REVIEW ARTICLE OLSON AND KARVELLAS

Critical Care Management of the Patient

With Cirrhosis Awaiting Liver
Transplant in the Intensive Care Unit
Jody C. Olson1 and Constantine J. Karvellas 2,3

1
Divisions of Critical Care Medicine and Hepatology, University of Kansas Medical Center, Kansas City, KS; and Department of
2
Critical Care Medicine and 3Division of Gastroenterology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton,
Alberta, Canada

Patients with cirrhosis who are awaiting liver transplantation (LT) are at high risk for developing critical illnesses. Current
liver allocation policies that dictate a “sickest first” approach coupled with a mismatch between need and availability of
organs result in longer wait times, and thus, patients are becoming increasingly ill while awaiting organ transplantation.
Even patients with well-compensated cirrhosis may suffer acute deterioration; the syndrome of acute-on-chronic liver fail-
ure (ACLF) results in multisystem organ dysfunction and a marked increase in associated short-term morbidity and mor-
tality. For patients on transplant waiting lists, the development of multisystem organ failure may eliminate candidacy for
transplant by virtue of being “too sick” to safely undergo transplantation surgery. The goals of intensive care management
of patients suffering ACLF are to rapidly recognize and treat inciting events (eg, infection and bleeding) and to aggres-
sively support failing organ systems to ensure that patients may successfully undergo LT. Management of the critically ill
ACLF patient awaiting transplantation is best accomplished by multidisciplinary teams with expertise in critical care and
transplant medicine. Such teams are well suited to address the needs of this unique patient population and to identify
patients who may be too ill to proceed to transplantation surgery. The focus of this review is to identify the common com-
plications of ACLF and to describe our approach management in critically ill patients awaiting LT in our centers.

Liver Transplantation 23 1465–1476 2017 AASLD.

Received April 26, 2017; accepted June 29, 2017.

Liver transplantation (LT) has revolutionized the
treatment of patients with advanced liver disease.
However, access to this lifesaving procedure is limited
because demand for organs far outpaces availability.
Current liver allocation policies dictate that patients
with the highest risk of short-term mortality receive
top priority; thus, patients awaiting LT are becoming
increasingly ill on LT waiting lists. Cirrhosis is a
progressive disease in the vast majority of cases, given
the natural history of liver failure; advancing liver dis-
ease frequently results in progressive multisystem organ
dysfunction which culminates in a requirement for
intensive care support in many patients (acute-on-
chronic liver failure [ACLF]). The focus of this review
is to highlight the common complications of cirrhosis
occurring in critically ill ACLF patients and our
approach to management in patients awaiting LT.

Abbreviations: ACLF, acute-on-chronic liver failure; AKI, acute kid-

ney injury; APACHE, acute physiology and chronic health evalua-
tion; ATN, acute tubular necrosis; CGRP, calcitonin gene–related
peptide; CKD, chronic kidney disease; CNS, central nervous system;
CO, cardiac output; CVP, central venous pressure; CVS, cardiovascu-
lar system; ECLS, extracorporeal liver support; ELAD, extracorpo-
real liver assist device; GIB, gastrointestinal bleeding; HE, hepatic
encephalopathy; HR, heart rate; HRS, hepatorenal syndrome; HVP,
high volume plasmapheresis; ICU, intensive care unit; INR, interna-
tional normalized ratio; IV, intravenously; LT, liver transplanta-
tion; MARS, molecular adsorbent recirculating system; N/A, not
assessed; NO, nitric oxide; NSBB, nonselective beta-blocker; PEG-
3350, polyethylene glycol; RAAS, renin angiotensin system;
ROTEM, thromboelastometry; RRT, renal replacement therapy;
SBP, spontaneous bacterial peritonitis; SC, subcutaneous route; sCr,
Cardiovascular
Abnormalities
Both circulatory and cardiac abnormalities may develop
in patients with cirrhosis (Fig. 1). Portal hypertension
induces progressive systemic and splanchnic vasodila-
tion mediated by nitric oxide (NO) and other vasoac-
tive molecules,(1) which in turn leads to a
hyperdynamic state. The hyperdynamic circulatory
state typical of cirrhosis includes a high cardiac output
(CO) with low systemic vascular resistance (SVR) and
REVIEW ARTICLE | 1465
OLSON AND KARVELLAS


