managed by giving blood products, volume expanders, or there is strong suspicion of active infection or an ICP monitor is in
both. Because plasma albumin levels are invariably low, salt-poor place. However, our decision threshold for initiating antibiotic

9. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 9 HEPATIC FAILURE — 9
therapy is low, given that the usual clinical presentation (fever and taneous recovery must be assessed. In addition to determining the
leukocytosis) may be absent in as many as 30% of FHF patients.57 King’s College prognostic score on admission, we follow the gen-
Surveillance cultures for bacteria and fungi must be obtained at eral trend in clinical course with respect to the development of
frequent intervals from blood (peripheral and central lines), urine, encephalopathy, ICP elevation, coagulopathy, metabolic acidosis,
sputum, and open wounds. If ascites is present, the ascitic fluid and renal failure. The decision whether to continue with medical
should be cultured. In addition, chest radiographs should be ob- therapy or to perform liver transplantation must be made whenev-
tained to identify developing infiltrates. Administration of broad- er a donor liver becomes available. In general, patients who appear
spectrum antibiotics should be initiated at the first sign of infec- to be deteriorating rapidly and who have no contraindications
tion; as soon as an organism is identified, specific treatment may to liver transplantation should undergo emergency liver transplan-
be focused more narrowly. Initiation of antifungal therapy with tation. Similarly, patients whose synthetic function does not im-
either fluconazole or another agent should be considered if a fun- prove within the first 48 to 72 hours should be considered for
gal culture is positive and if fever persists beyond 5 days while the liver transplantation: the risk of complications and death from
patient is on antibiotics, especially if renal failure is present. The MODS if transplantation is not performed outweighs the risk of
duration of antimicrobial therapy should be individualized for each the procedure.
patient. Follow-up cultures are recommended if a specific organ-
ism is isolated. Toxic Liver Syndrome
Even with a multidisciplinary, comprehensive approach to ther-
Coagulopathy and bleeding Bleeding is a frequent compli- apy, a few patients with FHF go on to manifest the so-called toxic
cation of FHF, typically resulting from massive liver necrosis, liver syndrome, characterized by severe intracranial hypertension,
impaired hepatic synthesis of clotting factors, and platelet dysfunc- profound lactic acidosis, hemodynamic instability, and MODS. It
tion. All clotting factors synthesized by the liver (i.e., factors II, V, has been suggested that removal of the necrotic liver may improve
VII, IX, and X) exhibit depressed plasma activity in FHF. Factor the hemodynamic status of these patients and lower their ICP. In
II, with a half-life of 2 hours, is the first to be depleted with hepa- such extreme cases, a two-stage procedure has been performed:
tocellular dysfunction and also the first to be repleted during hepa- total hepatectomy with an end-to-side portacaval shunt, followed
tocellular recovery. PT is invariably prolonged, reflecting a gener- by liver transplantation when an allograft becomes available. In
alized clotting factor deficiency; it is used as one of the criteria for one large series,61,62 32 adult patients with toxic liver syndrome
determining the likelihood of spontaneous recovery. At some cen- underwent total hepatectomy with a portacaval shunt.The patients
ters, FFP transfusion is withheld and PT is followed carefully to were anhepatic for 6.5 to 41.4 hours.Whereas 13 patients showed
determine upward or downward trends in the course of the disease no signs of improvement after hepatectomy and soon died of
and hence the likelihood of either spontaneous recovery or need MODS, 19 became more stable and underwent the full procedure.
for transplantation (unless the PT is greater than 25 seconds or the Only seven patients were alive at 46 months.
