INTENSIVE CARE
Acute liver failure
KJ Farley
Stephen J Warrillow
Abstract
Acute liver failure (ALF) is a life-threatening condition with many possible
causes. In developed countries, common causes include paracetamol over-
dose, toxin exposure (e.g. mushrooms), and idiosyncratic drug reactions.
Viral hepatitis is much more common in developing countries, although
must be considered in any geographical location. The clinical syndrome
of ALF is remarkably independent of the cause and comprises the following
key features: jaundice, encephalopathy with cerebral oedema, coagulop-
athy, vasodilatory state, renal dysfunction, hypoglycaemia and immune
dysfunction. Management of the patient with severe ALF is threefold in
aim: (a) prevent further liver damage by treating the underlying cause of
ALF where possible; (b) prevent and treat complications of ALF (e.g. cere-
bral oedema, shock and infection) and (c) early referral to specialist centre
for consideration of liver transplantation. Despite modern intensive care
practices, the mortality of severe ALF remains high. Optimal supportive
care aims to extend the period available to source an organ for transplanta-
tion and/or to allow full recovery. This article provides a practical approach
to the diagnosis and management of critically ill patients with ALF.
Keywords Cerebral oedema; fulminant liver failure; severe acute liver
failure
Royal College of Anaesthetists CPD matrix: 2C00
Liver failure is traditionally classified according to the time be-
tween development of jaundice and encephalopathy. This clas-
sification is valuable when determining the cause, prognosis and
appropriate treatment of severe acute liver failure. Encephalop-
athy develops within 1 week of jaundice in hyperacute liver
failure, between 1 and 4 weeks in acute liver failure and between
5 and 12 weeks in subacute liver failure. Chronic liver failure
involves more gradual onset of symptoms and signs of liver
dysfunction, associated with cirrhosis. The pathophysiology,
natural history and treatments differ considerably between
chronic liver disease and the acute spectrum of liver disease.
Severe acute liver failure (ALF) is a rare, although life threat-
ening condition, with multiple possible causes and complica-
tions. This article will consider the major diagnostic and
management issues in patients with ALF.
Key clinical features of ALF
Important details include: previous state of health, history of
cirrhosis (to differentiate from decompensated chronic liver
K J Farley MBBS BMedSci FCICM FRACP is an Intensive Care Fellow at the
Austin Hospital, Heidelberg, Melbourne, Australia. Conflicts of interest:
none declared.
Stephen J Warrillow MBBS FCICM FRACP GradCertEmergHth is a Senior
Intensive Care Consultant at the Austin Hospital, Heidelberg,
Melbourne, Australia. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 16:4
Learning objectives
After reading this article, you should be able to:
C recognize the key features of severe acute liver failure
C have an approach to the assessment and management of the
patient with acute liver failure
C know the rationale for early referral to a specialist (liver
transplant) centre for patients with severe acute liver failure
disease), family history of liver failure, and risk factors for viral
hepatitis (intravenous drugs, travel, sexual history, tattoos). Fe-
male patients should be asked about the possibility of pregnancy.
A thorough drug history (non-prescription, herbal remedies and
illicit as well as prescribed therapies) must be obtained. Mush-
room ingestion should also be asked about.
After initial resuscitation, patients must be examined for evi-
dence of chronic liver disease (e.g. sarcopenia, gynecomastia,
clubbing, leuconychia, spider nevi, prominent abdominal wall
veins, and advanced ascites). Encephalopathy can be graded ac-
cording to the West Haven criteria (Table 1), but critical care
physicians may be more familiar with the Glasgow Coma Scale for
describing abnormal conscious states. Whichever approach is
utilized, repeated assessment will assist in detecting deterioration.
Abdominal examination should evaluate liver and spleen size as
well as the presence of ascites. Herpetic skin lesions, tattoos and
evidence of needle tracks should be looked for on the skin. Eye
examination should include looking for Kayser-Fleischer rings
which indicate copper deposition in Wilson’s disease.
Investigation of ALF
Although the complications of ALF are largely independent of the
underlying cause, it is still important to identify the aetiology
where possible, as specific therapy may be available. Table 2 lists
suggested initial investigations for causes and complications of
ALF.
Management of ALF
Treatment of patients with ALF is primarily aimed at preventing
or treating complications, to allow time for endogenous hepato-
cyte regeneration, or for a transplant organ to become available.
Some causes of ALF have specific treatment modalities to
minimize further hepatocyte damage (Table 3). Note that pa-
tients with severe ALF from causes other than paracetamol or
hepatotropic viruses are unlikely to survive without trans-
plantation. Referral to a specialist centre capable of Liver
Transplantation should be undertaken early.
N-Acetylcysteine
Intravenous administration of N-acetylcysteine (NAC) improves
survival in paracetamol induced ALF. The time elapsed between
paracetamol intake and commencement of NAC correlates with
outcome. Immediate commencement of NAC infusion is recom-
mended even in the initial absence of evidence for overdose.
NAC is an inexpensive and effective therapy if paracetamol is
implicated, and a harmless treatment if paracetamol ingestion
is later ruled out. Patients who may have overdosed on
174 Ó 2015 Elsevier Ltd. All rights reserved.
 INTENSIVE CARE