decreased arterial blood pressure. Though the total
blood and plasma volume increases, “effective” central
blood volume decreases because of pooling within the
splanchnic vascular bed.(2) Low effective circulating
volume results in activation of the neurohormonal axis
with associated sodium and water retention and
increases in heart rate (HR). In compensated disease
and in stable patients, these compensatory mechanisms
are able to maintain appropriate end organ perfusion;
however, even small perturbations in this system may
result in significant hypotension.
serum creatinine; ScvO2, central venous saturation; SOFA, Sequen-
tial Organ Failure Assessment; SVR, systemic vascular resistance;
TAFI, thrombin-activated fibrinolysis inhibitor; TIPS, transjugular
intrahepatic portosystemic shunt; tPA, tissue plasminogen activator;
VWF, von Willebrand factor.
Address reprint requests to Constantine J. Karvellas, M.D., S.M.,
F.R.C.P.C., Department of Critical Care Medicine, Liver Unit,
Division of Gastroenterology, School of Public Health, University of
Alberta, Edmonton, AB, Canada. E-mail: dean.karvellas@ualberta.ca
Copyright V
C 2017 by the American Association for the Study of Liver
Diseases.
View this article online at wileyonlinelibrary.com.
DOI 10.1002/lt.24815
Potential conflict of interest: Nothing to report.
1466 | REVIEW ARTICLE
LIVER TRANSPLANTATION, November 2017
FIG. 1. Circulatory abnormali-
ties in cirrhosis. In advancing
liver disease, progressive fibrosis
and hepatocellular dysfunction
results in development of porto-
systemic shunting. Increasing
levels of vasodilators further
exacerbate circulatory abnormal-
ities leading to hyperdynamic
circulatory changes and the
development of cardiac dysfunc-
tion (cirrhotic cardiomyopathy).
These circulatory changes also
result in renal blood flow abnor-
malities and HRS.
In addition to the circulatory abnormalities present
in cirrhosis, both structural and functional cardiac
abnormalities occur in approximately 40%-50% of
patients with cirrhosis, which is termed cirrhotic car-
diomyopathy.(3) Cirrhotic cardiomyopathy is charac-
terized by both systolic and diastolic dysfunction and
presence of electrophysiological abnormalities such as
prolongation of the QT interval occurring in the
absence of other known cardiac disease.(4) When pre-
sent this cardiac dysfunction further impairs hemody-
namic status and may impact the patient’s ability to
tolerate surgical procedures and may also impact
prognosis.
In ACLF patients presenting to the intensive care
unit (ICU) with hypotension and concomitant organ
failure, the approach should be guided by a systematic
assessment of volume status and correction of hypoten-
sion in an effort to restore adequate end organ perfu-
sion. For the critically ill patient with cirrhosis who
experiences circulatory shock, arterial catheters are rec-
ommended for guidance of resuscitative efforts. Cen-
tral venous access is also recommended as both an aid
for assessment of hemodynamic status (eg, measure-
ment of central venous pressure [CVP]) and a route
for vasoactive medications. Assessment of volume sta-
tus in this patient population can be particularly chal-
lenging due to ascites and edema. Dynamic measures
of volume and circulatory function such as
LIVER TRANSPLANTATION, Vol. 23, No. 11, 2017
echocardiography, changes in CVP in response to fluid
challenge, and passive leg raise are likely superior in
assessing hemodynamic status as compared with static
measures.(5,6) Although noninvasive hemodynamic
assessment tools have gained increasing popularity in
the ICU, data from such devices must be interpreted
with caution because they have not been validated in
cirrhosis and in fact have failed to demonstrate accept-
able accuracy in patients undergoing LT.(7) The use of
pulmonary artery catheters may be of benefit in this
population as a guide to resuscitation in difficult cases
when pulmonary hypertension is present or in patients
in whom fluid management is critical, eg, patients with
concomitant respiratory failure.
Resuscitation endpoints have not been systemati-
cally studied in patients with cirrhosis. In critically ill
patients with cirrhosis with additional organ failures, it
is our recommendation that a goal mean arterial blood
pressure that ensures organ perfusion be achieved, typi-
cally 60-65 mm Hg.(8) No specific target for central
venous saturation (ScvO2) or lactate can be recom-
mended,(9) and again, trends are more instructive than
a single time point measurement. In patients who suf-
fer from impaired circulatory volume, volume expan-
sion with 0.9% NaCl, balanced salt solutions, or
concentrated albumin (25% 100 cc as needed) is
appropriate with fluid choice being guided by the