INR is greater than 5, especially if an ICP monitor is in place). In the early 1990s, we used this approach to treat an 18-year-old
Intracranial bleeding is the most devastating complication of coag- female patient with uncontrollable cerebral edema secondary to
ulopathy in FHF patients with ICP monitors in place. In a 2003 FHF; she underwent total hepatectomy with a portacaval shunt,
study, administration of recombinant factor VIIa showed promis- followed by orthotopic liver transplantation (OLT) 14 hours later.63
ing results in a group of patients with refractory coagulopathy.59 During the anhepatic period, she was supported with the help of a
Thrombocytopenia and abnormalities of platelet function are bioartificial liver (BAL) [see Discussion, Bioartificial Liver Support
also common in FHF. Acute splenomegaly, consumptive coagu- System, below]. With artificial liver support, the severe neurologic
lopathy, and bone marrow suppression all contribute to the devel- dysfunction was reversed, ICP was normalized, and the serum
opment of thrombocytopenia. Conversely, clearance of older plate- ammonia level was reduced.The patient recovered completely, with
lets from the blood by the reticuloendothelial system is hindered, no neurologic deficits. We subsequently used the same approach
resulting in an older, less effective platelet pool. In one study, a with another FHF patient, also successfully (unpublished data). It
mean platelet count of 50,000/mm3 was associated with a higher appears that for highly selected patients exhibiting severe toxic
incidence of GI hemorrhage.60 Our current practice is to give plate- metabolic derangement and uncontrollable intracranial hyperten-
lets to patients who either are thrombocytopenic (platelet count sion, total hepatectomy with a portacaval shunt—preferably ac-
< 50,000/mm3) or are actively bleeding. companied by some form of artificial liver support—followed by
OLT may be considered as a desperate salvage measure.
MULTIDISCIPLINARY
MEDICAL THERAPY AND LIVER TRANSPLANTATION
INDICATIONS FOR LIVER
With the introduction of orthotopic OLT as a treatment modal-
TRANSPLANTATION
ity for FHF patients, overall patient survival improved from less
Because of the complexity than 20% to greater than 60%.64,65 As more experience was gained
of the underlying disease, with OLT, it became apparent that optimal patient selection is
medical management of FHF essential for a successful outcome. FHF patients must be consid-
requires a multidisciplinary ered for OLT before irreversible brain injury, MODS, and sepsis
approach. Hemodynamic and develop. Patient selection should be based on a clear understand-
respiratory support and prevention and treatment of cerebral ing of the natural history of the disease, the underlying cause, and
edema are major goals. Complications of hepatic failure must be the likelihood of spontaneous recovery without transplantation.
treated aggressively to prevent sepsis, ARDS, and MODS, which One of the most difficult aspects of managing FHF patients is
is the second most common cause of death in these patients if they the lack of reliable prognostic criteria predicting outcome. In our
survive the first few days. As noted [see Assessment of Prognosis, experience, the King’s College criteria are less sensitive and spe-
above], liver transplant evaluation must be carried out simultane- cific in determining prognosis for patients with acetaminophen-
ously with aggressive ICU care, and the patient’s chances of spon- induced FHF than for patients with FHF from other causes. As

10. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 9 HEPATIC FAILURE — 10
TREATMENT OF COMPLICATIONS
a result, a small number of patients who either might have recov-
ered spontaneously or might have sustained irreversible brain Chronic liver disease may be associated with a variety of com-
damage undergo unnecessary or unwarranted liver transplanta- plications, depending on the nature and extent of hepatocyte
tion. Given the severe shortage of organ donors, as well as the injury and regeneration. Most patients with chronic liver disease
cost and morbidity of liver transplantation and a commitment to and possible cirrhosis are well compensated, maintain a relatively
lifelong immunosuppression, this is a significant problem. normal functional status, and remain essentially undiagnosed;
Two interacting factors tend to influence the outcome of however, a small percentage of patients become symptomatic.
transplantation in the setting of ALF: (1) the severity of the ill- Hepatic failure secondary to cirrhosis is not an all-or-none
ness before transplantation and (2) the condition of the graft process: patients may lose one or more specific liver functions
used.The importance of the second factor was illustrated by the while retaining the remainder. In addition to hepatic effects, cir-
early experience with liver transplantation in France. Initially, rhosis and hepatic failure can exert a wide range of extrahepatic
French surgeons used the first available graft for ALF patients, effects that involve virtually every organ system, leading to MODS
regardless of its size, quality, or blood group compatibility. and death in most cases if appropriate therapy is not instituted
Subsequently, a study of 116 patients demonstrated that out- promptly. Consequently, treatment of cirrhosis and chronic hepat-
comes were significantly worse when adverse graft conditions ic failure must focus on treating both the underlying primary dis-
(i.e., marginal quality, reduced size, and ABO incompatibility) ease and all of its extrahepatic manifestations and complications.
were present.66
Some centers have successfully performed living donor liver Portal Hypertension
transplantation in ALF patients.67 This approach has been more In most patients with
commonly employed in pediatric patients.68 Wider application chronic liver disease and
has been limited by the risks this procedure poses to the donor cirrhosis, PHT develops as
in a setting where, because of the rapid progression of the dis- a result of increased resis-
ease, there is rarely enough time to evaluate potential donors tance to portal venous
appropriately and to eliminate the elements of pressure and blood flow within the liver.