Ammonia concentrations of more than 117 mmol/L are highly

West Haven grading of hepatic encephalopathy associated with the development of severe cerebral oedema and
Grade Salient symptoms and signs dangerous intracranial hypertension.3 Severe ALF also results in
the accumulation of various other toxins, such as false neuro-
1 C GCS 14e15 transmitters, CNS depressants, and inflammatory mediators,
C Mild confusion which further induce CNS injury.
C Euphoria; anxiety Normally, cerebral blood flow is tightly regulated across a
C Word finding difficulties wide range of arterial pressures. Autoregulation is lost, however,
C Decreased attention in patients with severe ALF due to abnormal regulation of
NB: this grade of encephalopathy may be vasoactive mediators within the brain and cerebral hyperaemia
extremely subtle will occur. This in turn then leads to vasogenic oedema in
2 C GCS 12e15 severely encephalopathic patients.
C Inattention Clinical features of severe cerebral oedema with resultant
C Moderate confusion e.g. disorientation to intracranial hypertension will be obscured in complex critically
time, place or person ill patients and regular skilled assessment is necessary.
C Disinhibition; inappropriate behaviours The risk of death from cerebral oedema-induced refractory
C Lethargy intracranial hypertension from ALF is high if immediate action is
C Asterixis not taken to address the pathophysiological processes involved.
C Slurred speech A number of strategies have been trialled and it may be that the
C Hyporeflexia or hyper-reflexia application of combination therapy offers the most benefit. The
3 C GCS 8e12 combination of mild hyperventilation,4 high-dose haemodiafil-
C Drowsy but rousable tration, hypernatraemia and mild hypothermia5 has been termed
C Marked confusion quadruple-H therapy,6 and may be an effective means of
C Marked behavioural abnormalities e.g. reducing the risk of adverse neurological outcomes associated
paranoia, delusions, aggression with ALF. The four interventions are outlined in Table 4 along
C Asterixis with therapeutic targets and likely mechanism of benefit.
C Ataxia Additional measures to prevent cerebral oedema include:
4 C GCS 3e7
Patient positioning 30 degrees head up.
C Pupillary abnormalities
Avoiding interventions which decrease cerebral venous
C Loss of airway reflexes drainage (such as constrictive ties around the neck or
bilateral internal jugular venous access devices; keep the
NB: Assessment of encephalopathy grade should be made after the best
attempt to exclude other causes of delirium and altered conscious state e.g. head in a neutral position).
hypoglycaemia, sepsis, intracranial haemorrhage. GCS, Glasgow Coma Scale.
Ensuring adequate oxygenation (e.g. PaO2 >70 mmHg).

