CE Article #1

Acute Liver Failure

Illustration by Felecia Paras

Johanna Cooper, DVM

Cynthia R. L. Webster, DVM, DACVIM
Tufts University

ABSTRACT: Few medical conditions are more devastating than acute liver failure (ALF), in which a
previously healthy patient can undergo rapid deterioration in liver function and be near death within
5 to 7 days after the onset of clinical signs. In veterinary medicine, ALF has been associated with
adverse drug reactions, alternative medicines, environmental toxins, food additives, infectious agents,
ischemic injury, neoplasia, and metabolic disease. Secondary complications of ALF, such as
encephalopathy, renal failure, and sepsis, often result in clinical deterioration and death. Rapid
recognition of ALF, early initiation of intensive supportive care, vigilant monitoring, and treatment of
secondary complications are required to improve patient outcome.

A
clinical distinction must be made be-
tween acute liver disease (ALD) and
acute liver failure (ALF). ALD is
defined as liver dysfunction occurring in the
absence of known preexisting liver disease,
whereas ALF includes these parameters plus
the presence of encephalopathy and coagulopa-
thy.1–3 ALF is a rare syndrome associated with
high morbidity and mortality. In veterinary
medicine, isolated case reports4–18 of ALF have
mortality rates of 25% to 100%. In humans, the
survival rate is only approximately 65%, even
with the option of liver transplantation.1
In veterinary medicine, ALD has been asso-
ciated with adverse drug reactions, food addi-
tives, alternative medicines, environmental
toxins, infectious diseases, ischemic injury, neo-
plasia, and metabolic diseases (see box on page
499).2–25 Although veterinary reports often con-
tain information on individual
Send comments/questions via email patients with ALF, no com-
editor@CompendiumVet.com prehensive reviews of ALF
or fax 800-556-3288.
exist in the veterinary litera-
Visit CompendiumVet.com for ture. This lack of information
full-text articles, CE testing, and CE complicates the recognition
test answers. and appropriate management
of ALF. This review summarizes information
from veterinary case reports and integrates this
information with what is known about ALF in
humans and/or animal models to better acquaint
veterinarians with this syndrome.
ALF occurs when over 70% of hepatocellular
mass is lost so that insufficient hepatic paren-
chyma remains to maintain synthetic and excre-
tory homeostasis.2,3 This compromise of hepatic
function results in many of the clinical manifes-
tations of ALF, including icterus, hypoglycemia,
bleeding tendencies, hepatic encephalopathy,
cerebral edema, and increased susceptibility to
infection.2,3,26–31
DIAGNOSIS
In ALF, there is typically a history of acute
onset of clinical signs (fewer than 8 weeks) in a
previously healthy animal. Pertinent historical
information includes administration of any drugs,
supplements, or nutraceuticals; exposure to any
environmental toxins, infectious agents, or recent
anesthetic events; and details on housing, outdoor
supervision, travel, and vaccination status.
Clinical signs are typically nonspecific and may
include weakness, depression, anorexia, polyuria,

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 Acute Liver Failure CE 499

polydipsia, vomiting, abdominal pain, and/or Causes of Acute Liver Disease

diarrhea.2–18 On occasion, more specific signs of Chemicals2,3,19 Infectious agents
liver failure, such as icterus or hepatomegaly, are • Arsenic Viral 2,3
present. An abnormal fundic examination may • Carbon tetrachloride • FIP
signal the presence of a systemic infectious dis- • Chlorinated hydrocarbon • Herpesvirus
ease.16 In some cases, predominant findings are • Dimethylnitrosamine • Infectious canine hepatitis
related to secondary complications of ALF, • Heavy metals
• Pine oil Bacterial 2,3
including diffuse cerebral signs from hepatic • Leptospirosis
• Selenium
encephalopathy, weakness or seizures secondary • Salmonellosis
• Tannic acid
to hypoglycemia, or bleeding tendencies due to • Suppurative hepatitis
coagulopathy.1–3,6,26–30 Clinicians should be alert Neoplasia2 • Tyzzer’s disease
to physical examination findings suggestive of • Carcinoma
— Biliary Protozoal 2,3,16
chronicity, including poor body condition and • Neospora spp
ascites, because chronic liver disease may be — Pancreatic
• Lymphoma • Toxoplasma spp
occult with vague clinical signs that are unrecog- • Malignant histiocytosis
nized until the final phase of decompensation. Fungal 2,3
• Histoplasma spp
Alternative medicines18,25
Clinicopathologic Findings • Chaparral leaf Parasitic 2,3
Clinicopathologic evaluation helps verify • Comfrey • Dirofilariasis
the existence of liver disease and determine • Germander • Trematodes
• Jin Bu Huan
the degree to which other organ systems are • Kava Metabolic2,3,23
affected. The initial database should include a • Pennyroyal oil • Idiopathic hepatic lipidosis
biochemical profile, complete blood count, • Inborn errors of copper
and urinalysis. Drugs2–10,19–22 metabolism
In ALF, serum aminotransferases are moder- • Acetaminophen
ately to markedly increased.2,3,26,27 Increases in • Amiodarone Ischemic2,3
• Asparaginase • Immune-mediated hemolytic
serum alanine aminotransferase and aspartate • Carprofen anemia
transaminase occur secondary to leakage from • Diazepam • Shock
damaged hepatocytes.3 The magnitude of their • Griseofulvin
increase is roughly proportional to the degree • Halothane Environmental agents2,3,11–15
of damage but is not prognostic because the • Ketoconazole • Aflatoxins
liver has a large functional reserve and strong • Mebendazole • Amanita mushrooms
regenerative capacity. Serum alkaline phos- • Methotrexate • Blue–green algae toxins
• Oxibendazole– • Cycad seeds
phatase (ALP) and γ-glutamyl transferase are
diethylcarbamazine
also frequently elevated in patients with ALF. • Phenobarbital Food additives24
Because alkaline phosphatase is present on • Potentiated sulfonamides • Xylitol
both the hepatocyte biliary membrane and bile • Stanozolol
duct cells and γ-glutamyl transferase is found • Tetracyclines Miscellaneous
primarily on the latter, larger increases in these • Thiacetarsamide • Immune mediated
enzymes occur in ALF syndromes associated
with cholestasis.3
Clues to hepatic functional status can be found via clinicians to a more chronic condition. However,
routine serum biochemical profile by looking at the con- hypoalbuminemia may occur in ALF secondary to con-
centrations of substances that rely on the liver for syn- current vasculitis or blood loss.
thesis and/or excretion.2,3,31 Serum hyperbilirubinemia, Assessment of the coagulation profile provides further
hypoglycemia (see the section on this, p. 508), and information about the functional status of the liver.1–3
hypoalbuminemia may be present with compromised The presence of coagulopathy is required for a diagnosis
2,3,29
hepatic function. Given the long serum half-life of of ALF. Prolongation of the prothrombin time (PT)
albumin, the presence of hypoalbuminemia should alert and activated partial thromboplastin time (APTT)