coercion.69 The potential for not just one but possibly two tragic PHT is defined as a portal
outcomes must be emphasized. venous pressure higher than
12 mm Hg or a hepatic wedge venous pressure that exceeds the
inferior vena cava pressure by more than 5 mm Hg. It is classified
Management of Chronic as prehepatic, hepatic, or posthepatic according to the anatomic
Liver Disease site of increased portal venous resistance. Hepatic PHT is further
Chronic liver disease classified according to the functional relationship to the hepatic
usually develops as a result sinusoids [see 5:10 Portal Hypertension]. Sinusoidal obstruction is
of long-standing, ongoing more frequently seen with postnecrotic cirrhosis (e.g., cirrhosis
liver injury. The repeated resulting from HCV and HBV infection), whereas postsinusoidal
injury and the ensuing obstruction is more common with alcoholic cirrhosis. Prehepatic
repair usually result in and posthepatic causes of PHT are less often encountered in
deposition of an excessive
amount of extracellular matrix (ECM), with or without accom-
panying inflammation. As the disease process progresses, excess
ECM forms connective tissue bridges linking portal and central
Table 4 Etiology of Chronic Liver Disease
areas (so-called bridging fibrosis), eventually leading to cirrhosis.
Cirrhosis is an irreversible state that gives rise to significant phys- Alcoholic liver disease (exclude acute alcoholic hepatitis)
iologic impairment, including poor exchange of nutrients and Viral hepatitis
metabolites between sinusoidal blood and hepatocytes. Hepatitis B virus
Eventually, the lobular architecture becomes distorted and blood Hepatitis C virus
flow altered, leading to PHT and its numerous complications. In Biliary cirrhosis
addition to PHT, repeated parenchymal injury results in the loss Primary biliary cirrhosis
of a large number of functioning hepatocytes and subsequently Primary sclerosing cholangitis
leads to hepatic failure. Secondary sclerosing cholangitis
Biliary atresia
CLASSIFICATION
Autoimmune hepatitis
Like ALF, chronic liver disease is usually classified on the basis Metabolic abnormalities
of the underlying cause [see Table 4]. According to the United Wilson disease
Network for Organ Sharing (UNOS), the most common indica- α 1-Antitrypsin deficiency
tion for liver transplantation in North America is chronic liver dis- Hemochromatosis
ease resulting from HCV infection. Other common indications are Inborn errors of metabolism
alcohol-induced liver disease, cholestatic liver disease (primary Cryptogenic cirrhosis
sclerosing cholangitis, primary biliary cirrhosis, autoimmune liver Miscellaneous
disease), and cryptogenic cirrhosis. The occurrence of the meta- Vascular anomalies (Budd-Chiari syndrome)
bolic syndrome (obesity, diabetes, and hypertension) is the most Toxin- or drug-induced
important risk factor for the development of nonalcoholic steato- Inborn errors of metabolism
hepatitis (NASH), which is the most common cause of crypto- Other
genic cirrhosis.

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8 CRITICAL CARE 9 HEPATIC FAILURE — 11
patients with cirrhosis; however, efforts should always be made to Table 5 Differentiation of Spontaneous Bacterial
rule out such causes, because these conditions all require different Peritonitis from Secondary Bacterial Peritonitis
therapeutic approaches.
PHT is associated with numerous complications, most of
through Analysis of Ascitic Fluid
which are life-threatening if not diagnosed and treated promptly.
Spontaneous Secondary
The most dramatic and catastrophic complication of PHT is Fluid Assay Bacterial Bacterial
bleeding from esophageal and gastric varices. Prompt diagnosis Peritonitis Peritonitis
and management are vital. Since the early 1990s, management of
variceal bleeding has evolved significantly, thanks to the advent of WBC (cells/mm 3 ) > 500 > 500
novel endoscopic therapies and nonoperative portosystemic shunt
Total protein (g/dl) < 1.0 > 1.0
procedures. Although the esophagus and the stomach are the
most common sites of bleeding varices, other sites within the GI Glucose (mg/dl) > 50 < 50
tract may be involved as well, including the duodenum, the
Lactic dehydrogenase (U/L) < 225 > 225
jejunum, the rectum, and ileostomy and colostomy sites.