patient’s clinical status. For example, in patients with
hyperchloremic acidosis, usage of chloride-containing
solutions may exacerbate acid-base abnormalities and
should be minimized. Albumin has a proven benefit in
certain clinical situations including spontaneous bacte-
rial peritonitis (SBP), after large-volume paracentesis,
and in type 1 hepatorenal syndrome (HRS).(10) Con-
centrated albumin also provides significant volume
expansion while limiting additional sodium, chloride,
and water in edematous patients.
In patients with persistent shock after appropriate
correction of volume deficiencies, pharmacological
management is indicated. Norepinephrine is the rec-
ommended first-line agent because it is associated with
fewer adverse events.(11) Vasopressin or terlipressin
may be used as second-line agents and have demon-
strated improvement in hemodynamics in patients
with cirrhosis.(12,13) Adrenal insufficiency is common
in critically ill patients with cirrhosis and should be
considered in cases of refractory shock.(14,15) In
patients where adrenal insufficiency is suspected, it is
our practice to empirically administer hydrocortisone
200 mg intravenously (IV) in 4 divided doses.(15,16)
Nonselective beta-blockers (NSBBs) are routinely used
OLSON AND KARVELLAS
in patients with advanced liver disease as prophylaxis
against variceal bleeding. Studies have demonstrated a
deleterious effect of NSBBs in patients with refractory
ascites and SBP,(17-19) whereas other studies suggest a
protective effect of NSBBs in patients with ACLF.(20)
Currently, we recommend discontinuing NSBBs for
patients with cirrhosis admitted to the ICU with
shock, renal failure, or persistent hypotension.
The presence of hypotension and vasopressor usage
is not necessarily an absolute contraindication to pro-
ceeding with transplantation in a patient awaiting LT.
In our centers, we use a “room to move” principle
when determining when a patient may be “too ill” to
proceed to the operating suite. Depending on center
expertise, patients on vasopressor agents at low- or
mid-range doses and who have room for up-titration
may be considered for surgery after thoughtful evalua-
tion with the principle team members including sur-
geons, anesthesiology, and intensivists.
Pulmonary Disorders
Pulmonary complications in the ACLF patient can be
broadly categorized into 2 categories: acute respiratory
failure, eg, pneumonia, acute lung injury, or hepatic
hydrothorax; and respiratory complications that are a
direct consequence of cirrhosis, such as portopulmo-
nary hypertension and hepatopulmonary syndrome.
Decreased thoracic compliance occurs in the presence
of tense abdominal ascites, chest wall edema, and
hepatic hydrothorax and may complicate mechanical
ventilation.
At the present time, there are no studies that indi-
cate respiratory failure should be managed differently
in patients with cirrhosis, and we recommend typical
lung protective ventilation strategies using low tidal
volume ventilation and use of positive end-expiratory
pressure to maintain appropriate oxygenation.(21,22) In
patients with unexplained hypoxia and/or evidence of
pulmonary hypertension on echocardiography, diag-
nostic studies to evaluate for hepatopulmonary syn-
drome and portopulmonary hypertension should be
considered. These studies may include contrast echo-
cardiography, use of pulmonary artery catheterization,
and/or microaggregated albumin shunt studies.
Neurological Dysfunction
The most common etiology of neurological dysfunc-
tion in patients with cirrhosis is that of hepatic
REVIEW ARTICLE | 1467
OLSON AND KARVELLAS
encephalopathy (HE) and may often be exacerbated by
infections and electrolyte abnormalities,(23) which are
often present in the critically ill. The approach to neu-
rological dysfunction in the cirrhotic should be aimed
at treating possible precipitating factors and at evalua-
tion of the response to ammonia-lowering therapies.
In patients who fail to respond to standard treatments,
or in patients whose HE onset is particularly abrupt or
severe, brain imaging is indicated.(24) An electroen-
cephalogram may also be considered to exclude other
causes of altered mental status in patients who fail to
respond to standard therapy. Although we do not rec-
ommend routine measurement of ammonia levels in
critically ill patients with cirrhosis, serum ammonia
levels may be used to aid in the differentiation of HE
from other neurologic conditions. The finding of a
normal serum ammonia level should prompt a search
for alternative neurologic abnormalities.(25) Although
arterial blood samples are preferred for assessment of
ammonia levels in patients with acute liver failure,
venous samples are likely adequate in patients with
