Pediatric Resident Curriculum for the PICU
UTHSCSA
Fulminant Hepatic Failure &
Liver Transplantation
Pediatric Resident Curriculum for the PICU
UTHSCSA
Fulminant Hepatic Failure
Definition - Altered mental status with
coagulopathy in setting of acute liver
disease. Hepatic encephalopathy
occurring within 8 weeks of onset of
illness defines FHF.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Etiology
• Viral hepatitis
• Toxins
– Hepatitis A – Carbon
rarely
tetrachloride
– Hepatitis B - appx
– Phosphorus
1% of hep B
– Amanita
– Hep C -- probably
phalloides
not, but ??
(antidote
– Hep D -- delta
penicillin and
agent coinfects
silybin)
with Hep B
– Hep E
– Industrial
cleaning solvents
– CMV, HSV
Pediatric Resident Curriculum for the PICU
UTHSCSA
Etiology
• Drugs
– Acetaminophen
– Acetaminophen
in Tx doses with
alcohol
– Idiosyncratic
reaction -halothane,
sulfonamides,
phenytoin, and
others.

Vascular
— Heart failure -centrolobular
necrosis
— Sinusoidal
obstruction
secondary to
metastatic dz
— Budd Chiari
— Veno-occlusive
disease
Pediatric Resident Curriculum for the PICU
UTHSCSA
Pathology
• Viral, toxic -- hepatocellular necrosis,
diffuse, extensive, resulting in caseating
necrosis.
• Cardiac -- similar, with particularly
severe centrolobular necrosis from higher
intravascular pressure and watershed
effect. Blood flows from portal triad
(hepatic artery and portal vein) to central
veins to hepatic vein. With poor cardiac
output, splanchnic flow markedly
decreased, resulting in markedly
decreased portal flow, which is a large
proportion of flow to liver.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Pathology
• Fatty liver of pregnancy and Reye’s show
microvesicular collections of fat in
hepatocytes and much less necrosis.
• Special stains -- iron in hemochromatosis,
copper in Wilson’s, etc.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Clinical Presentation
• Typically -- nonspecific symptoms, nausea,
malaise, jaundice, altered mental status,
coma -- all over a few days.
• The altered mental status occasionally
precedes clinical jaundice.
• Mental status changes often start with
agitation, delusions, irritability before
progressing to lethargy, stupor, and coma.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Clinical Presentation
• Laboratory -• Transaminases usually high (>1000)
• Bilirubin -- usually mixed
hyperbilirubinemia
• Ammonia -- usually elevated
• Coagulopathy with prolonged PT, PTT,
decreased factors
• Low level DIC
• Low level fibrinolysis
• Respiratory alkalosis
• Metabolic acidosis, increased lactate
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatic Encephalopathy
Etiology
Etiology uncertain.
Suggested mechanisms:
Depressed neural energy metabolism -but autopsied animals show no
changes of ischemia
Decreased hepatic clearance of neuro
toxic substances
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatic Encephalopathy
Neurotoxins
• Ammonia -- correlates poorly with
encephalopathy
• Amino acids --aromatic and straight chain aa
are increased in liver failure -- tryptophan may
be preferentially transported into CNS
• Methionine, mercaptans
• Gamma aminobutyric acid (GABA) -- this is an
inhibitory neurotransmitter. GABA receptor is
site of benzodiazepine action. GABA levels and
endogenous benzodiazepines are elevated in
hepatic failure. Enteric bacteria produce GABA
and this may be absorbed across gut.
Flumazenil anecdotally improves
encephalopathy.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatic Encephalopathy
Grading System
• Grade 0 -- Normal
• Grade I -- Altered spatial orientation, sleep
patterns, and affect
• Grade II -- Drowsy but arousable, slurred
speech, confusion, and asterixis
• Grade III-- Stuporous but responsive to
painful stimuli
• Grade IV-- Unresponsive, with or without
decorticate or decerebrate posturing
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatic Encephalopathy
Cerebral Edema
• Etiology uncertain -- Correlated with degree
of encephalopathy. Occurs in 50 - 85% of
patients with late grade 3 to grade 4
encephalopathy.
• Evidence of altered blood brain barrier
• Impaired cellular Na+K+ -ATP pump
resulting in glial cell edema
• Inappropriate cerebral vasodilatation
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatic Encephalopathy
Cerebral Edema
Signs of increased ICP (may not be
present until late)
– Increased muscle tone
– Increased DTRs
– Dilated sluggish pupils
– Hyperventilation
– Cushing reflex (very late)
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatic Encephalopathy
Treatment
• Protect airway -- Most patients with grade
III to IV should be intubated.
• Avoid precipitants:
– Excessive protein load -- particularly in
form of GI bleed
– CNS depressants
– Infection
– Electrolyte abnormalities
– Respiratory alkalosis
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatic Encephalopathy
Treatment
• Prevent hypotension
• Lactulose -- although not shown to
work well in FHF and felt to be less
effective than in chronic liver disease.
