REVIEW

CURRENT
OPINION Update on the management of acute liver failure
Francesca M. Trovato, Liane Rabinowich, and Mark J.W. McPhail

Purpose of review
This review describes the current intensive care management of acute liver failure (ALF) and the latest
evidence for emerging therapies.
Recent findings
Mortality from ALF continues to improve and in some cases, medical therapy can negate the need for liver
transplantation because of protocolized management in specialist centres. Liver transplantation remains the
cornerstone of management for poor prognosis ALF. The reduced use of blood products in ALF reflects
growing evidence of balanced haemostasis in severe liver disease. Prophylactic therapeutic hypothermia is
no longer recommended for neuroprotection. In cases not suitable for liver transplantation, high-volume
plasma exchange (HVP) has potential benefit, although further research on the optimal timing and dosing is
needed. Although sepsis remains an important complication in ALF, the use of prophylactic antimicrobials
is being questioned in the era of emerging bacterial resistance.
Summary
ICU management of ALF has improved such that liver transplantation is not required in some cases. HVP
has emerged as a potential therapy for patients who may not be good liver transplantation candidates.
Nevertheless in suitable patients with poor prognosis liver transplantation remains the optimal therapy.
Keywords
acute liver failure, fulminant hepatic failure, hepatic encephalopathy, intensive care management, liver
transplantation

INTRODUCTION (HAV)-related ALF [6]. Other causes are rarer and

Acute liver failure (ALF) is a rare syndrome, character- described in Table 1 and may require specialist inves-
ized by acute derangement of liver biochemistry tigations. Recent analysis of long-term outcomes has
(without underlying chronic liver disease) with jaun- suggested that women are at higher risk for develop-
&

dice, coagulopathy [International Normalised Ratio ing ALF for many causes [4 ], particularly, DILI-ALF
(INR) > 1.5] and altered level of consciousness from potentially because of different drug metabolism and
&

hepatic encephalopathy [1]. ALF leads often to a
severe and rapidly progressive multiorgan failure with
unpredictable complications. ALF is further stratified
into hyperacute, acute and sub-acute liver failure
dependent on the time interval between develop-
ment of jaundice and progression to encephalopathy
(J-E period) of 1, 2–4 and 5–12 weeks, respectively [2].
For paracetamol (acetaminophen or APAP)-ALF,
where jaundice develops later, the interval between
the first presentation of symptoms to development of
hepatic encephalopathy is used [3].
The most frequent cause of ALF in Europe and
North America is drug-induced liver injury (DILI),
&
particularly from APAP overdose [3,4 ]. The inci-
dence of virally induced disease has dramatically
declined in Europe and North America [3] whereas
worldwide hepatitis A, E and B remain the common-
est cause of ALF [5]. Vaccination programs dramati-
cally reduced the incidence of hepatitis A virus
a greater use of hepatotoxic medications [4 ].
Urgent decision-making for emergency liver
transplantation, is crucial for those with advanced
disease [7], although only 8% of all transplants have
ALF as primary indication. In those not trans-
planted, a progressive rise in hospital survival over
time is now evident, rising from 17% in 1973–1978
to 48% in 2004–2008 [8]. It has recently been
reported that spontaneous survivors may have a
better long-term outcome compared with patients
Liver Intensive Therapy Unit, Institute of Liver Studies, King’s College
Hospital, Denmark Hill, London, UK
Correspondence to Mark J.W. McPhail, Senior Lecturer & Honorary
Consultant in Liver Critical Care & Hepatology, Institute of Liver Studies,
3rd floor Cheyne Wing, Kings College Hospital, Denmark Hill, London
SE5 9RS, UK. E-mail: mark.mcphail@kcl.ac.uk
Curr Opin Crit Care 2019, 25:157–164
DOI:10.1097/MCC.0000000000000583

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Gastrointestinal system
KEY POINTS
 The epidemiological trend in ALF is of improving
prognosis and reduced rates of intracranial
hypertension; female patients may have a more severe
clinical course.
 High-volume plasmapheresis can improve prognosis in
patients not undergoing liver transplantation but optimal
modalities and timing remain unknown.
 Although sepsis is an important, life-threatening
complication, universal antimicrobial prophylaxis is
now in question and the most high-risk groups
need redefining.
 Prophylactic hypothermia for all patients is no longer
recommended as standard management against
intracranial hypertension.
treated with emergency liver transplantation [9]
questioning the supremacy of liver transplantation
compared with medical management of poor
prognosis ALF.
Thus, intensive care management remain cru-
cial for patients affected by ALF and we discuss
current recommendations and latest developments.