July 2006 COMPENDIUM

500 CE Acute Liver Failure
occurs as a result of decreased synthesis and activation of
clotting factors and may be further compromised by
vitamin K depletion and/or increased factor consump-
tion. ALF may also be accompanied by increased
fibrinogen-degradation products, decreased fibrinogen,
and prolongation of PT and APTT and may be clini-
cally indistinguishable from disseminated intravascular
coagulation (DIC).2,3
Complete blood count results are often nonspecific.2,3
Anemia may be present because of hemorrhage or fail-
ure of erythropoiesis and must be distinguished from
hemolysis in icteric patients. Changes in leukocyte
counts are variable. Mature neutrophilia may suggest the
presence of an inflammatory or infectious disease. Neu-
tropenia may be noted in patients with concurrent
sepsis. Platelet counts may be low secondary to con-
sumption due to ongoing hemorrhage, active thrombo-
sis, or DIC or decreased production due to drug toxicity
or neoplastic infiltration of the bone marrow.2
Urinalysis in combination with serum creatinine per-
mits evaluation of renal function. The findings of exces-
sive cellular or granular casts, glucosuria, proteinuria, or
isosthenuria are suggestive of concurrent renal disease.
Renal disease may occur in cases of ALF due to acute
tubular necrosis from ischemic or toxic injury or second-
ary to infectious or immune-mediated disease.1–3
Ancillary clinicopathologic testing that may be indi-
cated includes serology for infectious disease (lep-
tospirosis, ehrlichiosis, Rocky Mountain spotted fever,
toxoplasmosis, neosporosis, histoplasmosis, dirofilaria-
sis), assessment of serum lipase levels, and autoantibody
testing (Coombs’ or antinuclear antibody).2,3,16 In addi-
tion, if abdominal effusion is present, fluid analysis may
provide etiologic clues. The presence of neutrophils and
bacteria is indicative of septic peritonitis, free bile is
consistent with bile duct or gallbladder rupture, and
abnormal cells may indicate neoplasia. Identification of
a pure transudate would be more suggestive of portal
hypertension secondary to chronic liver disease.
Diagnostic Imaging
Diagnostic imaging is indicated in most patients with
suspected liver disease. Plain abdominal radiography
may reveal visible hepatomegaly, choleliths, or the pres-
ence of abdominal effusion or free gas. Microhepatica is
more consistent with chronic liver disease.2 Ultrasono-
graphic findings may be variable in cases of ALF. Typi-
cally, the liver is enlarged with normal to hypoechoic
parenchyma.32 However, in some conditions (e.g., feline
COMPENDIUM
idiopathic hepatic lipidosis, lymphosarcoma), the
parenchyma may be hyperechoic.32
Thoracic radiography is indicated to evaluate for pul-
monary metastases and, in patients with concurrent vas-
culitis or hypoproteinemia, may help identify pleural
effusion or pulmonary edema.
Histopathology
Once the presence of ALF has been confirmed but no
cause has been identified, the next step in defining a cause
is to obtain a hepatic biopsy. Histopathology provides a
definitive diagnosis in cases of ALF secondary to meta-
bolic (feline hepatic lipidosis), infectious, and neoplastic
disease.2,3 It also allows assessment of the duration of ill-
ness, which has prognostic significance, because end-stage
liver disease marked by prominent fibrosis has a poor
prognosis.31 In addition, biopsy provides tissue for special
stains and cultures that aid in evaluating both metabolic
(copper storage diseases) and infectious causes of ALF.3,31
Although the classic histologic picture of ALF involves
hepatic necrosis, several different histopathologic patterns
may be seen. ALF can result from parenchymal infiltra-
tion by lipid, inflammatory, or neoplastic cells without
marked necrosis. Some causes of ALF result in severe
cholestasis secondary to bile duct and canalicular injury.
Although biopsy provides valuable information that
might influence treatment strategies, acquisition of
hepatic tissue is often contraindicated because of the
presence of coagulopathy and encephalopathy. In cases
in which infiltrative disease (e.g., hepatic lipidosis, lym-
phosarcoma) is suspected, fine-needle aspiration may be
diagnostic and involves less risk. Because the clinical
management of ALF may be similar regardless of the
underlying cause, biopsy should be delayed until the
patient has been stabilized.
CAUSES
Adverse Drug Reactions
Hepatotoxic drugs are either intrinsic or idiosyncratic
toxins. Intrinsic hepatotoxins, such as acetaminophen,
are characterized by a predictable, dose-dependent toxi-
city.5,26 Idiosyncratic hepatotoxins, usually due to meta-
bolic aberrations in susceptible individuals, have a
random, largely dose-independent toxicity. Most hepa-
totoxicities reported in veterinary medicine are idiosyn-
cratic4,6–10,19–22,24 (see box on page 499).
Acetaminophen is rarely prescribed in veterinary
medicine but has been associated with life-threatening
toxicities secondary to accidental ingestion or inten-
July 2006
 Acute Liver Failure CE 501