One of the principal clinical manifestations of cirrhosis and Gram stain Monomicrobial Polymicrobial
PHT is ascites (i.e., leakage of lymph fluid into the peritoneal cav-
ity). The appearance of ascites is indicative of advanced liver dis-
ease and is associated with a poor prognosis.70 It is believed that avoided during the initial assessment period if possible; if sedation
increased hepatic sinusoidal pressure results in increased forma- or paralysis is required, the combination of poor hepatic function
tion of lymph and causes hepatic lymph to weep from Glisson’s with the shunting of blood away from the liver may greatly length-
capsule into the peritoneal cavity. As ascitic fluid accumulates, en drug elimination, thereby complicating patient assessment.
patients exhibit increasing abdominal distention, which in turn Frequently, patients with PSE carry out normal activities while
causes abdominal pain, decreased appetite, dyspnea, and, occa- the disorder goes unrecognized, and PSE is diagnosed only when
sionally, pleural effusion (so-called hepatic hydrothorax). its presentation is exaggerated by infection or GI bleeding. PSE is
An elevated WBC count in the ascitic fluid provides immediate also exacerbated by constipation, the onset of portal vein throm-
information about possible bacterial infection. Cell counts higher bosis, and the development of a liver malignancy.
than 500/mm3 suggest bacterial peritonitis, especially when the Management of PSE begins with treatment of all potential pre-
absolute neutrophil count exceeds 250/mm3.71 More than 20% of cipitating factors: sedatives and other drugs with CNS effects
cirrhotic patients with ascites eventually manifest SBP. Patients should be discontinued, fluid and electrolyte abnormalities should
with a low total protein level in their ascitic fluid (< 1.5 g/dl) be corrected, GI bleeding should be controlled, and underlying
appear to be at highest risk as a result of the reduced complement infections (especially SBP) should be treated. Early endotracheal
level and opsonic activity in the fluid.The diagnosis of SBP should intubation for airway protection may be needed in patients with
be considered in any cirrhotic patient with fever, abdominal pain, stage III or IV encephalopathy because of the high risk of aspira-
worsening encephalopathy, or deteriorating renal function. Ascitic tion and subsequent pneumonia.
fluid analysis [see Table 5] distinguishes SBP from secondary bac- The therapeutic objectives in the management of hepatic
terial peritonitis that develops as a consequence of an intra- encephalopathy are (1) to minimize ammonia formation and (2)
abdominal abscess or a perforated viscus. Like ascites, SBP carries to augment ammonia elimination [see Discussion, Mechanism of
a grave prognosis: the estimated 1-year survival is less than 50% Hepatic Encephalopathy, below]. Lactulose and certain antibiotics
without liver transplantation.72,73 are commonly employed to achieve these ends. Lactulose is a syn-
Evaluation and management of PHT and its associated thetic disaccharide cathartic that can be delivered orally, through
complications are addressed further elsewhere [see 5:10 Portal a nasogastric tube, or via a high enema and can be administered
Hypertension]. early in the course of the disease. The dosage should begin at 25
g/day and then be titrated to a level at which the patient can pro-
Hepatic Encephalopathy duce three or four loose bowel movements daily. Lactulose is nei-
Hepatic encephalopathy
is a complex neuropsychi-
atric syndrome that is seen
in patients with severe Table 6 Grading of Hepatic Encephalopathy
hepatic insufficiency and
Encephalopathy
cirrhosis. It is characterized Stage Neurologic Changes
by progressive alteration of
cognitive function and coor- Mild confusion, euphoria or depression, decreased
dination and depression of consciousness, leading to deep coma. Stage I attention span, slowing of ability to perform mental
tasks, irritability, disorder of sleep pattern
Hepatic encephalopathy takes two main forms: (1) acute
encephalopathy associated with FHF and (2) portosystemic Drowsiness, lethargy, gross deficit in ability to
encephalopathy (PSE) associated with cirrhosis and portosys- perform mental tasks, obvious personality changes,
Stage II
inappropriate behavior, intermittent and short-lived
temic shunts. It is classified into four stages according to the sever- disorientation
ity and extent of CNS impairment [see Table 6].