ASSESSMENT AND GENERAL ICU
MANAGEMENT
The clinical history, physical findings of jaundice
and altered mental status, together with laboratory
abnormalities (coagulopathy, exceedingly elevated
Table 1. Nonsurgical treatment based on cause of acute liver failure
Cause
Acetaminophen
Mushroom (Amanita) poisoning
Drug-induced liver injury
Hepatitis B
HSV or VZV hepatitis
Wilson disease
HELLP, pregnancy-related
Budd–Chiari syndrome
CMV, cytomegalovirus; DRESS, Drug Rash with Eosinophilia and Systemic Symptoms; HELLP, Haemolysis, Elevated Liver enzymes, Low Platelet count; HSV, herpes
simplex virus; NAC, N-acetylcysteine; TIPSS, Transjugular Intrahepatic PortoSystemic Shunt; VZV, varicella zoster virus.
158 www.co-criticalcare.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
aminotransferase levels, variable hyperbilrubinae-
mia and lactic acidosis) are fundamental to make
the diagnosis [10]. Abdominal imaging, ultrasound
with Doppler or computed tomography (CT), can
provide important information regarding the
chronicity or cause of liver disease [10].
Returning to premorbid hepatic function and
preventing the development of complications are
the aim of ICU organ-system support [7]. Although
in some cases, treatment can be tailored according
to the cause with additional specific measures aimed
at identification and removal or amelioration of the
insult that caused hepatic injury (see Table 1), the
general ICU management closely follow the modern
management of sepsis and acute brain injury (see
Table 2).
N-acetylcysteine (NAC) is currently used to pre-
vent hepatic damage and promote regeneration
& &
[11 ,12] in both APAP and non-APAP ALF [11 ].
Patients with drug-induced ALF showed improved
outcome compared with other causes. NAC is well
tolerated and decreases encephalopathy, hospital
stay, ICU admission and failure of other organs
& &
[11 ,13 ]. An older meta-analysis failed to demon-
strate an improvement of the overall survival.
The insertion of a nasogastric tube allows gastric
decompression and facilitates enteral feeding. Gas-
trointestinal prophylaxis with H2 blockers or proton
pump inhibitors is recommended [14]. The optimal
timing for initiation of enteral feeding, particularly
with early severe hyperammonaemia, is not known.
Renal replacement therapy is used not only for
standard reasons associated with acute kidney injury
Treatment
N-acetylcysteine (NAC)
Silibinin
Penicillin G
Discontinue offending agent
Consider NAC
Steroids only if drug reaction with eosinophilia or systemic symptoms (DRESS syndrome)
or positive autoimmune hepatitis features
Nucleoside analogues (e.g. Entecavir, Tenofovir)
Acyclovir, Valacyclovir
Continuous hemofiltration
Copper chelation
Plasmapheresis
Delivery, supporting care
Anticoagulation
Revascularization (angioplasty, stent)
TIPSS
Volume 25  Number 2  April 2019
 Update on the management of acute liver failure Trovato et al.
Table 2. Organ specific general ICU measures in acute liver failure
Organ system and common conditions
Cardiovascular system
Hypotension
Vasodilatation
Low cardiac output and right ventricular failure
Respiratory system
Risk of aspiration
ARDS
Metabolic and renal system
Hypoglycaemia
Hyponatremia
Renal dysfunction, lactic acidosis, hyperammonaemia
Central nervous system
Progressive encephalopathy
Hematologic system
Coagulopathy
Immunologic system
High risk of sepsis
ARDS, acute respiratory distress syndrome; ICP, intra-cranial pressure; VV-ECMO, veno-venous extracorporeal membrane oxygenation.
but also for metabolic and neurological support for
lactate and ammonia clearance as described below.
HAEMODYNAMIC SUPPORT
Mortality in ALF is usually caused by multiorgan
dysfunction syndrome, sepsis and, with reducing
&
incidence, cerebral oedema [11 ]. The haemody-
namic profile of distributive shock is common in
ALF and similar to sepsis, with systemic vasodilation
resulting in low systemic resistance [14]. Moreover,
patients with ALF are at risk of hypovolaemia
because of poor oral intake and vomiting and
decrease in effective circulating blood volume.
Thus, maintaining effective circulating volume,
mainly with crystalloids, is required to preserve
kidney and brain perfusion [10]. If hypotension
persists, treatment with vasopressors is required
(noradrenaline being preferred), with or without
adjunctive use of vasopressin or vasopressin ana-
logues. Arterial pressure monitoring should be
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Specific elements of care
Correction of volume depletion
Vasopressors
Inotropic support
Early tracheal intubation for depressed level of consciousness
Lung-protective ventilatory strategies
Avoid hypercapnia in high-grade hepatic encephalopathy
VV-ECMO recently described
Maintain normoglycemia
Active fluid management/hypertonic saline
Renal replacement therapy
Endotracheal intubation for high grade hepatic encephalopathy
Elevation of the head of the bed to 15–308
Minimizing painful stimuli including suctioning.
Treatment of sepsis
Aim PaCO2 34–38 mmHg;
Maintain serum sodium 145–150 mmol/l
High-volume hemofiltration
Bolus osmotherapy for ICP surges
No routine correction of coagulation abnormalities, Only for
significant invasive procedures (e.g. liver transplant)
Antibiotic prophylaxis
Antifungal prophylaxis (in high-risk cases)
considered and mean arterial pressure should be
maintained above 75 mmHg particularly in high-
grade hepatic encephalopathy [3]. Hyperlactatemia
is a common finding and, at least initially, is proba-
bly a consequence of volume depletion, and
responds to volume loading. Its persistence is asso-
ciated with poor prognosis. Early echocardiography
rules out low flow states contributing to hepatic
hypoxia and allows cardiac risk stratification for
liver transplantation.