Table 1. Treatment of Acute Liver Failure and Its Complications

Manifestations Treatment Dosage
Acetaminophen toxicosis N-Acetylcysteine 140 mg/kg IV (first dose), then 70 mg/kg q6h IV for
seven treatments
Amanita mushroom Penicillin G (potassium 20,000 IU/kg IV q4h
toxicosis or sodium)
Silibinin dihemisuccinate 5 mg/kg IV over 1 hr, then 70 mg/kg IV q12h
Copper toxicosis Penicillamine 10–15 mg/kg PO q12h
Zinc acetate 100 mg PO q12h for 2 to 3 mo, then 50 mg PO q12h;
monitor zinc levels
Trientine 10–15 mg/kg PO q12h
Coagulopathy Vitamin K 0.5–1 mg/kg SC q24h for 3 days
Fresh-frozen plasma 10–20 ml/kg IV over 4 hr
Whole blood 5–10 ml/kg IV over 4 hr
GI ulceration Famotidine 0.5 mg/kg IV q12–24h
Lansoprazole 0.7 mg/kg IV q24h
Hemodynamics/ Dopamine 10 µg/kg/min (pressor effect)
microcirculatory disturbance N-Acetylcysteine 140 mg/kg IV initially, then 70 mg/kg IV q4h (17 doses)
Encephalopathy/ Lactulose 0.25–0.5 ml/kg PO q8h or 20 ml/kg of a 30% solution
cerebral edema given as a retention enema
Neomycin 22 mg/kg PO q8h
Mannitol 0.5 g/kg over 10–15 min as needed
Pentobarbital (plus 2 mg/kg IV initially, followed by 2 mg/kg/hr for 1 hr,
mechanical ventilation) then 0.1 mg/kg q2h
Infections Enrofloxacin 10 mg/kg IV q24h (dogs) or 5 mg/kg IV q24h (cats)
and
Ampicillin 22 mg/kg IV q8h
or
Ticarcillin/clavulanate 40 mg/kg IV q6–8h
Acute oliguric renal failure Furosemide 2–4 mg/kg (dogs) or 2 mg/kg (cats) IV bolus, followed
by 1 mg/kg/hr CRI for 4 hr
Dopamine 2.5–5 µg/kg/min CRI
Metabolic disturbances
Hypophosphatemia Sodium phosphate or 0.03–0.06 mmol/kg/hr for 6–24 hr
potassium phosphate
Hypokalemia Potassium chloride Maximum rate: 0.5 mEq/kg/hr
Hypoglycemia 50% dextrose 1–2 ml/kg of 50% dextrose (diluted to 25%) given as a
slow bolus, followed by CRI of 2.5%–10%
CRI = constant-rate infusion

tional administration by owners. Under normal circum-
stances, acetaminophen is metabolized in the liver by
phase II enzymes to nontoxic glucuronic or sulfate con-
jugates and is then excreted in the urine. If the amount
ingested exceeds the capacity of the phase II enzymes,
acetaminophen is biotransformed by phase I enzymes
(cytochrome P-450 enzymes) into an electrophilic,
potentially hepatotoxic compound called N-acetyl-p-
benzoquinoneimine, which can covalently bind to cell
proteins, resulting in hepatocellular necrosis.5 In the
presence of adequate hepatocyte glutathione stores, N-
acetyl-p-benzoquinoneimine can be conjugated to a
harmless mercapturic acid derivative that undergoes
renal elimination. When glutathione reserves are