For accurate diagnosis of hepatic encephalopathy, it is neces- Somnolent but arousable, unable to perform mental
tasks, disorientation with respect to time or place,
sary to recognize and correct all other disorders that affect cere- Stage III
marked confusion, amnesia, occasional fits of rage,
bral function, including fluid and electrolyte abnormalities, hypo- speech present but incomprehensible
glycemia, azotemia, metabolic acidosis or alkalosis, hypoxia, and
Stage IV Coma
plasma hyperosmolality. Sedatives and paralytic agents should be

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8 CRITICAL CARE 9 HEPATIC FAILURE — 12
ther absorbed nor metabolized in the upper GI tract. When it ing to reverse renal vasoconstriction through I.V. administration of
reaches the colon, the ensuing bacterial degradation acidifies the vasodilators (e.g., dopamine, misoprostol, and aminophylline) or
luminal contents and causes an intraluminal osmotic shift. The drugs that inhibit the synthesis or the effects of endogenous vaso-
more acidic environment inhibits coliform bacterial growth, there- constrictors (e.g., captopril and thromboxane inhibitors). These
by reducing ammonia production. Additionally, the low intralumi- approaches have not yielded effective and reproducible improve-
nal gut pH causes ammonia to be converted to ammonium ions, ments in renal hemodynamics and renal function. Several investi-
which do not enter the bloodstream easily. Finally, the cathartic gators have reported improved renal function after OLT.46,77
action of lactulose clears ammonium ions from the bowel. An approach to the management of HRS has been introduced
Aggressive lactulose therapy may induce volume depletion and that is aimed at correcting the primary underlying defect (i.e., sys-
electrolyte imbalance; metabolic acidosis is a rare occurrence. temic vasodilatation) instead of the secondary renal vasoconstric-
Neomycin, an agent commonly used for bowel preparation, tion. Two classes of drugs have been investigated: (1) agents that
alters gut flora, especially Escherichia coli and other urease-produc- inhibit the effects of endogenous systemic vasodilators (e.g.,
ing organisms, and reduces the production of ammonia. About prostacyclin, nitric oxide, and glucagon) and (2) agents that cause
1% of neomycin is absorbed systemically; because of possible oto- systemic vasoconstriction (e.g., ornipressin and terlipressin). In
toxicity and nephrotoxicity, special care should be taken if it is one small series of patients with type 1 HRS, a combination of an
administered on a continuous basis.74 Other oral antibiotics used oral beta-adrenergic drug with midodrine and octreotide led to
to treat hepatic encephalopathy are polymyxin B, metronidazole, improved renal function and better long-term outcome.78
and vancomycin, which affect gut flora in much the same fashion Besides functional renal failure, various types of nonfunctional
as neomycin. (i.e., organic) renal failure may occur in patients with cirrhosis
Aromatic amino acids (AAAs) are known neurotransmitter pre- (e.g., ATN, renal tubular acidosis [RTA], and drug-induced inter-
cursors. It has been suggested that their products interfere with the stitial nephritis). ATN is especially common in patients with
activity of true neurotransmitters. It has also been shown that the chronic liver disease or FHF and is usually seen in patients who
ratio of branched-chain amino acids (BCAAs) to AAAs in plasma are poorly resuscitated, have experienced prolonged hypotension,
decreases steeply with worsening encephalopathy. Because AAAs have undergone severe septic episodes, or have ingested hepato-
and BCAAs compete for the same blood-brain barrier carrier trans- toxins that are also nephrotoxic (e.g., acetaminophen). ATN is
port sites, the relative paucity of BCAAs leads to increased cere- characterized by an abrupt rise in blood urea nitrogen (BUN) and
bral uptake of AAAs, which in turn promotes synthesis of false serum creatinine levels, accompanied by oliguria or anuria. Unlike
neurotransmitters that then compete with the endogenous trans- HRS, ATN leads to impairment of the concentrating ability of the
mitters dopamine and norepinephrine.75 Parenteral administration tubular system and to excessive urinary sodium excretion; accord-
of BCAA-enriched formulas to patients with hepatic encephalop- ingly, a urine sodium concentration greater than 10 mEq/L is con-
athy has been advocated, but it has not proved beneficial when com- sidered diagnostic for ATN in cirrhotic patients [see Table 7]. RTA
pared with administration of conventional amino acid solutions.76 is commonly seen in patients with primary biliary cirrhosis,
autoimmune liver disease, and alcoholic cirrhosis. It is character-
Renal Failure ized by the inability of the renal tubules to acidify the urine in the
Liver disease and cirrho- presence of a normal GFR.