Relative adrenal insufficiency may be present in
patients with cardiovascular instability and is asso-
ciated with increased mortality, but whether sup-
plemental corticosteroids improve survival is
unclear [12,15,16]. Hydrocortisone is often empiri-
cally included in the management of these patients
on the basis of previous results in septic shock
[17,18] and difficulty in interpreting SynACTHen
test. Massive hepatic necrosis triggers an innate
immune response, with inflammatory cell recruit-
ment and pro-inflammatory cytokines production,
www.co-criticalcare.com 159
Gastrointestinal system
which exacerbates the initial liver injury [5]. The risk
of increasing the incidence of infection has been
cited as a rationale to avoid corticosteroids in this
patient population but is not borne in recent evi-
dence [15,16] with some authors suggesting faster
disease resolution with corticosteroids without
increasing infective complications [5].
RESPIRATORY SUPPORT
The prevalence of lung injury is relatively low in
acute liver failure, where 21% fulfilled acute respi-
ratory distress syndrome criteria in one series, and
appeared to have a limited impact on outcome [19].
Nevertheless, endotracheal intubation and sedation
are recommended in patients with progression to
agitation or coma, in order to better control oxygen
and carbon dioxide levels, prevent aspiration pneu-
monitis, and facilitate general care [12]. Sustained
hyperventilation should be avoided [12], to avoid
cerebral vasoconstriction [14] and in contrast to the
management of acute respiratory distress syndrome
permissive hypercapnia is contraindicated.
NEUROLOGICAL MANAGEMENT
One of the most feared complications of hepatic
encephalopathy is the progression from cerebral
oedema towards intracranial hypertension (ICH),
with the risk of herniation and death. The incidence
of patients developing ICH has decreased, from 76%
in the 1980s to 20% more recently [8] although
some degree of cerebral oedema is inevitable.
The comprehensive package of care underlying
this improvement includes airway support, sedation,
targeting PaCO2 levels between 30 and 45 mmHg,
elevation of the head of the bed to 15–308 and
minimizing painful stimuli (e.g. suctioning). Meta-
bolic aims are to maintain serum sodium between 145
and 150 mmol/l and normoglycemia [12]. Induction
of moderate hypothermia targeting core body tem-
perature of 348 C, aimed to decrease cerebral meta-
bolic activity has no clinical benefit over a target
temperature of 36 8C and on the basis of a negative
randomized controlled trial is now not recommended
&&
prophylactically [20 ]. It remains a potential bridge
to transplant in patients with uncontrolled ICH [21].
Rescue measures include mannitol bolus, hyper-
tonic saline, seizure treatment, short-term hyper-
ventilation for maintaining pCO2 level in the
range of 25 and 30 mmHg [10] and rescue therapy,
such as indomethacin and thiopentone [12].
The use of invasive intra-cranial pressure (ICP)
monitoring is rapidly decreasing. Although it is
considered the gold standard allowing accurate
and timely measurement [22,23], invasive ICP
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monitoring was historically associated with hemor-
rhagic complications. In fact, the risk of reported
intracranial haemorrhage is decreasing and ranges
between 3 and 15%, depending on the degree of
invasiveness used as a monitoring method (epidural
< intraparenchymal < subdural) [22,24,25].
Noninvasive ultrasonographic techniques are of
widening interest. Optic nerve sheath diameter
measurement is promising [26], although neither
this technique nor middle cerebral artery pulsatility
index on transcranial Doppler reliably detected con-
current ICP elevation [27]. Estimation of ICP from
transcranial Doppler flow velocities using the esti-
mated cerebral perfusion pressure technique is,
however, associated with concurrent ICP elevation
with AUC of 0.90 [27].
The severity and prognostic implications of
developing hepatic encephalopathy are reflected
in a recent Japanese study attempting to define a
probability score to better identify patients with
more than 20% probability of developing hepatic
encephalopathy that should potentially be trans-
ferred to a tertiary transplant centre [28].
Ammonia level more than 100 mmol/l predicts
the onset of severe hepatic encephalopathy with
70% accuracy and a level more than 200 mmol/l
correlates with development of ICH [29]. There is
a correlation between the level of ammonia on
admission and risk of neurological mortality
&&
[30 ]. Thus, ammonia lowering remains a therapeu-
tic goal. Lactulose and Rifaximin, used in chronic
liver patients, have no proven value in ALF patients.
Furthermore, lactulose might precipitate an
increased risk for ileus and bowel dilatation [3]. L-
ornithine L-aspartate (LOLA) does not improve sur-
vival in ALF patients [31] but may lower circulating
ammonia as may L-orinithine phenylacetate [32].