July 2006 COMPENDIUM

504 CE Acute Liver Failure
depleted by oxidant stress and/or starvation, acetamino-
phen hepatotoxicity occurs.5
Any dose of acetaminophen is contraindicated in cats
because of their reduced ability to metabolize the drug
by phase I conjugation.3 In cats, respiratory distress sec-
ondary to methemoglobinemia due to oxidant damage
to erythrocytes is most common.3 Treatment of aceta-
minophen toxicity involves parenteral administration of
N-acetylcysteine, which acts as an antidote by supplying
cysteine, which is the rate-limiting step in hepatic pro-
duction of glutathione5 (Table 1).
Potentiated sulfonamides were implicated in 20% of
adverse drug reactions in dogs reported to the Center
for Veterinary Medicine from 1988 to 1990.19 In addi-
tion to hepatotoxicity, dogs may have fever, arthropathy,
blood dyscrasias, proteinuria, skin eruptions, uveitis,
and/or keratoconjunctivitis sicca.20–22 A recent retrospec-
tive study21 showed that dogs with hepatotoxicity have a
significantly worse prognosis (only 46% of patients with
hepatopathy recover versus 89% of patients without
hepatopathy). The typical histopathologic lesion in dogs
involves massive hepatic necrosis; however, cholestatic
hepatopathy has also been reported.21 Time to onset of
clinical signs is usually 5 to 36 days.20,21 Pathogenesis
may involve a T cell–mediated response to proteins hap-
tenated by oxidative sulfonamide metabolites, resulting
in immune-mediated hepatocyte destruction.21 Sulfon-
amide hypersensitivity has also been reported in cats,
but reported cases involve ulcerative dermatitis without
liver involvement.22
Oral diazepam therapy causes idiosyncratic ALF in
cats. Clinical signs, including anorexia and lethargy, are
typically noted within 5 to 10 days after treatment, and
mortality rates may be as high as 90%.6 Histopathology
is consistent with a mixed pattern of injury, including
hepatocellular necrosis, cholestasis, and mild hepatic
lipidosis.6 Diazepam is metabolized in the liver to sev-
eral pharmacologically active metabolites that are even-
tually conjugated with glucuronide and eliminated
primarily in the urine. It has been hypothesized that the
inability of cats to glucuronidate some metabolites may
predispose them to diazepam toxicity.
A 100% mortality rate has been reported in dogs expe-
riencing ALF due to repeated anesthesia using halothane
or methoxyflurane.2,7,8,19 Histopathology reveals subacute
centrilobular necrosis. In susceptible patients, initial expo-
sure to halothane results in formation of a hapten that
serves as an antigenic stimulus that with repeat exposure
triggers immune-mediated hepatocyte destruction.
COMPENDIUM
An idiosyncratic acute hepatotoxic reaction to carpro-
fen has been reported9 in dogs. Clinical signs typically
develop within the first 3 weeks of treatment and
include inappetence and vomiting. Mortality was 20%.9
Histopathologic changes are variable, including balloon-
ing degeneration, vacuolar change, lymphoplasmacytic
inflammation, multifocal hepatocellular necrosis, and
apoptosis. A breed predisposition in Labrador retrievers
has been noted.9 Several NSAIDs have been reported1
to cause ALF in humans. Thus all NSAIDs should be
considered potential hepatotoxins. The mechanism of
NSAID-induced hepatotoxicity is not fully understood;
however, interaction between reactive glucuronide
metabolites of acidic NSAIDs with plasma and hepato-
cellular proteins may result in formation of antigenic-
altered proteins, causing immune-mediated toxicosis.9
Hepatotoxicity developed in cats during a prospective
study10 evaluating the use of stanozolol in patients with
renal failure and stomatitis. Clinical signs, including
anorexia and lethargy, developed within 7 to 10 days.
Histopathologic changes included diffuse hepatic lipi-
dosis and cholestasis.10 ALF developed in four of 21 cats
treated; within this subset, the mortality rate was 25%.10
Environmental Toxins
A number of environmental toxins, including aflatox-
ins, Amanita mushrooms, cycad seeds, and blue–green
algae, cause ALF in veterinary patients. Aflatoxins are
toxic compounds produced by Aspergillus flavus, a sapro-
phytic fungus. Hepatotoxicosis commonly occurs after
ingestion of food containing moldy corn. Clinical signs
include anorexia, depression, and icterus followed by
hemorrhagic diathesis and death. Histopathology
reveals hepatocellular fatty degeneration, bile duct pro-
liferation, and centrilobular hepatocellular necrosis.13–15
Recent reports33 of ALF secondary to ingestion of afla-
toxin-contaminated pet food illustrate the continuing
importance of this toxin as a cause of ALF. Amanita
mushroom ingestion results in severe gastrointestinal
(GI) signs within 8 to 36 hours, followed by hepatic
failure in 1 to 3 days. In most cases, ingestion is uni-
formly fatal. Accepted antidotes include the use of peni-
cillin G or silibinin1–3 (Table 1). Cycad seed ingestion
results in gastroenteritis followed by hepatic failure.
Histopathology is consistent with marked centrilobular
necrosis, with mild infiltration of lymphocytes and
plugging of bile duct canaliculi.11 Blue–green algae toxi-
city is secondary to microcystin, a toxic cyclic heptapep-
tide produced during an algal bloom.12 Ingestion results
July 2006
506 CE Acute Liver Failure
in vomiting, diarrhea, lethargy, and icterus. Histopathol-
ogy is generally consistent with massive centrilobular
and midzonal hemorrhagic necrosis.12
Infectious Causes
Infectious causes of acute liver disease include viral, pro-
tozoal, bacterial, and fungal agents as well as heartworm
infection.2,3 Viral diseases implicated in ALF include
infectious canine hepatitis and FIP.2,3 ALF resulting from
In acute liver failure, rapid deterioration of liver function results in
encephalopathy and coagulopathy in a previously healthy animal.
infectious canine hepatitis is rare but may occur in areas
where vaccination for canine adenovirus-1 is not routine.
FIP may cause ALF as a result of massive pyogranuloma-
tous infiltration. The protozoal agents Toxoplasma and
Neospora spp may cause ALF.16 Clinical signs associated
with FIP as well as Toxoplasma and Neospora infections are
typically not limited to the hepatobiliary system, with ocu-
lar and/or neuromuscular involvement occurring in most
cases.3 ALF has also been reported in Tyzzer’s disease
(Bacillus piliformis infection) and leptospirosis.3 Suppura-
tive hepatitis of bacterial origin may also cause ALF.3 Sup-
purative hepatitis is associated with ascension of bacteria
via the biliary tree or hematogenous spread of bacteria
from another infectious foci or penetrating abdominal
wound. Although all systemic fungal infections can
include the liver, Histoplasma spp are most likely to result
in severe liver disease.2,3 Caval syndrome due to dirofilaria-
sis may result in hepatic necrosis secondary to hepatic
congestion and ischemia.2
Ischemic Causes
Arterial or venous occlusion, severe hypotension, or
hemolytic anemia may cause hepatocellular necrosis suf-
ficient enough to result in liver failure.2,3,23
Malignant Infiltration
Although hematopoietic cell neoplasms (lymphoma,
malignant histiocytosis) have the greatest potential for
massive hepatic infiltration, any primary or metastatic
tumor (carcinoma) can cause liver failure if sufficient
hepatic parenchyma is replaced by neoplastic cells.2,3 Neo-
plastic conditions may also lead to hepatocellular necrosis
secondary to ischemia because diffuse intrasinusoidal
infiltration by tumor cells may obstruct hepatic vessels.
Metabolic Disease
Feline idiopathic hepatic lipidosis syndrome is one of
the most common causes of ALF in veterinary medi-
cine. In this syndrome, accumulation of intracellular
lipid results in progressive hepatic dysfunction.2,3 Inborn
errors of copper metabolism (e.g., in Bedlington terriers,
West Highland white terriers, and dalmatians) resulting
in accumulation of copper within hepatocytes may also
result in ALF.3,17,23
Miscellaneous
Food additives and alternative medicines have been
implicated in hepatotoxicity.18,24,25 Ingestion of xylitol, a
sugar alcohol used in sugar-free products, has been
related to liver dysfunction and failure in some dogs.24
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Dermal application of pennyroyal oil, an herbal remedy,
resulted in ALF and death in a dog.18 Other alternative
medicines, including germander, chaparral leaf, comfrey,
Jin Bu Huan, and kava, have been associated with ALF
in humans and may also become an important differen-
tial in veterinary patients.25 Immune-mediated ALF has
been identified in humans, and a similar autoimmune