cirrhosis.(26,27)
For patients with advanced HE with a Glasgow
coma score of 8, endotracheal intubation is recom-
mended for airway protection. In patients who are
intubated only for depressed mental status, avoidance
of sedation is recommended. For patients who require
mechanical ventilation for respiratory failure, usage of
short-acting agents such as fentanyl (25-200 lg/hour)
or propofol (50-150 lg/kg/minute) should be consid-
ered. Avoidance of benzodiazepines is recommended
because these agents precipitate more pronounced neu-
rocognitive impairment in the patient with cirrhosis
population.(28)
Specific therapies for HE are used in conjunction
with concomitant treatment of possible precipitating fac-
tors, eg, gastrointestinal bleeding or infection. Lactulose
has long been the cornerstone of therapy for HE despite
large randomized trials. Typical dosing strategies include
20 g orally every hour until the first bowel movement
and then titrated to maintain 2-3 soft bowel movements
daily. In patients who cannot take lactulose by the oral
route, lactulose may be administered by nasogastric tube
or as a retention enema of 200 g/300 mL of solution. In
the ICU, titration to number of stools can be difficult,
particularly when rectal tubes are used; care must be
used to avoid profuse stool output as this may result in
significant electrolyte abnormalities and thus may
worsen encephalopathy. In addition, caution must be
used when administering lactulose in the critically ill
patient, and ileus and or bowel obstruction are
1468 | REVIEW ARTICLE
LIVER TRANSPLANTATION, November 2017
contraindications to oral administration. A recent study
comparing lactulose to polyethylene glycol (PEG-3350)
bowel irrigation solution demonstrated a shorter time to
improvement in HE and a trend toward shorter hospital
stay in the PEG-3350 group.(29) Although further
large-scale studies (preferentially in ICU patients) are
required, PEG-3350 has attractive qualities including
ease of use and lack of fermentation, which may decrease
risk of bowel distention and ileus.
Rifaximin, a minimally absorbed antibiotic, has
demonstrated efficacy in prevention of HE-related
events including hospitalizations.(30) A randomized,
double-blind, controlled study demonstrated that com-
pared with lactulose alone, lactulose plus rifaximin
resulted in a significant decrease in the primary end-
point of mortality (23.8% versus 49.1%; P < 0.05) and
a significant decrease in the secondary endpoint of
length of stay (5.8 versus 8.2 days; P 5 0.001).(31) It is
our practice to use rifaximin in our hospitalized
patients with HE dosed at 550 mg bid.
Renal Dysfunction
Acute kidney injury (AKI) is a relatively frequent com-
plication of cirrhosis, occurring in up to 50% of hospi-
talized patients.(32-36) Traditional diagnostic criteria
focused particular attention on HRS and its physiology
of renal vasoconstriction and splanchnic vasodilata-
tion(37) with criteria based on elevation in serum creati-
nine (sCr) > 50% over baseline with a value of >133
lmol/L (1.5 mg/dL). HRS is a consequence of intense
renal vasoconstriction leading to a reduction in renal
perfusion and glomerular filtration. The ability of the
kidney to excrete sodium and free water is also severely
impaired without histological changes accounting for
this renal impairment. Initial studies suggested that
irreversibility of HRS had a deleterious impact on
mortality.(38) However, subsequent studies have ques-
tioned these criteria as narrow and require a broader
look at AKI in cirrhosis.(36) Other causes of AKI
include hypovolemia/prerenal azotemia, intrinsic renal/
parenchymal disorders (acute tubular necrosis [ATN],
nephrotoxicity, interstitial nephritis, glomerulonephri-
tis/nephropathy), and obstructive nephropathy.
Although LT is the only definitive treatment for
HRS, it is clear that patients with AKI at the time of
LT have poorer outcomes than those who do not. Fur-
thermore, increased duration of renal dysfunction
(HRS or ATN) before LT is associated with poorer
post-LT renal recovery.(39) The main purpose of
LIVER TRANSPLANTATION, Vol. 23, No. 11, 2017
treatments investigated for HRS is to provide a bridge
to LT. To date, therapies that have been evaluated
include albumin, vasoconstrictor therapy, transjugular
intrahepatic portosystemic shunt (TIPS), and extracor-
poreal liver support (ECLS). Previous studies have
shown that albumin prevented type 1 HRS in SBP
patients with a typical dose of 1 g/kg (20%-25%) on
day 1, then 20-60 g/day thereafter.(40) Adding albumin
to other pharmacological therapies likely provides the
most benefit. Vasoconstrictor therapies have been rela-
tively well studied in the treatment of HRS and in par-