Adequate sedation (propofol may be the preferred agent).
Table 1
Early recognition and treatment of seizure activity (EEG
required to diagnose).
slow-release paracetamol preparations should be discussed with If severe cerebral oedema worsens despite aggressive mea-
a toxicologist as standard treatment algorithms may not apply. sures and transplantation is an option, there may be a role for
Additionally, there is evidence to support the benefit of NAC in rescue therapies such as more extreme therapeutic hypothermia,
non-paracetamol induced hepatic failure, where haemodynamics further hyperventilation or indomethacin.7
and oxygen delivery may be enhanced.1 The decision to stop The use of ICP monitoring devices in these patients is
NAC in a patient with severe ALF should be made by hepatolo- controversial. Coagulopathy increases the risk of life-threatening
gists in conjunction with the treating intensivist. intracranial haemorrhage, and immune suppression increases
the infection risk of these devices. There is no evidence that
Management of encephalopathy and cerebral oedema patient outcome is improved when invasive ICP monitors are
Cerebral oedema occurs in many patients with high-grade en- used.8 The decision to monitor ICP should be individualized to
cephalopathy and brainstem herniation is a common cause of each patient’s clinical state and should involve hepatologists,
death in ALF. Neurological injury occurs as a result of severe intensivists and neurosurgeons. Monitoring of jugular venous
cerebral swelling causing refractory intracranial hypertension. parameters such as oxygen saturation, lactate or glucose may be
The pathophysiology of ALF associated cerebral oedema is of assistance in titrating therapies to ensure adequate cerebral
complex, but the accumulation of ammonia and other metabolic perfusion and metabolic function. Interpretation of values ob-
toxins, as well as the loss of cerebral autoregulation resulting in tained from jugular venous bulb monitoring may be difficult and
cerebral hyperaemia,2 are the likely two main drivers. expert guidance should be sought early.
Ammonia is a waste product of nitrogen metabolism and
undergoes detoxification via the urea cycle. Over 85% of this
Non-neurological management of ALF patients
detoxification occurs in the liver and hyperammonaemia is
therefore a key feature of severe liver failure. Ammonia crosses Circulatory disturbances
the bloodebrain barrier and causes neuroexcitation, disruption Patients with ALF commonly present with shock. Cardiac per-
to many crucial neuronal processes and also astrocyte swelling. formance is usually maintained in the setting of marked

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 INTENSIVE CARE

Investigations in ALF
Blood tests FBE (high white cell in inflammation, platelets low or normal, anaemia in bleeding)
Blood film (e.g. haemolytic anaemia in autoimmune disease & Wilson’s disease)
U&E (renal impairment)
LFT (usually high ALT & AST, initially normal bilirubin and GGT & ALP)
Lipase
Coagulation studies (including INR, PT, APTT, fibrinogen, functional studies if available)
Ammonia
Paracetamol level (and other toxicology screen depending on history and examination)
Alcohol level
bHCG
ABG & lactate
Caeruloplasmin (plasma levels are low in Wilson’s disease)
Serology HAV, HBV, HDV, HEV
EBV, CMV, HSV, VZV
Parvovirus B19
Auto-immune investigations ANA, ANCA, AMA
Anti-LKM, anti-SM
Radiology Hepatic Ultrasound with Doppler of vessels (esp. Hepatic vein: BuddeChiari syndrome)
CXR (ARDS, pneumonia, line and tube placement)
Other 12 lead ECG (toxidromes, arrhythmia from electrolyte abnormality, myocardial ischaemia)
EEG (if seizures suspected)