sis are commonly associated
with functional renal fail-
ure—that is, impaired renal
function in the absence of Table 7 Differentiation of Hepatorenal
significant underlying renal Syndrome from Acute Tubular Necrosis
pathology. The most com-
mon functional renal abnor- Hepatorenal Acute Tubular
Criteria Syndrome Necrosis
mality in cirrhotic patients is HRS, which is defined as a reversible
state of renal failure characterized by azotemia, oliguria (< 10
Advanced liver damage with
mEq/L), and an increased urine-plasma osmolality ratio (U/P > Underlying
jaundice and impaired syn-
Mild or severe liver
1.0) in the absence of urinary sedimentation. HRS occurs in 18% liver disease disease
thetic function
to 55% of cirrhotic patients with ascites and is typified by intense
GI bleeding, diuretics, para- Shock, nephrotoxins,
renal vasoconstriction, a decreased glomerular filtration rate Precipitant
centesis, sepsis, or none sepsis
(GFR), preserved tubular function, and normal renal histol-
ogy.46,77 Although the exact cause of HRS is not known, current Onset Days to weeks Hours to days
evidence suggests that it is multifactorial, involving systemic Renal epithelial cells with or Pigmented granular
vasodilatation and reduced effective plasma volume, along with Urinalysis without pigmented granular casts with or without
increased activity of the renin-angiotensin-aldosterone system, cells RBCs, WBCs
which causes further reduction of the GFR. HRS is classified as Urinary
either type 1 or type 2. In type 1 HRS, renal failure is rapidly pro- sodium < 10 mEq/L > 10 mEq/L
gressive, as defined by a doubling of the initial serum creatinine concentration
level to a value higher than 2.5 mg/dl or a 50% reduction in the Urinary
initial creatinine clearance to a value lower than 20 ml/min in less > Serum osmolarity Isotonic
osmolarity
than 2 weeks. In type 2 HRS, renal failure takes a slower, more
Urinary volume Oliguric Variable
gradual course.
The prognosis for patients with HRS is poor: to date, all thera- Deterioration followed
peutic approaches have proved unsuccessful. Pharmacologic ther- Course Progressive, unremitting by improved renal
function
apy has consisted of correcting effective volume status and attempt-

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8 CRITICAL CARE 9 HEPATIC FAILURE — 13
Management of renal failure is usually aimed at correcting the Coagulopathy and
underlying precipitating causes. In patients with ascites, who expe- Nonvariceal Bleeding
rience ongoing loss of fluid and protein into the peritoneum, it is The spectrum of coagu-
important to maintain an adequate intravascular volume. If intra- lation disorders in patients
vascular volume is depleted, blood components, volume expanders, with liver disease ranges
or both should be given. Given that the plasma albumin level is in- from minor localized bleed-
variably low in these patients, salt-poor albumin solutions may be ing to massive life-threaten-
preferable to carbohydrate-based volume expanders. Albumin re- ing hemorrhage. Abnormal
placement has been effectively used for volume expansion after LVP.79 bleeding may be sponta-
Because of the complex physiologic liver-kidney interaction, neous in some patients, but it is more often the result of a hemo-
fluid and electrolyte management often proves challenging. It is static challenge (e.g., surgical wounds or procedures, gastritis, por-
difficult to estimate the actual intravascular volume, which is tal hypertensive gastropathy, gastric or duodenal ulcers, or rup-
depleted in most cirrhotic patients even though total body fluid tured varices).The underlying anatomic lesion is believed to be as
volume is greater than normal. Sodium retention and free water responsible for bleeding as the hemostatic defect; accordingly,
retention are the two most common abnormalities of renal func- therapy should be directed at correcting both. In addition, gener-
tion that lead to ascites and dilutional hyponatremia. Typically, al physiologic monitoring is maintained. A physiologic pH and a
sodium retention is an early manifestation, whereas water reten- normal core temperature optimize coagulation factors and platelet
tion and renal failure are late findings. Nephrotoxic drugs and I.V. function. Poor nutrition and cholestatic diseases are associated
contrast agents should be avoided, and dosages of antibiotics and with depleted levels of vitamin K. I.V. administration of vitamin
other medications should be adjusted appropriately. K1 can be accomplished with minor complications.