process may be involved in some cases of canine and
feline ALD.1,2
MEDICAL MANAGEMENT
Medical management of ALF involves:
• Identification and removal of the inciting cause or
administration of a specific antidote
• Provision of supportive care to promote hepatic
regeneration
• Anticipation, control, and prevention of complications
All potentially hepatotoxic agents should be discontin-
ued. If recent ingestion (i.e., 1 to 2 hours) of a potentially
hepatotoxic substance is suspected, emesis or gastric lavage
followed by administration of activated charcoal should be
considered. In rare cases in which specific antidotes are
available, they should be promptly administered (Table 1).
Infectious causes should be treated appropriately and
chemotherapy initiated in cases of infiltrative neoplasia.
Secondary complications in acute liver failure include hypoglycemia, encephalopathy,
coagulopathy, infection, acute renal failure, and acute respiratory distress.
ALF is characterized by hypotension secondary to
hypovolemia and low systemic vascular resistance with a
compensatory increase in cardiac output.2,26–29 Decreased
systemic vascular resistance is postulated to be the result
of abnormal vasomotor tone secondary to the effects of
cytokines or factors released by a necrotic liver.29 ALF
also causes impaired extraction of oxygen at the tissue
capillary beds.28,29 The exact mechanism by which this
microcirculatory dysfunction occurs is incompletely
understood but may involve plugging of vessels by
platelets, interstitial edema, and/or abnormal vasomotor
tone.3 The net effect of this microcirculatory disturbance
is increased dependence on anaerobic metabolism for
energy, resulting in lactate production and acidosis in
peripheral tissues.3
July 2006
Acute Liver Failure CE 507
Correction of the hemodynamic abnormalities noted
in ALF begins with fluid replacement. Sodium chloride
(0.9%) can initially be administered while waiting for
blood work results. Lactated Ringer’s solution is gener-
ally avoided because liver function is required to metab-
olize lactate and unmetabolized lactate may exacerbate
acidemia. A sufficient fluid volume should be adminis-
tered to restore intravascular volume using systemic
blood pressure as a guide for resuscitative efforts. If
crystalloid fluid therapy alone does not correct hypoten-
sion, vasopressors such as dopamine may be required,
along with colloid therapy.1,28
Symptomatic anemic patients (packed cell volume:
<20%; tachycardic or tachypneic) should receive fresh
packed erythrocytes or whole blood. Stored blood compo-
nents should be avoided because of their ammonia con-
tent, which may exacerbate existing encephalopathy.2,34
Prolonged use of isotonic crystalloids may result in
fluid overload and further dilution of factors involved in
coagulation and maintenance of oncotic pressure. Peri-
odic reassessment of colloid osmotic pressure is warranted
to prevent third-space fluid losses. If colloid osmotic
pressure is decreased (<15 mm Hg) and the patient is not
anemic or spontaneously bleeding, administration of a
colloid (e.g., pentastarch, hetastarch, human serum albu-
min, fresh-frozen plasma) should be considered in addi-
tion to or instead of crystalloid administration.
Although achievement of normotension helps correct
microcirculatory changes associated with ALF by
increasing peripheral perfusion, impaired tissue oxygen
extraction may continue. Intravenous infusion of N-
acetylcysteine has been shown to improve microcircula-
tory blood flow in both a porcine and feline model of
ALF28,29 (Table 1). In these models, improvement was
also noted in the mean arterial pressure, which may
decrease the need for inotrope support in ALF cases.29
N-acetylcysteine may work by restoring normal vascular
responsiveness to nitric oxide and has also been found to
be cytoprotective to endothelial cells.1,29
Electrolyte derangements are common in ALF; thus
frequent assessment of electrolyte status is indicated.2,3,34
Hypophosphatemia may occur due to increased excre-
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508 CE Acute Liver Failure
tion, decreased absorption (steatorrhea), and internal
redistribution (e.g., refeeding syndrome, hyperventila-
tion, or cellular regeneration).3 Hypokalemia may result
secondary to anorexia, vomiting, and/or prolonged use
of potassium-deficient intravenous fluids. In addition,
many drugs (e.g., mannitol, furosemide) used in treating
the secondary complications of ALF may promote
potassium loss.3 Hyponatremia may result from third-
space loss or an inability to excrete free water.3 Hyper-
natremia and hyperphosphatemia may be noted with
the onset of renal insufficiency.
Although volume replacement, correction of electrolyte
imbalances, and treatment of microcirculatory distur-
bances may improve systemic acidosis, acidemia persists
in some cases. Persistent acidemia indicates continued
hypoxia at the level of the peripheral tissues and may
Multiorgan failure and brain herniation are the
most common causes of death in animals with acute liver failure.
result in multiorgan failure. Inability to correct acidosis in
humans with ALF is a poor prognostic sign and a crite-
rion used to determine the need for liver transplantation.1
The early provision of nutrition is important in treating
ALF. Animals with ALF typically have a profoundly neg-
ative nitrogen balance, resulting in rapid depletion and
redistribution of protein stores.35 Protein depletion delays
hepatic regeneration, compromises the immune system,
and worsens encephalopathy. In addition, in patients with
idiopathic hepatic lipidosis, nutrition is essential to stop
mobilization of fatty acids to the liver and prevent further
disease progression. Although enteral nutrition is most
beneficial, patients with ALF may not be able to tolerate
oral feeding because of severe encephalopathy or in-
tractable vomiting. In these cases, parenteral nutrition
should be instituted with the guidance of a board-certified
veterinary nutritionist because its composition needs to be
tailored to meet the individual needs of patients with pro-
found deficiencies in metabolism.
COMPLICATIONS
Caring for patients with ALF requires vigilant moni-
toring and prompt treatment of secondary complica-
tions, including hypoglycemia, encephalopathy,
coagulopathy, infection, acute renal failure, and acute
respiratory distress2,3,26–29,34 (Table 1).
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Hypoglycemia
Hypoglycemia in patients with ALF results from
decreased glycogenolysis and gluconeogenesis combined
with hyperinsulinemia due to decreased hepatic metabo-
lism.2 Concurrent sepsis may also contribute to hypo-
glycemia. Clinical signs of hypoglycemia include a
depressed mentation, weakness, and, if severe, seizures.26
Hypoglycemia may develop rapidly in patients with
ALF and may be difficult to distinguish from ongoing
encephalopathy or the onset of cerebral edema.1,26 Blood
glucose levels should be assessed every 4 hours; if hypo-
glycemia is noted, a bolus of 50% dextrose (diluted to
25%) should be given followed by the addition of dex-
trose (2.5% to 5%) to ongoing fluids. In some patients,
hypoglycemia may be refractory and dextrose infusions
may need to be increased to 10%.29
Encephalopathy
In contrast to encephalopathy accompanying chronic
liver disease or congenital portovascular anomalies,
ALF-associated encephalopathy has a sudden onset,
is rapidly progressive, is more often accompanied by ini-
tial excitatory manifestations, and frequently results
in the development of cerebral edema and intracranial
hypertension.26–30,34
Hyperammonemia has a central role in the develop-
ment of ALF-associated encephalopathy. 34,36 In ALF,
hepatic extraction and metabolism of ammonia are
severely impaired, resulting in systemic hyperammonemia.
As with encephalopathy associated with chronic liver dis-
ease, the resultant increase in brain ammonia alters astro-
cyte function and brain metabolism. In ALF-associated
encephalopathy, however, evidence links increased plasma
ammonia to the development of cerebral edema and
intracranial hypertension.26–29 In several animal models,36
ammonia infusion results in accumulation of glutamine in
the astrocytes, leading to astrocyte swelling, cerebral
edema, and increased intracranial pressure (ICP). Cerebral
edema may also develop due to increased cerebral blood
flow secondary to vasodilation of cerebrovascular beds,
altered blood–brain transport, and the effects of cytokines
produced in the systemic inflammatory response syn-
drome.1,26–29 Hyperammonemia also leads to increased
July 2006
510 CE Acute Liver Failure