ABG, arterial blood gas; ALP, alkaline phosphatase; ALT, alanine transaminase; ANA, antinuclear antibody; ANCA, anti-neutrophil cytoplasmic antibody; Anti-LKM, anti-
liver kidney microsomal antibody; Anti-SM, anti-Smith antibody; APTT, activated partial thromboplastin time; ARDS, acute respiratory distress syndrome; AST, aspartate
transaminase; bHCG, beta human chorionic gonadotrophin; CMV, cytomegalovirus; CXR, chest X-ray; EBV, Epstein Barr virus; ECG, electrocardiograph; EEG, electro-
encephalograph; FBE, full blood examination; G&H, group and hold; GGT, gamma glutamyl transpeptidase; HAV, hepatitis A virus; HBV, hepatitis B virus; HDV, hepatitis
D virus; HEV, hepatitis E virus; HSV, herpes simplex virus; INR, international normalized ratio; LFT, liver function tests; PT, prothrombin time; U&E, urea and electrolytes;
VZV, varicella zoster virus; WCC, white cell count.

Table 2

Specific treatments for different causes of ALF

Cause Specific Treatment

Paracetamol N-Acetylcysteine Survival possible with optimal supportive care

HBV Nucleoside analogues
(e.g. lamivudine, entecavir)
HSV Acyclovir
VZV and CMV Ganciclovir
Acute Fatty Liver of Pregnancy Deliver foetus

Amanita mushroom poisoning Penicillin (high dose) or silibinin/silymarin Survival unlikely without liver transplantation
BuddeChiari syndrome Anticoagulation if severe ALF develops
Revascularization procedures
e.g. systemic/catheter directed thrombolysis,
balloon angioplasty or stent insertion into hepatic vein
Wilson’s disease Chelating agent (zinc, penicillamine, trientine)
Plasmapheresis
Drug reaction (e.g. beta-lactams, Withdraw causative agent
NSAIDS, isoniazid)
Autoimmune diseases Immunosuppression e.g. high-dose steroids

These treatments are in addition to maximal supportive care & assessment for liver transplantation.

Table 3

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 INTENSIVE CARE

Quadruple-H approach to neuroprotection in ALF

Intervention Therapeutic Targets Application of Therapy Mechanism of Action

Hyperventilation Lower of either:
C PaCO2 ¼ 35 mmHg
C that achieved by the
patient prior to intubation
Haemodiafiltration C Blood ammonia <60 mmol/L
C Even daily fluid balance
Hypernatraemia Serum sodium 145e155 mmol/L
Hypothermia Mild hypothermia:
C Core temperature 33e35 C
C Set mechanical ventilation to achieve
sufficiently high minute ventilation
C High volume CRRT utilizing dialysis and
filtration with blood flow of 250 ml/min
and replacement fluid exchange volumes
of 40e50 m/kg/h
C Anticoagulation is generally not required
C Use lactate free replacement fluid to avoid
contributing to blood lactate concentrations
C Continuous infusion of concentrated saline
(e.g. 20% NaCl) via central venous catheter
C CRRT circuit
C External cooling blanket
C Reduces cerebral hyperaemia
C Lowers intracranial pressure
C Lowers blood ammonia
concentration
C Gives precise metabolic,
electrolyte and fluid
management
C Effective cooling effect
C Increases serum tonicity and
reduces cerebral oedema
C Reduces ammonia production
and CNS uptake
C Attenuates cerebral hyperaemia
and reduces cerebral metabolic
rate
C Reduces neuro-excitation