Optimal ammonia control is by continuous renal
&&
replacement therapy (CRRT) [30 ]. Ammonia clear-
ance is closely correlated with ultrafiltration rate
[33], even if no association between CRRT intensity
and mortality has been demonstrated [34,35] until
recent evidence in a large cohort from the USALFSG
&&
[30 ]. Patients with ALF and hyperammonaemia,
especially those at greater risk for cerebral oedema
and intracranial hypertension should be considered
&&
for early CRRT [30 ], and IRRT should be avoided in
these patients because of the lack of association with
ammonia clearance and the suggestion that IRRT
may in fact be detrimental to survival.
MANAGEMENT OF COAGULOPATHY
Both bleeding and thrombosis can complicate the
course of ALF patients [36]. The apparent lack of a
high risk of haemostasis-related bleeding seems
Volume 25  Number 2  April 2019
 Update on the management of acute liver failure Trovato et al.
because of the parallel decline in pro-haemostatic
and antihaemostatic factors and has led to the con-
cept of ‘rebalanced haemostasis’ [36].
Few bleeding complications in patients with ALF
are major or even clinically significant and,
although postprocedural bleeding complications
remain a significant concern for clinicians, data
&&
suggest that they are rare [37 ]. Moreover bleeding
complications were the proximate cause of death in
only 5% of cases mainly for spontaneous or post-
procedural intracranial haemorrhage (related to ICP
&&
monitor placement) [37 ]. The same study showed
an association between low platelet count and
&&
bleeding [37 ] but failed to show similar results
&&
for INR [37 ].
In addition to the lack of clinical benefit, admin-
istering prophylactic blood products may have
important adverse effects, like circulatory overload
and transfusion reaction [36]. Conversely, in case of
active bleeding, likely related to defective haemo-
stasis, resuscitation with platelets, fibrinogen con-
centrate or cryoprecipitate, and/or FFP is indicated,
which may be guided by global haemostasis assays,
such as viscoelastic tests [36].
SEPSIS AND ANTIMICROBIAL USE
Infection is a common late complication of ALF and
a leading cause of mortality [38]. ALF causes modu-
lation of several important inflammatory pathways,
affecting the function of circulating monocytes and
hepatic macrophages, as well as impaired bacteri-
cidal function of circulating neutrophils and com-
plement deficiency [39,40].
The most common sources of infection are the
respiratory and urinary tracts and bacteraemia
[38,41]. Although earlier studies demonstrate a
majority (56–70%) of Gram-positive bacteria infec-
tions [42,43]; more recent epidemiological data
show that 17% to over 50% of infections are
Gram-negative bacteria-related and 35–56% to
Gram-positive bacteria [44–46]. Bacterial infections
are most common but fungal infections have been
reported in up to one-third of the patients [38] in
early studies and between 4 and 14% more recently
[44–46], predominantly candidiasis [45,47].
Development of infection in ALF patients has
prognostic implications [45,46] with mortality rate
increasing to around 60% [41,48,49]. Uncontrolled
sepsis might complicate or impede liver transplan-
tation [38].
Antimicrobial prophylaxis is still debatable con-
sidering the uncertainty of the prognostic value for the
individual patients as well as wider considerations
regarding emergence of resistant organisms. Although
early studies suggested a reduced rate of infection
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following the introduction of prophylactic antibiotics
[43], later studies have questioned the survival benefit
or the likelihood of patients to have positive cultures
[46]. Practise is not consistent with prophylaxis used
between 39 and 94% of cases [22,46], with greater use
in ICUs and tertiary centers [50]. The use of prophy-
lactic antifungals is similarly debated [50]. European
Association of the Study of the Liver (EASL) guidelines
recommend empirical broad spectrum antimicrobial
treatment for ALF patients with systemic inflamatory
response syndrome, refractory hypotension or wors-
ening hepatic encephalopathy; as well as patients
listed for super-urgent liver transplantation [3]. Anti-
fungals should be considered in a deteriorating
patient, especially one not responsive to antibiotic
treatment. Generalizing from the chronic liver patient
population, b D Glucan (BDG) levels and Galacto-
mannan index may be useful markers to guide anti-
fungal therapy in patients at high risk [51].
EXTACORPOREAL SUPPORT
Only high-volume plasma exchange has been
shown to improve transplant-free survival in
&&
patients with ALF [52 ] with no proven benefit in
those who underwent liver transplantation. This is
attributable to attenuation of innate immune acti-
vation and amelioration of multiorgan dysfunction
as both monocyte and neutrophil-derived produc-
tion of pro-inflammatory mediators was markedly
&&
attenuated following HVP [52 ].
The combination of plasma exchange and hae-
modiafiltration (HDF) has been described but is not
used widely. The rationale is that haemodialysis
removes low-molecular-weight substances, includ-
ing ammonia, and haemofiltration removes middle-
molecular-weight substances, including proinflam-
matory cytokines [53]. In general, HVP appears
promising and its role and indications require
refinement to maximise individual patient benefit.