extracellular concentration of the excitatory neurotransmitter glutamate, which

may be responsible for early hyperexcitability in patients with ALF.36
Clinically, ALF-associated encephalopathy manifests as a rapidly devel-
oping sequence of agitation, delirium, convulsions, and coma. Death may
result from brain herniation. The neurologic status of patients with ALF
should be assessed hourly for prompt recognition of alterations. As
encephalopathy progresses, sudden deterioration in mental status, increased
appendicular muscle tone, pupillary dilation with decreased pupillary light
response, and an altered respiratory pattern may be noted with the onset of
cerebral edema.26 Acute systemic hypertension and concurrent bradycardia
(Cushing reflex) may signify impending brain herniation.
One of the goals in treating ALF-associated encephalopathy is reduc-
tion of blood ammonia levels.2,34 This is accomplished by reducing produc-
tion and absorption of ammonia at the level of the GI tract through
dietary protein restriction, the use of lactulose, and administration of
antibiotics that selectively kill urease-producing bacteria. Lactulose, a
nonabsorbable disaccharide, is metabolized in the colon to fatty acids that
convert diffusible NH3 (ammonia) into nonpermeant NH4+ within the GI
lumen. Lactulose also alters bacterial metabolism so that less bacterial tox-
ins are produced.2,34 Antibiotics, including nonabsorbable aminoglycosides
or amoxicillin, can alter colonic bacteria and decrease ammonia produc-
tion.2,34 Metronidazole should not be used in patients with ALF because it
requires hepatic metabolism and elimination, possibly resulting in neuro-
toxicity. Although the combination of lactulose and antibiotics is highly
effective in treating veterinary patients with chronic hepatic encephalopa-
thy due to portosystemic shunts, the combination is much less effective in
managing ALF-associated encephalopathy, likely because of a divergent
pathophysiology.
Treatment of encephalopathy also involves controlling factors that may
worsen it. Alkalosis and hypokalemia both promote production of ammonia
and its subsequent diffusion across the blood–brain barrier.34 Thus it is
important to maintain a normal pH and provide potassium supplementa-
tion. GI bleeding, infections, and administration of stored blood, sedatives,
or diuretics can also potentiate encephalopathic severity.2,34
In cases of ALF in which encephalopathy manifests as agitation and
delirium and sedation is required, administration of a short-acting benzo-
diazepine may be necessary (Table 1). Although benzodiazepines can
potentiate encephalopathy, they act rapidly, can be given intravenously, and
can be reversed using flumazenil if necessary.1 Intravenous phenobarbital or
small doses of propofol can be used to treat protracted seizure activity.
Although several measures have been proposed to prevent and treat cere-
bral edema and intracranial hypertension, these are the most serious compli-
cations of ALF, are fairly refractory to therapy, and often result in death.1,2,30
Therapeutic measures to decrease ICP include administration of mannitol,
hypertonic saline, or barbiturates; controlled hypothermia; and ventilation to
achieve normocapnia.1,2,30 There is no benefit to corticosteroid administra-
tion.1 Interventions to prevent increases in ICP include head elevation to
10˚ to 20˚, strict rest, avoidance of stimulation, and control of events that
may increase ICP, including seizures, coughing, and vomiting. Stuporous,