Table 4

vasodilation in a manner similar to severe sepsis. Lactic acid
tends to accumulate due to impaired oxygen delivery and utili-
zation within tissues. Failure of hepatic clearance of lactate
further contributes to the very high blood concentrations which
are often present. As with all critically unwell patients, initial
resuscitation includes judicious fluid replacement, and treatment
of reversible causes of hypotension such as pneumothorax (e.g.
from recent CVC insertion) bleeding (e.g. associated with coa-
gulopathy) and severe infection.
Vasopressors such as noradrenaline are often required to
maintain systemic blood pressure and organ perfusion. Vasodi-
lation may be exacerbated by associated adrenal insufficiency
and a trial of low dose steroid therapy may be considered in
refractory vasodilatory shock.
Cardiac output may be compromised in advanced states of
critical illness or in the setting of pre-existing cardiac disease.
Measurement of cardiac output (e.g. with PAC, echocardiogra-
phy, PICCO etc.) may be useful to guide therapy in these cases.
Infection
Patients with ALF have impaired immune function and are
especially vulnerable to Gram negative and fungal sepsis. Com-
mon problems include pneumonia, urinary tract infection,
vascular devices and intra-abdominal infections. Prophylactic
antibiotics (according to local antibiograms and guidelines)
should be considered in patients with severe ALF, particularly
those who are intubated for encephalopathy or who require renal
replacement therapy. Any deterioration in the patient’s clinical
state should prompt investigation and treatment of new sepsis.
Daily chest X-Ray and regular cultures of blood, tracheal aspirate
and urine should be undertaken. Vascular devices such as central
lines should be monitored for signs of infection and removed if
catheter related blood stream infection is a possibility. Early
advice from Infectious Diseases specialists should be sought.
Coagulopathy
Patients with ALF may have an unusual pattern of coagulopathy
with decreased hepatic synthesis of both pro-coagulant and anti-
coagulant factors. As a consequence, they may manifest both a
bleeding tendency and be at risk of thrombotic complications.
Consider the use of functional studies of clotting (e.g. TEG,
ROTEM) where possible. Classically there is an elevated PT and
INR, while low fibrinogen and thrombocytopenia may also occur.
The trend in INR provides a guide to liver synthetic function and
improvement in the absence of factor support suggests hepatic
recovery. Clotting factor support should not be administered un-
less the coagulopathy is extreme (e.g. INR > 6), there is evidence of
severe bleeding or invasive procedures are planned.
All patients should receive supplemental vitamin K, and a
proton pump inhibitor to reduce the risk of upper GI bleeding.
The use of norethisterone or other agents to stop potentially
profuse menstrual bleeding may be considered in appropriate
female patients.
Hypoglycaemia
Hypoglycaemia may occur as a relatively late problem in advanced
states of ALF due to decreased capacity for hepatic gluconeogen-
esis combined with poor oral intake and vomiting leading to
decreased glycogen stores. Hypoglycaemia must be treated
immediately as the neurological damage may be catastrophic.
Blood glucose should be measured at least 4 hourly in patients with
severe liver failure and more frequently if levels are low. A
reasonable blood glucose target is 6.0e10 mmol/L, using hyper-
tonic dextrose solutions if necessary. Low concentrations of

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 INTENSIVE CARE

dextrose (e.g. 5e10% dextrose solutions) should be avoided due
to the risk of hyponatraemia and exacerbation of cerebral oedema.
Acid-base disturbances
Patients with ALF commonly present with a combined respira-
tory alkalosis as well as a metabolic acidosis due to a combina-
tion of lactate, renal dysfunction and toxins. There may also be a
metabolic alkalosis (e.g. from vomiting or bicarbonate
administration).
Acute kidney injury
Acute kidney injury may result from the underlying cause of ALF
(e.g. paracetamol induced nephrotoxicity) or may be a compo-
nent of the multiorgan dysfunction and vasodilatory shock
commonly seen in severe ALF. In patients in whom renal
replacement therapy is required, high-volume continuous veno-
venous haemodiafiltration (CVVHDF) is recommended as a
neuroprotective measure. High-volume haemodiafiltration in-
creases the clearance of ammonia and other toxins implicated in
the development of ALF associated cerebral oedema. Renal
replacement therapy should not be delayed until overt renal
failure is evident. Continuous modes of renal replacement ther-
apy avoid the metabolic and cardiovascular instability associated
with intermittent modes. Bicarbonate buffers should be used in
replacement fluids as the failing liver cannot metabolize lactate
or acetate buffers. Nephrotoxins (e.g. contrast media, NSAIDs,
aminoglycosides, and vancomycin) should be avoided where
possible.
Acute lung injury (ALI)
ALI may occur in ALF as a result of systemic inflammation,
infection or oedema. Management is largely aimed at prevention.
Use lung protective ventilation strategies such as TV 4e6 ml/kg,
avoiding plateau pressures >30 cm H2O and careful application
of PEEP to reduce alveolar shear stress (while not exacerbating
intracranial hypertension by reducing cerebral venous return).
Acute liver diseases in pregnancy
In addition to the usual causes of acute liver disease, pregnant
women may develop acute fatty liver of pregnancy (AFLP),
HELLP syndrome (haemolysis, elevated liver enzymes & low
platelets), pre-eclampsia/eclampsia, or hepatitis E as well as
rarer conditions such as liver rupture. A high index of suspicion
is needed in pregnant women with abnormal liver function tests
as patients with these conditions may deteriorate quickly and
urgent or emergent delivery may be needed. Early referral to a
centre capable of high level critical care support as well as ob-
stetric and neonatal expertise is appropriate.
Indications for referral to a liver transplantation centre
Patients with ALF who should be referred to a centre capable of
liver transplantation include:

Any patient requiring ICU/HDU level care.

Any patient who is rapidly deteriorating clinically or who
is expected to have significant deterioration (e.g. late pre-
sentation of significant paracetamol overdose).

Patients with:
 INR >3
 pH <7.2
 lactate >4 mmol/L
 ALT >1000 U/L
 GCS <14.
Liver transplantation
The decision to proceed to listing a patient for urgent liver
transplantation to treat ALF is complex and must balance both
the individual’s risk of death without transplantation, their
ability to survive the transplant surgery and the subsequent need
for lifelong immunosuppression. This decision must be made in
an environment where transplantable organs are scarce, neces-
sitating wise allocation. The King’s College criteria (Table 5) are
the most commonly used to assess which patients may require
transplantation in order to survive, although its performance
may not be sufficient given recent advances in care. Improved
models which enable accurate identification of patients who will
not survive without transplantation are required and early
referral to a liver transplant centre is essential.
Novel liver assist devices
The high mortality of acute severe liver failure combined with
the scarcity of organs for transplantation makes a temporary liver
replacement system very appealing. However, techniques
including MARS (molecular adsorbent recirculating system),
Prometheus (fractionated plasma separation & adsorption),
ELAD (extracorporeal liver assist device) and NELP (normo-
thermic extracorporeal liver perfusion)9 remain experimental

Modified King’s College criteria for liver transplantation in ALF

Paracetamol induced ALF Non-paracetamol induced ALF

Either one of: INR >6.5

C pH < 7.30 Or, three or more of:
C lactate >3.0 mmol/L after 12 h of appropriate C >40 years old or <10 years old
resuscitation or >3.5 mmol/L after 4 h of appropriate C Bilirubin >300 mmol/L
resuscitation C >7 days between jaundice & encephalopathy
Or, all of: C INR >3.5
C INR >6.5 or PT >100 s C Aetiology of ALF (non-A non-B or halothane hepatitis, idiosyncratic drug reaction)
C Creatinine >300 mmol/L
C Grade 3 or 4 encephalopathy

Table 5

ANAESTHESIA AND INTENSIVE CARE MEDICINE 16:4 178 Ó 2015 Elsevier Ltd. All rights reserved.
 INTENSIVE CARE

therapies. Other potential treatments that are of unproven benefit 5 Jalan R. Acute liver failure: current management and future prospects.
in ALF include high volume plasma exchange and high cut-off J Hepatol. 2005; 42(suppl 1): S115e23.
renal replacement therapy. These novel therapies should only 6 Warrillow SJ, Bellomo R. Preventing cerebral oedema in acute liver
be used as part of a clinical trial at the current time. A failure: the case for quadruple-H therapy. Anaesth Intensive Care
2014; 42: 78e88.
7 Tofteng F, Larsen FS. The effect of indomethacin on intracranial pres-
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