ticular, vasopressin analogues. The high prevalence of
V1 receptors in the splanchnic vasculature makes it
especially sensitive to the vasoconstrictive effect of
vasopressin analogues, and therefore it is an important
target for HRS therapy. Terlipressin has a strong affin-
ity toward the V1 receptors with a longer half-life and
can be dosed intermittently. Sanyal et al.(32) demon-
strated in patients with type 1 HRS comparing albu-
min versus terlipressin plus albumin that HRS reversal
occurred significantly more frequently in the terlipres-
sin group.(32) Terlipressin should be dosed progres-
sively, starting at a continuous infusion of 2.0 mg/day.
If sCr does not decrease by 30% in 3 days, the dose
should be doubled. In general, a patient not respond-
ing to 12 mg/day will not respond to higher doses.(41)
In patients who respond to terlipressin, treatment
should be continued until normalization of sCr (<1.5
mg/dL). Norepinephrine is a reasonable alternative to
terlipressin. A recent systematic review examined the
major vasoconstrictors available for HRS, focusing on
terlipressin and norepinephrine. In this review of 4
studies and a total of 154 patients, it was found that
terlipressin and norepinephrine appeared to be equiva-
lent in terms of HRS reversal, mortality at 30 days,
and recurrence of HRS. Notably, adverse events were
less frequent in patients who received norepinephrine
(0.01-0.3 lg/kg/minute).(42)
The role of intermittent or continuous renal replace-
ment therapy (RRT) in HRS is primarily as a bridge to
LT. Observational studies have shown that RRT is not
predictive of improved transplant-free survival. The
use of RRT in patients with HRS is likely only appro-
priate in the setting of a patient who is listed for LT or
has another indication for RRT (ie, uremia, acidosis,
hyperkalemia).(43) Exact timing of the initiation of
RRT, similar to the general critically ill population, is
controversial.(44)
In cirrhotic patients with AKI, the potential for
renal recovery is etiology dependent.(45) Prerenal azote-
mia (ie, diuretics, diarrhea) is usually reversible
OLSON AND KARVELLAS
following discontinuation of the precipitating cause.(46)
The severity of AKI associated with bacterial infection
depends on the resolution of the infection.(47) Etiology
of AKI also has a significant impact on patient and
renal outcomes after LT. A recent study from Nadim
et al. revealed that patient survival and renal outcomes
1 and 5 years after LT were significantly worse for
those with ATN.(39) The American Association for
the Study of Liver Diseases recommends the following
for consideration for a combined liver-kidney trans-
plant: (1) end-stage renal disease (acute HRS etiology
excluded) with cirrhosis; (2) liver failure with chronic
kidney disease (CKD) and glomerular filtration rate of
<30 mL/minute; (3) AKI or HRS with creatinine
2.0 mg/dL and dialysis for 8 weeks; or (4) liver fail-
ure with CKD and renal biopsy demonstrating >30%
glomerulosclerosis or >30% fibrosis.(48)
Hemostatic Disorders
Patients with cirrhosis are in the fragile continuum
between ineffective hemostasis and inappropriate
thrombosis due to decreased production of procoagu-
lant factors (II, V, VII, IX, X, XI),(49) and they often
demonstrate hyperfibrinolysis due to high endogenous
levels of tissue plasminogen activator (tPA) and
decreased thrombin-activated fibrinolysis inhibitor
(TAFI) levels (see Fig. 2).(50-52) Physiological condi-
tions may also disturb hemostatic balance including
hemodynamic instability,(50,53) endothelial dysfunc-
tion,(50) development of endogenous heparin-like sub-
stances due to infection,(50,53) and renal failure.(54) The
international normalized ratio (INR) is based on the
prothrombin time, which itself depends on the level of
procoagulant factors and does not account for deficien-
cies of the anticoagulation system (especially low pro-
tein C), which may result in a hypercoagulable state not
reflected in prolongation of the INR. Although pro-
longation may be an indirect marker of system instabil-
ity and carries prognostic value, it cannot be used to
predict clot formation in cirrhosis. Thrombocytopenia
is common in cirrhosis due to portal hypertension/
splenomegaly, decreased thrombopoietin production,
and possible immune mechanisms. Platelet adhesion
in vitro is normal despite thrombocytopenia due to
increased von Willebrand factor (VWF; decreased
ADAMTS-13).(55) Using thrombin (factor II) pro-
duction as a surrogate for activity of clot formation,
platelet counts exceeding 50 3 109/L have been shown
to be associated with adequate thrombin formation.
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OLSON AND KARVELLAS LIVER TRANSPLANTATION, November 2017