• Branch chain amino acids -theoretically appealing but studies are
mixed results -- most authors feel they
are not helpful.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatic Encephalopathy
Treatment
• Beware and intervene for cerebral edema
• ICP monitoring -- somewhat controversial
because studies have not shown altered
outcome and risk is significant because of
coagulopathy. Reasons favoring
monitoring:
– Intracranial hypertension is erratic and can
develop rapidly with few clinical signs
– Monitoring allows for early detection and
minute-to-minute titration of therapy
– Cerebral perfusion pressure is prognostic sign
and would spare poor risk patients a
transplant (CPP < 50 for 2 hrs)
– Allows management of intraoperative events
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatic Encephalopathy
Treatment
Consider ICP monitoring if
– Grade 3 - 4 with posturing
– PT corrected to < 20, platelets
corrected
– Patient is listed for transplant and felt
to be a candidate for transplant
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatic Encephalopathy
Treatment
• Mannitol -- shown to be effective in improving
outcome
• Hyperventilation -- probably useful for acute
spikes in ICP. Has not been shown to be
effective in hepatic failure. Concerns about
effect on cerebral perfusion warrant
consideration.
• Elevation of head -- ?? What is effect on CPP?
Keep head midline, perhaps 20 - 30 degrees of
elevation.
• Pentobarbital coma, hypothermia -- unproven,
occasionally may be indicated.
• Steroids -- no good, may worsen outcome
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatic Encephalopathy
Treatment
Get better liver
or
Get liver better
Pediatric Resident Curriculum for the PICU
UTHSCSA
Coagulopathy
• Decreased production of liver clotting
factors (all but factor VIII), fibrinogen,
ATIII, thrombocytopenia (splenic
sequestration, low level DIC, other)
• PT/PTT prolonged
• Factors V and VII often followed as they
are relatively labile
• Factor VIII normal or increased if just liver
failure, decreased in DIC
• Euglobulin clot lysis time abnormal in
primary fibrinolysis
Pediatric Resident Curriculum for the PICU
UTHSCSA
Coagulopathy
Management
Avoid bleeding
GI prophylaxis
Avoid nasal intubation
Beware with surgical procedures, line
placement, etc.
• FFP -- Not shown to be effective in changing
bleeding risk (?). Most authors discourage
routine attempts at normalizing PT. Use for
active bleeding and procedures.
• Antifibrinolytics (Amicar) may be considered if
bleeding and primary fibrinolysis is occurring.
Caution with DIC.
• Maintain platelet count >50K, or 100K if
bleeding
•
•
•
•
Pediatric Resident Curriculum for the PICU
UTHSCSA
Metabolic Considerations
• Hypoglycemia -- decreased hepatic glycogen
stores, impaired gluconeogenesis results in
hyperinsulin state and insulin resistance.
There is impaired glucose homeostasis and
hypoglycemia.
• glucagon, insulin secondary to
decreased hepatic clearance, leads to
decreased insulin/glucagon ratio, which
favors catabolism.
• Aromatic amino acids are increased,
probably because of decreased hepatic
clearance.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Metabolic Considerations
• Branch chain amino acids are cleared into skeletal
muscle and are not elevated, so AAA > BCAA
• AAA and BCAA compete for entry to CNS. AAA,
particularly tryptophan is converted to serotonin
and other possible false neurotransmitters.
• Supplementing BCAA theoretically may improve
encephalopathy, but studies give mixed results
and most authorities feel the evidence does not
favor their use for this indication.
• BCAA may also be more readily available for
nutrition since the hyperinsulin state favors
uptake by muscle, which is not true for other AA.
Evidence indicates less catabolism and less muscle
wasting with use of BCAA.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hemodynamic Effects
• Increased cardiac output
• Decreased systemic vascular resistance
• Decreased oxygen extraction ratio and
decreased consumption despite increased
delivery
• Oxygen consumption often becomes
supply dependent.
• Lactic acidosis secondary to anaerobic
metabolism ensues.
• Lactic acidosis has been shown to herald
a poor prognosis.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Renal Effects
Renal failure common



Prerenal azotemia
Acute tubular necrosis
Hepatorenal syndrome
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatorenal Syndrome



Etiology uncertain -- prominent theory is that
low SVR results in “arterial underfilling” and
subsequent increase in renin, aldosterone,
ADH, and norepinephrine resulting in renal
arteriole vasoconstriction. Renal vasodilatory
prostaglandins are important to attenuate this,
so that when NSAIDS are given this
compensation is lost. NSAIDS are known
precipitants of hepatorenal syndrome.
Diagnosis -- in absence of hypovolemia see
very low urine sodium, normal urine sediment.
Exclude other causes.
Treatment -- recover hepatic function,
otherwise the renal failure is very recalcitrant.