Hypernatremia and metabolic acidosis can develop secondary to Although most bleeding episodes are secondary to decreased
excessive lactulose therapy and dehydration and result in renal func- synthesis of clotting factors, other causes of bleeding (e.g., defec-
tion deterioration. Hypokalemia is also common; it develops secon- tive or dysfunctional factor synthesis and increased consumption
dary to increased serum aldosterone concentration, which leads to of clotting components) must be ruled out. In most patients, the
excessive excretion of potassium in exchange for sodium. Once renal decreased levels of clotting factors parallel the progressive loss of
failure develops, hyperkalemia, hypercalcemia, and hyperphos- parenchymal cell function. Usually, the levels of the vitamin
phatemia become significant problems, often necessitating dialysis. K–dependent factors (i.e., prothrombin, factor VII, factor IX, fac-
tor X, protein S, and protein C) fall first, followed by the levels of
Malnutrition
other factors as cirrhosis progresses. Factor V is synthesized inde-
Most cirrhotic patients pendently of vitamin K availability, and its concentration is of spe-
present with depleted glyco- cial interest because the plasma factor V level seems to be a pre-
gen stores, severe protein- dictor of the extent of liver cell damage. Impaired synthesis of
calorie malnutrition, and coagulation proteins also has an impact on antithrombin III (AT-
wasting. Impaired hepatic III), protein C inhibitor, plasminogen, and α2-antiplasmin, as well
synthetic activity, causing a as on several other inhibitors and activators of both the extrinsic
deficiency of both visceral coagulation pathway and the intrinsic pathway. The combination
and structural proteins, is of decreased factor levels and impaired synthesis of coagulation
one of the hallmarks of advanced liver disease. In addition, poor proteins explains the prolongation of the PT, the activated partial
appetite, tense ascites, abdominal pain, and excessive loss of pro- thromboplastin time (aPTT), and the thrombin clotting time
tein through repeated LVP and overall increased energy expendi- (TCT) in these patients.82,83
ture tend to exacerbate malnutrition. Given the complexity of hemostasis in cirrhotic patients, accu-
Excessive protein administration can induce hepatic enceph- rate diagnosis of a bleeding disorder is often hard to achieve.
alopathy; accordingly, protein intake should be limited to 1 to 1.2 Several disorders and abnormalities may be present simultaneous-
g/kg/day. Glucose is the main energy source given to malnourished ly, and one or more parameters of hemostasis and coagulation
cirrhotic patients; however, its use is not without complications, in may be impaired. Therefore, any effective treatment approach
that these patients typically exhibit glucose intolerance. Lipid should be broad-based and aimed at correcting several deficien-
emulsion can be safely administered to most patients with hepatic cies or abnormalities at once. FFP contains all of the components
failure and should be withheld only from patients with overt of the clotting and fibrinolytic systems but lacks platelets. In most
coma.80 It is generally agreed that the ideal energy source should cases, transfusion of 6 to 8 units of FFP corrects severe clotting
consist of a mixture of glucose and fat emulsion. Approximately factor defects; however, the excess volume may not be well toler-
30% to 40% of all nonprotein calories can be provided in the form ated. Cryoprecipitate, the precipitate formed when FFP is thawed
of fat.The total energy requirement should be 25 to 35 kcal/kg/day. at 4° C, is rich in factor VIII, von Willebrand factor, and fibrino-
As noted [see Hepatic Encephalopathy, above], although AAAs gen but lacks the vitamin K–dependent factors. Therefore, it
have been implicated in the pathogenesis of hepatic encephalopa- should be given only when the fibrinogen level is lower than 100
thy, administration of BCAA solutions has not proved helpful, and mg/dl. Prothrombin complex concentrates contain only the vita-
current evidence does not support their routine use.76,81 min K–dependent factors and proteins, and their use can provoke
In general, the potential risks and complications associated with serious thromboembolic complications, including DIC. There-
total parenteral nutrition (TPN) outweigh the benefits in patients fore, their potential utility must be weighed carefully against the
with a functioning GI tract. When properly administered, enteral risk that thrombotic events may develop.84
nutrition is safer, more physiologically appropriate, and significant- Other major disorders of hemostasis in patients with chronic
ly more cost-effective than TPN. It should therefore be considered liver disease and cirrhosis involve platelets and are manifested as
the first choice for nutritional support in most patients with chron- thrombocytopenia, abnormal platelet function (thrombocytopa-
ic liver disease unless a contraindication to enteral feeding is present. thy), or both. In most cases, thrombocytopenia is related to sple-