FIG. 2. Hemostatic changes in cirrhosis. Chart modified from Lisman and Porte(52) (2010).


Hence, it is a practical clinical target in the setting of
active bleeding or as prophylaxis.(56) Although there
are significant concerns about bleeding in patients with
cirrhosis, a restrictive transfusion target (7 mg/dL) was
not inferior to a liberal strategy (9 mg/dL) independent
of age and vascular complications and may have poten-
tial benefit.(57)
Viscoelastic tests offer a means of assessing the
altered activity of the procoagulant and anticoagulant
pathways as well as providing a means of recognizing
hyperfibrinolysis or premature clot dissolution.(58)
Limitations of viscoelastic tests include device avail-
ability and the need for skilled interpretation within
the clinical context. The tests are in vitro assays and do
not account for the in vivo contributions of the endo-
thelium and blood flow. Viscoelastic tests of whole
blood (thromboelastography, thromboelastometry
[ROTEM]) potentially are advantageous as they give a
more complete hemostatic picture. Using viscoelastic
tests assessment of clotting can be performed 10-20
minutes after initiation of the analysis; fibrinolysis
takes 30-60 minutes to detect. Viscoelastic testing sug-
gests that hypercoagulability is prevalent in liver
patients with cholestatic diseases, acute liver failure,
and nonalcoholic steatohepatitis.(59,60) Increased maxi-
mum amplitude appears to be most useful to assess
thrombosis risk.(61) The management of patients with
hypercoagulability on viscoelastic testing is not clear;
however, procoagulants and antifibrinolytics should be
used cautiously in these patients.
Increased risks of venous thromboembolic disease
(0.5%-2% absolute risks, higher in patients under 45
and with hypoalbuminemia) have been demonstrated
in patients with cirrhosis.(62,63) Rates of portal vein
thrombosis have been reported as approximately
8% per year in patients with cirrhosis awaiting LT
with improved outcomes (survival, less decompensa-
tion) at 1 year with anticoagulation.(64,65) Anticoagula-
tion demonstrates the most utility in patients with
more extensive mesenteric thrombosis (occlusive, mes-
enteric extension).(64,66) Low-molecular-weight hepa-
rin (eg, enoxaparin 1 mg/kg subcutaneous route [sc]