Dialysis as needed and indicated.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Respiratory Effects
Respiratory failure can occur by several
mechanisms:
• Neurogenic pulmonary edema
• Fluid overload because of
hyperaldosterone and increased ADH
with conservation of salt and water
• ARDS secondary to sepsis or MSOF
• Also, some have suggested capillary
leak affecting pulmonary and CNS
vasculature
• Hepatopulmonary syndrome
Pediatric Resident Curriculum for the PICU
UTHSCSA
Hepatopulmonary syndrome
• Hypoxemia associated with chronic liver
disease.
• Thought to be secondary to
intrapulmonary vascular dilatations
with a-v shunting as well as diffusion
block because of dilated capillaries.
• Sometimes, but not always resolves with
transplant
Pediatric Resident Curriculum for the PICU
UTHSCSA
Infectious Disease Issues
• Impaired host defenses -• Defective opsonic activity
• Impaired PMN function
• Impaired cell and humoral immunity
• Decrease clearance of enteric organisms
by hepatic RES
• Ascites -- good culture medium
• Invasive lines, ETT, etc
Pediatric Resident Curriculum for the PICU
UTHSCSA
Infectious Disease Issues
• Infection risk: 80% of patients had
documented bacterial or fungal invasive
infections, with a suspicion of infection in half
the remaining patients. 25% had blood stream
infection, with a respiratory source
predominating in the remainder.
• Organisms: Predominantly gram positive
(strep and staph), gram negatives also occur.
30% have fungal infection.
• Prophylactic antibiotics have not been shown
to change outcome and most authors
recommend meticulous surveillance and
aggressive intervention with antibiotics when
infection suspected.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Fulminant Hepatic Failure
Therapy
“Authors tend to publish isolated cases with
a favorable outcome attributed to a given
therapy, but not to publish cases in which
therapy has failed. In fact it might be
argued that the best future one can wish
for a sufferer from SAHF (sudden acute
hepatic failure) is to undergo a new
treatment and have his case published -‘be published or perish!’ “
Benhanou, 1972
Pediatric Resident Curriculum for the PICU
UTHSCSA
Fulminant Hepatic Failure
Therapy
• Tried but failed -• Insulin and glucagon to stimulate
regeneration
• Prostaglandin E
• Corticosteroids
• Hemofiltration
• Charcoal hemoperfusion
• Plasma exchange
• Liver transplantation -- best results. Greater
than 60% one year survival in adult patients with
acute liver failure. Only 10% of patients are
deemed candidates and successfully supported
until transplantation.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Fulminant Hepatic Failure
Therapy
• ELAD (extracorporeal liver assist device) -most acute liver failure is thought to be
recoverable if patient survives long enough.
Most patients either die or have regeneration
and normal liver function. Goal would be to:
• Support patient while awaiting recovery
- thus avoiding transplant and its risks short and long term
• Stabilize patient while awaiting
transplant
• ELAD seems promising in animal studies and
has been used on a few patients with
encouraging results. Not yet a proven
therapy.
Pediatric Resident Curriculum for the PICU
UTHSCSA
Kings College, London
Criteria for Predicting Death and Need
for Liver Transplantation
• Depends on etiology
• For Acetaminophen poisoning
– pH < 7.3 (irrespective grade of
encephalopathy)
– or PT > 100 seconds and serum creatinine
> 3.4 in patients with grade III or IV
encephalopathy
Pediatric Resident Curriculum for the PICU
UTHSCSA
Kings College, London
Criteria for Predicting Death and Need
for Liver Transplantation
• All other etiologies
– PT > 100 seconds (irrespective of grade of
encephalopathy)
• OR any 3 of the following
– Age < 10 years or > 40
– Liver failure caused by non-A, non-B
hepatitis, halothane, or idiosyncratic drug
rxn
– Jaundice for > 10 days prior to
encephalopathy
– PT > 50 seconds
– Serum bilirubin > 17.5
Pediatric Resident Curriculum for the PICU
UTHSCSA
United Network for Organ Sharing (UNOS)
Status 1 - most urgent level
 Rapid development of grade 3 - 4
encephalopathy
 Prothrombin time > 25 sec
 On vasopressors or ventilatory support
 Have primary graft non-function
 Are expected to live less than 7 days
without a transplant
 Inborn error of metabolism with
metabolites that are toxic to the CNS
Pediatric Resident Curriculum for the PICU
UTHSCSA
Transplantation in FHF
Contraindications
 Uncontrolled sepsis
 Multi-organ system failure
 Irreversible brain damage
 By neurologic exam
 Imaging studies
 Sustained ICP > 50, or
 CPP < 40 for 1 - 2 hours
Pediatric Resident Curriculum for the PICU
UTHSCSA
Fulminant Hepatic Failure
Recommended Readings
• Lee WM. Acute Liver Failure. N Engl J Med
1993;329:1862 - 1872.
• Caraceni P, and Van Thiel DH. Acute Liver
Failure. Lancet 1995;345:163-9.
• Riordan SM, and Williams R. Treatment of
Hepatic Encephalopathy. N Engl J Med
1997;337:473-9.
• Whitington PF, et al. Pediatric Liver
Transplantation. Seminars in Liver Disease
1994; 14:303-317.