COMPENDIUM July 2006


comatose, or extremely agitated patients may require
constant-rate infusion of pentobarbital combined with
mechanical ventilation and muscle paralysis to lower
ICP.1,26,27 Because a significant side effect of barbiturate
infusion is systemic hypotension, additional measures
may be necessary to maintain adequate mean arterial
pressure.
Coagulopathy
The liver is the production site for all coagulation fac-
tors and related inhibitory compounds except for von
Willebrand’s factor. Reduced hepatic synthesis results in
a clinically significant hypocoagulable state.2,3 Patients
with ALF may also have concurrent thrombocytopathy
characterized by decreased platelet numbers and func-
tion. Vitamin-K deficiency may occur due to reduced
bile salt–facilitated fat absorption. Massive liver tissue
destruction with the release of toxic factors into the cir-
culation may also trigger DIC.13
Treatment of coagulopathy may involve the use of
vitamin K, fresh-frozen plasma, and fresh blood prod-
ucts. Vitamin-K supplementation (0.5 to 1 mg/kg SC)
should always be instituted.2 It is not necessary to cor-
Intensive supportive care and vigilant monitoring for secondary
complications are required to allow time for the liver to regenerate.
rect clotting abnormalities with fresh-frozen plasma in
the absence of bleeding. However, fresh-frozen plasma
should be administered before invasive procedures.
Upper GI hemorrhage commonly occurs in humans
with ALF; however, it is uncertain to what degree this
occurs in animals.2,3 Hemorrhage may be secondary to
stress-induced ulceration, decreased gastrin clearance,
and thrombocytopathy. Gastroprotectants, including
H2-blockers and proton pump inhibitors, are recom-
mended. 1 Famotidine is the H 2 -blocker of choice
because it has no effect on hepatic blood flow and does
not decrease hepatic cytochrome P-450 enzyme sys-
tems. Proton pump inhibitors, such as lansoprazole, can
also be used with the realization that they do inhibit
cytochrome P-450 enzymes (Table 1).
Infection
Patients with ALF have increased susceptibility to
infection related to decreased Kupffer cell function,
July 2006
Acute Liver Failure CE 511
abnormal neutrophil function secondary to complement
deficiency, and disruption of physical barriers through
the placement of endotracheal tubes as well as urinary
and intravenous catheters. Prospective human studies1
show that typical markers of infection, including fever
and leukocytosis, are frequently absent, even in the pres-
ence of positive results from blood cultures. Infections
are commonly due to gram-negative bacteria from the
GI tract and gram-positive bacteria from the respiratory
and urinary tracts.1
Infection should be suspected in patients experiencing
sudden clinical deterioration. Appropriate samples for
culture should be obtained and current antibiotic cover-
age evaluated. Broad-spectrum antibiotic coverage
should be considered at presentation in all patients with
ALF because of their high susceptibility to infection
(Table 1).
Acute Renal Failure
Acute oliguric renal failure may result secondary to
circulatory disturbances, endotoxemia, sepsis, or DIC.
Renal function should be carefully monitored by placing
an indwelling urinary catheter to quantify urine produc-
tion. If inadequate urine production (<1 ml/kg/hr) is
noted, a fluid bolus may be required while carefully
monitoring peripheral blood pressure (at least 50 to 60
mm Hg). If urine production continues to be inade-
quate, constant-rate infusion of furosemide or dopamine
may be required. Some form of renal replacement ther-
apy (hemodialysis) is required if acidosis, fluid overload,
hyperkalemia, or rising creatinine develops.
Acute Respiratory Distress Syndrome
Acute respiratory distress syndrome may result sec-
ondary to ALF. Other causes of lung injury in patients
with ALF include aspiration pneumonia, intrapul-
monary hemorrhage (secondary to DIC), and pul-
monar y thromboembolism. Respirator y function
should be monitored by frequent auscultation and
observation of respiratory patterns. Thoracic radiogra-
phy should be conducted as well as arterial blood gas
analysis or pulse oximetry in patients with a change in
COMPENDIUM
512 CE Acute Liver Failure
respiratory depth, rate, or effort. Supplemental oxygen
therapy should be initiated if oxygen saturation is less
than 94%. Mechanical ventilation is required if the oxy-
gen saturation is less than 90%, partial pressure of oxy-
gen is less than 60 mm Hg, or partial pressure of
carbon dioxide is greater than 50 mm Hg, even with
supplemental oxygen therapy.
PROGNOSIS
The prognosis for patients with ALF is variable and
depends more on the degree of insult than the nature of
the inciting event. Several negative prognostic markers
have been identified in humans with ALF that may be
useful in veterinary patients. These markers include a
PT of longer than 50 seconds, persistent acidemia
despite fluid therapy (pH: <7.3), a serum bilirubin level
greater than 17.5 mg/dl, persistent hypernatremia, and
the presence of cerebral edema.1
CONCLUSION
Managing patients with ALF is challenging. Specific
treatments and antidotes directed toward the inciting
cause of liver damage are rarely available. Rapid identi-
fication of affected patients and referral to a critical
care center offer the best chance to minimize morbidity
and mortality. Treatment largely consists of intensive
supportive care and vigilant monitoring. Anticipation
and treatment of complications are required to improve
outcome.
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10. Harkin KR, Cowan LA, Andrews GA, et al: Hepatotoxicity of stanozolol in
cats. JAVMA 217(5):681–684, 2000.
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12. DeVries SE, Galey FD, Namikoshi M, Woo JC: Clinical and pathologic
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failure in a dog. JAVMA 241(10):1502–1506, 1999.
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19. Bunch S: Hepatotoxicity associated with pharmacologic agents in dogs and
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24. Dunayer E: Hypoglycemia following canine ingestion of xylitol-containing
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25(7):514–524, 2003.
26. Kelly JH, Koussayer T, He DE, et al: An improved model of acetaminophen-
induced fulminant hepatic failure in dogs. Hepatology 15(2):329–335, 1992.
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Strombeck DR, Guilford WG (eds): Small Animal Gastroenterology. Davis,
CA, Stonegate Publishing, 1996, pp 130–180.
32. Biller DS, Kantrowitz B, Miyabayashi T: Ultrasonography of diffuse liver dis-
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34. Taboada J, Dimski D: Hepatic encephalopathy: Clinical signs, pathogenesis, and treatment. North Am Vet
Clin 25(2):337–355, 1995.
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Intern Med Forum:947, 1993.
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mate system, in Felipo V, Grisolia SM (eds): Advances in Cirrhosis, Hyperammonemia, and Hepatic
Encephalopathy. New York, Plenum Press, 1997.