PROGNOSIS AND LIVER
TRANSPLANTATION
Predicting mortality in ALF is a cornerstone of the
decision to list patients for emergency liver trans-
plantation. The most widespread in use are King’s
College Criteria (KCC) [54,55]. Due to the reduced
prevalence of viral hepatitis in the original King’s
cohort or concerns over the low sensitivity of KCC,
other criteria are also in use worldwide [56] (Table 3).
Novel scoring systems designed to improve on KCC
[57] have been developed for APAP ALF (using
advanced statistical methods) and for ALF related
to HAV infection [58]. Although the original cohorts
used to derive the KCC remain some of the largest
www.co-criticalcare.com 161
Gastrointestinal system

Table 3. The primary prognostic scores in present use (King’s College Criteria/Clichy/ Model for End-stage Liver Disease) or
under consideration (others) in acute liver failure
Score Variables considered References

King’s College Criteria APAP: O’Grady et al. [54]

Arterial pH < 7.3 after resuscitation and more than Bernal et al. [55]
24 h since ingestion
or Lactate >3.5 mmol/l
or ALL of below:
INR >6.5
Creatinine 3.5 mg/dl or >300 mmol/l
Hepatic encephalopathy grades III and IV
Non-APAP:
INR >6.5 or three out of five following criteria:
Cause: indeterminate cause hepatitis, drug-induced hepatitis
Age less than 10 years or more than 40 years
Interval jaundice-encephalopathy >7 days
Bilirubin >300 mol/l
INR >3.5
Beaujon-Paul Brousse criteria (Clichy) Confusion or coma (hepatic encephalopathy stage 3 or 4) Bismuth et al. [66]
Factor V <20% of normal if age <30 year or
Factor V <30% if age >30-year
Model for End-stage Liver Creatinine Wiesner et al. [67]
Disease (MELD) and MELD-Na Bilirubin Biggins et al. [68]
INR
Sodium
US-ALF Study Group Index Coma Grade Koch et al. [59]
Bilirubin Rutherford et al. [69]
INR
Phosphorus (3.7)
log10M-30
Dynamic risk score for APAP ALF Age Bernal et al. [57]
Cardiovascular failure
GCS
pH
Creatinine
INR
Lactate

used for prognostic score development in ALF, the
USALFSG has developed several prognostic indices
from multicentre data, which have potentially use-
ful accuracy, although they require external valida-
tion [59].
Over the last four decades, there has been a
dramatic improvement in survival of patients with
ALF, from less than 20% in the 1970s to over 60% in
the last decade in large part because of emergency
liver transplantation [8]. Although survival rates for
emergency liver transplantation were initially
lower, there has been significant improvement
and nowadays they are becoming closer to those
of elective liver transplantation. Overall, the post-
liver transplantation survival for ALF patients is
estimated at 80–90% 1-year survival, 70–80% 5-year
survival and 70% 10-year patient survival [60,61].
The corresponding graft survival rates are 79, 71,
66% for 1-year, 5-year and 10-year posttransplant,
respectively [60]. A higher mortality rate is seen
until 3 months but subsequently is parallel to that
of elective transplantation [60,62].
In the western world, whole, blood-group
matched, cadaveric grafts are used in the majority
of cases [60,62]. Given the high wait-list mortality
rate, the use of an extended criteria, such as reduced
size, steatotic, elderly, or ABO-incompatible may be
necessary for deteriorating recipients, given present
organ shortages [3].
Auxiliary liver transplantation involves the
placement of a partial liver graft beside the remaining
whole or partial native liver. This offers the possibility
of future withdrawal from immunosuppression, if
the native liver is able to regenerate sufficiently. Out-
comes are improving because of improved technical
experience and patient selection. In Europe, use of an
auxiliary graft is reported in 1–4% of cases [62].
Wherever deceased donor availability is poor,
adult living donor liver transplantation (LDLT) is
more commonly performed. LDLT shortens the

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 Update on the management of acute liver failure Trovato et al.
interval between listing and transplantation, lessens
the shortage of organs, and is the only option avail-
able in many countries. In experienced centres, the
success rate with LDLT in the context of ALF is
reported to be comparable with that of non-ALF
patients [63].
Contraindications to liver transplantation
include preclusive psychosocial background, severe
comorbidity [including malignancy or cardiac dys-
function as aetiological factors for ALF, uncon-
trolled sepsis and in some cases, severity of
multiorgan failure (particularly refractory hypoxae-
mia and requirement for multiple high-dose vaso-
pressors)]. Recent case series suggest that
venovenous extracorporeal membrane oxygenation
(VV ECMO) can be used to bridge patients to liver
transplantation or treat refractory hypoxaemia in
the peri-liver transplantation period [64,65]. Given
the previous dogma that patients with liver failure
are not suitable candidates for ECMO support, fur-
ther validation of these results is warranted to define
those patients most suitable.
CONCLUSION
Critical care management is central to the improve-
ments in mortality seen in patients with acute liver
failure. This therapy can bridge patients to liver
transplantation or to recovery. Plasma exchange
and other extracorporeal therapies are being utilized
and hold promise for future novel treatment para-
digms.
Acknowledgements
M.M. is grateful to the NIHR Biomedical Research Centre
at Guys and St Thomas NHS Foundation Trust for salary
and infrastructure support.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Bernal W, Wendon J. Acute liver failure. N Engl J Med 2013; 369:
2525–2534.
2. O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the
syndromes. Lancet 1993; 342:273–275.
3. Wendon J, et al., European Association for the Study of the Liver; Clinical
practice guidelines panel. EASL Clinical Practical Guidelines on the manage-
ment of acute (fulminant) liver failure. J Hepatol 2017; 66:1047–1081.
1070-5295 Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
4. Rubin JB, Hameed B, Gottfried M, et al. Acetaminophen-induced acute liver
& failure is more common and more severe in women. Clin Gastroenterol
Hepatol 2018; 16:936–946.
Female patients have a more severe clinical course, with more coingestions with
acetaminophen-induced ALF, differentially increasing their risk of high-grade
encephalopathy.
5. Fujiwara K, Yasui S, Haga Y, et al. Early combination therapy with corticos-
teroid and nucleoside analogue induces rapid resolution of inflammation in
acute liver failure due to transient hepatitis B virus infection. Intern Med 2018;
57:1543–1552.
6. Mendizabal M, Silva M. Acute liver failure: do the EASL guidelines address the
whole spectrum? J Hepatol 2017. [Epub ahead of print]
7. Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet 2010;
376:190–201.
8. Bernal W, Hyyrylainen A, Gera A, et al. Lessons from look-back in acute liver
failure? A single centre experience of 3300 patients. J Hepatol 2013;
59:74–80.
9. Putignano A, Figorilli F, Alabsawy E, et al. Long-term outcome in patients with
acute liver failure. Liver Int 2018; 38:2228–2238.
10. Brown SA, Axenfeld E, Stonesifer EG, et al. Current and prospective thera-
pies for acute liver failure. Dis Mon 2018; 64:493–522.
11. Nabi T, Nabi S, Rafiq N, Shah A. Role of N-acetylcysteine treatment in
& nonacetaminophen-induced acute liver failure: a prospective study. Saudi J
Gastroenterol 2017; 23:169–175.
Patients with drug-induced ALF showed improved outcome compared with other
causes. NAC is well tolerated and decreases encephalopathy, hospital stay, ICU
admission, and failure of other organs.
12. Joshi D, O’Grady J, Patel A, et al. Cerebral oedema is rare in acute-on-chronic
liver failure patients presenting with high-grade hepatic encephalopathy. Liver
Int 2013; 34:362–366.
13. Darweesh SK, Ibrahim MF, El-Tahawy MA. Effect of N-acetylcysteine on
& mortality and liver transplantation rate in non-acetaminophen-induced
acute liver failure: a multicenter study. Clin Drug Investig 2017;
37:473–482.
Patients with drug-induced ALF showed improved outcome compared with other
causes. NAC is safe and decreases encephalopathy, hospital stay, ICU admission,
and failure of other organs.
14. Rajaram P, Subramanian R. Management of acute liver failure in the intensive
care unit setting. Clin Liver Dis 2018; 22:403–408.
15. Karkhanis J, Verna EC, Chang MS, et al. Steroid use in acute liver failure.
Hepatology 2014; 59:612–621.
16. Yasui S, Fujiwara K, Haga Y, et al. Infectious complications, steroid use and
timing for emergency liver transplantation in acute liver failure: analysis in a
Japanese center. J Hepatobiliary Pancreat Sci 2016; 23:756–762.
17. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of
hydrocortisone and fludrocortisone on mortality in patients with septic shock.
JAMA 2002; 288:862–871.
18. Oppert M, Schindler R, Husung C, et al. Low-dose hydrocortisone improves
shock reversal and reduces cytokine levels in early hyperdynamic septic
shock. Crit Care Med 2005; 33:2457–2464.
19. Audimoolam VK, McPhail MJ, Wendon JA, et al. Lung injury and its prognostic
significance in acute liver failure. Crit Care Med 2014; 42:592–600.
20. Bernal W, Murphy N, Brown S, et al. A multicentre randomized controlled trial
&& of moderate hypothermia to prevent intracranial hypertension in acute liver
failure. J Hepatol 2016; 65:273–279.
Prophylactic hypothermia is no longer indicated on the basis of this large
randomized controlled trial.
21. Jalan R, Olde Damink SW, Deutz NE, et al. Moderate hypothermia in patients
with acute liver failure and uncontrolled intracranial hypertension. Gastro-
enterology 2004; 127:1338–1346.
22. Rajajee V, Fontana RJ, Courey AJ, Patil PG. Protocol based invasive intra-
cranial pressure monitoring in acute liver failure: feasibility, safety and impact
on management. Crit Care 2017; 21:178.
23. Raschke RA, Curry SC, Rempe S, et al. Results of a protocol for the
management of patients with fulminant liver failure. Crit Care Med 2008;
36:2244–2248.