ARTICLE #1 CE TEST
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from the Auburn University College of Veterinary Medicine. Paid subscribers
may purchase individual CE tests or sign up for our annual CE program.
Those who wish to apply this credit to fulfill state relicensure requirements should
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To participate, fill out the test form inserted at the end of this issue or take CE tests
online and get real-time scores at CompendiumVet.com.Test answers are
available online free to paid subscribers as well.

1. Secondary complications of ALF do not include

a. hypoglycemia. d. renal failure.
b. coagulopathy. e. diabetes mellitus.
c. cerebral edema.

2. Which is the most common lesion found via histopathology in

canine ALF?
a. acute hepatic necrosis
b. lymphocytic–plasmacytic inflammation
c. hepatic lipidosis
d. vacuolar hepatopathy
e. centrilobular fibrosis

3. Hemodynamic changes in patients with ALF do not include

a. decreased systemic vascular resistance.
b. increased cardiac output.
c. increased tissue oxygen extraction.
d. abnormal vasomotor tone.
e. microcirculatory plugging.

4. Which parameters have been associated with a poor prognosis in

human ALF?
a. persistent acidosis, hypophosphatemia, hypernatremia, and hypokalemia
b. prolonged PT, persistent acidosis, presence of cerebral edema, and hyper-
natremia
c. hyponatremia, hyperkalemia, refractory hypoglycemia, and prolonged PT
d. prolonged APTT, hyperphosphatemia, hyponatremia, and persistent acidosis
e. prolonged PT, persistent alkalosis, hyperphosphatemia, and hypernatremia

5. Which statement regarding ALF in cats is true?

a. Potentiated sulfonamides are one of the most common hepatotoxic drugs
in cats.

COMPENDIUM July 2006

 Acute Liver Failure CE 515

b. In idiopathic hepatic lipidosis, enteral nutrition is the
most important treatment in preventing progression
of hepatic dysfunction.
c. ALF secondary to stanozolol toxicity is character-
ized by acute hepatic necrosis via histopathology.
d. FIP and toxoplasmosis frequently cause acute hepa-
titis in the absence of other organ involvement.
e. Diazepam is a dose-dependent hepatotoxin that
causes acute hepatocellular necrosis.
6. Which statement regarding encephalopathy in
patients with ALF is correct?
a. The classic signs include depression, somnolence, and
head pressing.
b. Normal blood ammonia levels rule out hepatic en-
cephalopathy as the cause of the neurologic abnor-
malities.
c. A dramatic improvement in mentation occurs with
lactulose administration.
d. Encephalopathy is exacerbated by administration of
stored whole blood products and GI bleeding.
e. Cerebral edema is a rare complication in patients
with ALF.
9. Which statement regarding coagulopathy in
patients with ALF is correct?
a. Spontaneous bleeding is common and associated
with a poor prognosis.
b. Vitamin-K deficiency may contribute to coagulopathic
tendencies and is secondary to decreased hepatic
synthesis of the vitamin.
c. A PT of longer than 50 seconds has been associated
with a poor prognosis in human ALF.
d. To correct coagulation deficiencies, fresh-frozen
plasma should always be administered to patients
with ALF and an abnormal PT or APTT.
e. Vitamin K should be administered only in cases with
an abnormal PT and APTT.
10. Which is not used to address the microcircula-
tory disturbance in ALF?
a. N-acetylcysteine
b. crystalloid fluid therapy
c. dopamine
d. prednisone
e. colloid fluid therapy

7. Which statement regarding infection in patients

with ALF is correct?
a. Infection is a rare complication in humans with ALF.
b. Frequent surveillance for infection should be con-
ducted in all cases.
c. Infection is often associated with pyrexia and accom-
panying leukocytosis.
d. Initiation of antimicrobial therapy should be delayed
until there is evidence of infection.
e. Infections are most commonly due to gram-positive
bacteria from the GI tract.

8. Which statement regarding the development of

cerebral edema in ALF is incorrect?
a. The onset of cerebral edema is heralded by increased
sedation, miotic pupils, and loss of muscle tone.
b. The development of cerebral edema is partly due to
increased astrocyte swelling secondary to accumula-
tion of glutamine from ammonia metabolism.
c. Cerebral edema results in increased ICP, which may
be clinically recognized by concomitant hypertension
and bradycardia.
d. With the onset of cerebral edema, clinicians should
attempt to control any event that may increase ICP,
such as agitation, seizures, coughing, or vomiting.
e. Treatment of cerebral edema includes administration
of mannitol or hypertonic saline, controlled hypo-
thermia, and ventilation to achieve normocapnia.

July 2006 COMPENDIUM