24. Maloney PR, Mallory GW, Atkinson JL, et al. Intracranial pressure monitoring
in acute liver failure: institutional case series. Neurocrit Care 2016;
25:86–93.
25. Karvellas CJ, Fix OK, Battenhouse H, et al. Outcomes and complications of
intracranial pressure monitoring in acute liver failure: a retrospective cohort
study. Crit Care Med 2014; 42:1157–1167.
26. Dubourg J, Javouhey E, Geeraerts T, et al. Ultrasonography of optic nerve
sheath diameter for detection of raised intracranial pressure: a systematic
review and meta-analysis. Intensive Care Med 2011; 37:1059–1068.
27. Rajajee V, Williamson CA, Fontana RJ, et al. Noninvasive intracranial pressure
assessment in acute liver failure. Neurocrit Care 2018; 29:280–290.
28. Kakisaka K, Suzuki Y, Kataoka K, et al. Predictive formula of coma onset and
prothrombin time to distinguish patients who recover from acute liver injury. J
Gastroenterol Hepatol 2018; 33:277–282.
29. Bernal W, Hall C, Karvellas CJ, et al. Arterial ammonia and clinical risk factors
for encephalopathy and intracranial hypertension in acute liver failure. Hepa-
tology 2007; 46:1844–1852.
www.co-criticalcare.com 163
Gastrointestinal system
30. Cardoso FS, Gottfried M, Tujios S, et al. Continuous renal replacement
&& therapy is associated with reduced serum ammonia levels and mortality in
acute liver failure. Hepatology 2017. [Epub ahead of print]
This retrospective cohort study of patients enrolled in the United States ALF Study
Group (US-ALFSG) prospective registry showed a strong association between
CRRT use and reduction in serum ammonia level with improved 21-day poststudy
admission transplant-free survival.
31. Acharya SK, Bhatia V, Sreenivas V, et al. Efficacy of L-ornithine L-aspartate in
acute liver failure: a double-blind, randomized, placebo-controlled study.
Gastroenterology 2009; 136:2159–2168.
32. Stravitz RT, Gottfried M, Durkalski V, et al. Safety, tolerability, and pharma-
cokinetics of l-ornithine phenylacetate in patients with acute liver injury/failure
and hyperammonemia. Hepatology 2018; 67:1003–1013.
33. Slack AJ, Auzinger G, Willars C, et al. Ammonia clearance with haemofiltration
in adults with liver disease. Liver Int 2014; 34:42–48.
34. O’Brien Z, Cass A, Cole L, et al. Higher versus lower continuous renal
replacement therapy intensity in critically ill patients with liver dysfunction.
Blood Purif 2018; 45:36–43.
35. Fayad AI, Buamscha DG, Ciapponi A. Intensity of continuous renal replace-
ment therapy for acute kidney injury. Cochrane Database Syst Rev 2016;
10:CD010613.
36. Lisman T, Bernal W. Management of hemostatic disorders in patients with
advanced liver disease admitted to an intensive care unit. Transfus Med Rev
2017; 31:245–251.
37. Stravitz RT, Ellerbe C, Durkalski V, et al. Bleeding complications in acute liver
&& failure.; Acute Liver Failure Study Group Hepatology 2018; 67:1931–1942.
This retrospective cohort study of patients enrolled in the United States ALF Study
Group (US-ALFSG) prospective registry showed the decrease of the practice of
administering blood products between 1998 and 2015. Nevertheless, the inci-
dence of bleeding complications has remained stable over the same time frame.
38. Rolando N, Harvey F, Brahm J, et al. Prospective study of bacterial infection in
acute liver failure: an analysis of fifty patients. Hepatology 1990; 11:49–53.
39. Antoniades CG, Khamri W, Abeles RD, et al. Secretory leukocyte protease
inhibitor: a pivotal mediator of anti-inflammatory responses in acetaminophen-
induced acute liver failure. Hepatology 2014; 59:1564–1576.
40. Taylor NJ, Nishtala A, Manakkat Vijay GK, et al. Circulating neutrophil
dysfunction in acute liver failure. Hepatology 2013; 57:1142–1152.
41. Zider AD, Zopey R, Garg R, et al. Prognostic significance of infections in
critically ill adult patients with acute liver injury: a retrospective cohort study.
Liver Int 2016; 36:1143–1150.
42. Rolando N, Gimson A, Wade J, et al. Prospective controlled trial of selective
parenteral and enteral antimicrobial regimen in fulminant liver failure. Hepa-
tology 1993; 17:196–201.
43. Rolando N, Wade JJ, Stangou A, et al. Prospective study comparing the
efficacy of prophylactic parenteral antimicrobials, with or without enteral
decontamination, in patients with acute liver failure. Liver Transpl Surg
1996; 2:8–13.
44. Vaquero J, Polson J, Chung C, et al. Infection and the progression of hepatic
encephalopathy in acute liver failure. Gastroenterology 2003; 125:755–764.
45. Karvellas CJ, Pink F, McPhail M, et al. Predictors of bacteraemia and mortality
in patients with acute liver failure. Intensive Care Med 2009; 35:1390–1396.
46. Karvellas CJ, Cavazos J, Battenhouse H, et al., US Acute Liver Failure Study
Group. Effects of antimicrobial prophylaxis and blood stream infections in
patients with acute liver failure: a retrospective cohort study. Clin Gastro-
enterol Hepatol 2014; 12:1942.e1–1949.e1.
47. Rolando N, Harvey F, Brahm J, et al. Fungal infection: a common, unrecog-
nised complication of acute liver failure. J Hepatol 1991; 12:1–9.
48. Kumar R, Shalimar. Sharma H, et al. Persistent hyperammonemia is asso-
ciated with complications and poor outcomes in patients with acute liver
failure. Clin Gastroenterol Hepatol 2012; 10:925–931.
164 www.co-criticalcare.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
49. Shalimar. Kedia S, Sharma H, et al. Predictors of infection in viral-hepatitis
related acute liver failure. Scand J Gastroenterol 2017; 52:1413–1419.
50. Rabinowich L, Wendon J, Bernal W, Shibolet O. Clinical management of
acute liver failure: results of an international multicenter survey. World J
Gastroenterol 2016; 22:7595–7603.
51. Verma N, Singh S, Taneja S, et al. Invasive fungal infections amongst patients
with acute-on-chronic liver failure at high risk for fungal infections. Liver Int
2018. [Epub ahead of print]
52. Larsen FS, Schmidt LE, Bernsmeier C, et al. High-volume plasma exchange in
&& patients with acute liver failure: an open randomised controlled trial. J Hepatol
2016; 64:69–78.
High-volume plasmapheresis improves mortality and attenuates immune re-
sponses in patients with ALF in this multicentre study from Europe.
53. Fujiwara K, Yasui S, Yokosuka O, et al. A role of renal replacement therapy for
acute liver failure. Hepatology 2018; 68:1204.
54. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of
prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439–445.
55. Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early
predictor of outcome in paracetamol-induced acute liver failure: a cohort
study. Lancet 2002; 359:558–563.
56. Bismuth H, Samuel D, Gugenheim J, et al. Emergency liver transplantation for
fulminant hepatitis. Ann Intern Med 1987; 107:337–341.
57. Bernal W, Wang Y, Maggs J, et al. Development and validation of a dynamic
outcome prediction model for paracetamol-induced acute liver failure: a
cohort study. Lancet Gastroenterol Hepatol 2016; 1:217–225.
58. Kim JD, Cho EJ, Ahn C, et al. A novel model to predict 1-month risk of
transplant or death in hepatitis a-related acute liver failure. Hepatology 2018.
[Epub ahead of print]
59. Koch DG, Tillman H, Durkalski V, et al. Development of a model to predict
transplant-free survival of patients with acute liver failure. Clin Gastroenterol
Hepatol 2016; 14:1199.e2–1206.e2.
60. Sars C, Tranang M, Ericzon BG, Berglund E. Liver transplantation for acute
liver failure - a 30-year single center experience. Scand J Gastroenterol 2018;
53:876–882.
61. Germani G, Theocharidou E, Adam R, et al. Liver transplantation for acute liver
failure in Europe: outcomes over 20 years from the ELTR database. J Hepatol
2012; 57:288–296.
62. Koch DG, Speiser JL, Durkalski V, et al. The natural history of severe acute liver
injury. Am J Gastroenterol 2017; 112:1389–1396.
63. Yang HR, Thorat A, Jeng LB, et al. Living donor liver transplantation in acute
liver failure patients with grade IV encephalopathy: is deep hepatic coma still
an absolute contraindication? A successful single-center experience. Ann
Transplant 2018; 23:176–181.
64. Nandhabalan P, Loveridge R, Patel S, et al. Extracorporeal membrane
oxygenation and pediatric liver transplantation, ‘a step too far?’: results of
a single-center experience. Liver Transpl 2016; 22:1727–1733.
65. Auzinger G, Willars C, Loveridge R, et al. Extracorporeal membrane oxygenation
for refractory hypoxemia after liver transplantation in severe hepatopulmonary
syndrome: a solution with pitfalls. Liver Transpl 2014; 20:1141–1144.
66. Bismuth H, Samuel D, Castaing D, et al. Orthotopic liver transplantation in
fulminant and subfulminant hepatitis. The Paul Brousse experience. Ann Surg
1995; 222:109–119.
67. Wiesner R, Edwards E, Freeman R, et al., United Network for Organ Sharing
Liver Disease Severity Score Committee. Model for end-stage liver disease
(MELD) and allocation of donor livers. Gastroenterology 2003; 124:91–96.
68. Biggins SW, Kim WR, Terrault NA, et al. Evidence-based incorporation of serum
sodium concentration into MELD. Gastroenterology 2006; 130:1652–1660.
69. Rutherford A, King LY, Hynan LS, et al., ALF Study Group. Development of an
accurate index for predicting outcomes of patients with acute liver failure.
Gastroenterology 2012; 143:1237–1243.
Volume 25  Number 2  April 2019