1470 | REVIEW ARTICLE

LIVER TRANSPLANTATION, Vol. 23, No. 11, 2017
bid) is likely the safest choice; however, it should be
considered that it has an increased clinical effect
despite decreased antithrombin III levels in patients
with cirrhosis.(67)
Standard doses (30 mL/kg) of fresh frozen plasma
rarely correct coagulopathy of cirrhosis.(55,68) Although
the optimal fibrinogen level is uncertain (normal levels
are 2-4.5 g/L), in bleeding patients guidelines from
various societies typically recommend fibrinogen levels
of >1 g/L.(69,70) More recent guidelines suggest higher
levels (>1.5-2.0 g/L) are beneficial in major trauma
with significant bleeding, a recommendation which
aligns with in vitro levels required for optimal clot for-
mation times on ROTEM.(71,72) Fibrinogen can be
supplemented with cryoprecipitate (1 unit per 5 kg
body weight IV) or fibrinogen concentrates (dose
based on body weight and serum fibrinogen level).
Patients with cirrhosis have increased mortality and
morbidity during surgery, mainly due to increased
bleeding.(73) There is no direct correlation between
single coagulation parameters and risk of bleeding;
severity of liver disease and presence of portal hyper-
tension(74) influence the outcome. In LT candidates,
studies have failed to define factors related to bleeding
with the exception of the collateral circulation due to
portal hypertension and previous abdominal surgery
along with CVP, ischemia time, prior abdominal sur-
gery, and retransplant.(75,76) We suggest maintaining
fibrinogen concentrates of >1.5 g/L during the periop-
erative period of LT. The use of novel therapies (pro-
thrombin complexes, antifibrinolytic therapies) should
be guided by viscoelastic testing during the periopera-
tive period.
Variceal Bleeding
Acute variceal hemorrhage from esophageal/gastric vari-
ces is a severe consequence of portal hypertension, and
yet these patients may do better than other subgroups of
ACLF patients.(77) Predictors of mortality in variceal
hemorrhage correlate with severity of hepatic dysfunc-
tion and multiorgan dysfunction (correlates with ACLF
grade) and hepatic venous pressure gradient.(78,79)
Although there is little data regarding protection for
endoscopy, we recommend early intubation in cirrhotic/
ACLF patients with concomitant HE, respiratory dis-
tress, or large-volume hematemesis (>500 mL blood)
prior to performing endoscopy. Terlipressin (0.5-2.0
mg IV q6hours) has been demonstrated to be associated
with decreased mortality in variceal hemorrhage.(80)
OLSON AND KARVELLAS
In the event of failed endoscopy, a balloon tamponade
device, such as the Sengstaken-Blakemore or Minnesota
tube may be used as a bridge to more definitive therapy
including repeat endoscopy or TIPS.(81) A recent pilot
study demonstrated that self-expandable, covered,
esophageal metal stents may potentially be more effec-
tive than balloon tamponade in this setting with fewer
adverse events.(82) Although TIPS has been shown to
achieve hemostasis in up to 90% of salvage patients,(83)
more recent data have shown that early TIPS (after first
variceal bleed) may be associated with decreased treat-
ment failure (3% versus 50%) and mortality (14%-39%)
at 1 year compared with endoscopic eradication and
NSBBs.(84) We recommend prophylactic antibiotics
given potential reduction in rates of rebleeding and bac-
terial infections.(85)
Infectious Disorders
In ACLF patients awaiting LT, 2 significant chal-
lenges are prevention of infection and therapy/implica-
tions of infection. Following an episode of
gastrointestinal bleeding, antibiotic prophylaxis is cur-
rently recommended(86) as it decreases the risk of
infection, rebleeding, and infection-related and all-
cause mortality.(85,87) Most studies evaluated 7 days of
antibiotic therapy, but in patients with rapid control of
bleeding and less severe liver disease, shorter-course
therapy may be acceptable. When administering anti-
biotic prophylaxis after gastrointestinal bleeding
(GIB), the majority of studies used norfloxacin 400 mg
orally twice daily or ceftriaxone 1 g IV daily.(85,88) In
patients with more advanced liver disease with at least
2 of the following—ascites, HE, jaundice, or severe
malnutrition—superior results were achieved with IV
ceftriaxone.(14,89) Primary SBP prophylaxis should be
considered in highly selected patients: ascitic fluid total
protein < 1.5 g/dL and AKI (sCr  1.2 mg/dL, blood
urea nitrogen  25 mg/dL, or serum Na  130 mEq/
L) or Child-Turcotte-Pugh  9 with serum bilirubin
 3 mg/dL. A meta-analysis confirmed improved out-
comes in patients receiving primary prophylaxis with a
decrease in serious infections, SBP, and mortality.(90)
However, development of resistant infections is the
major concern with this approach. Resistant infections
can occur in patients on SBP prophylaxis, after which
the ideal antibiotic prophylactic strategy is not known.
Regarding other forms of prophylaxis/prevention, it
has been demonstrated that universal decontamination
of patients, using twice daily intranasal mupirocin and
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OLSON AND KARVELLAS LIVER TRANSPLANTATION, November 2017

TABLE 1. Evidence for ECLS in ACLF

Study Patients, n Device Biochemical CVS CNS Survival
(104)
Mitzner et al. (2000) 13 MARS Yes Yes No Yes (38% versus 0% at 7 days)
Heemann et al.(102) (2002) 24 MARS Yes Yes Yes Yes (90% versus 55% at 30 days)
Sen et al.(108) (2004) 18 MARS Yes No Yes No (45% in both)
Laleman et al.(103) (2006) 18 MARS/Prometheus Yes No N/A N/A
Hassinien et al.(105) (2007) 70 MARS Yes NA Yes N/A
Kribben et al.(107) (2012) 143 Prometheus Yes NA N/A No effect on 28-/90-day survival
Ba~nares et al.(106) (2013) 189 MARS Yes NA Yes No effect on 28-day survival
VTI-208 (2015) 203 ELAD Yes No N/A (90-day survival, 59% versus 62%;
P 5 0.74)

NOTE: Biochemical improvements: Statistically significant reduction in bilirubin, bile acids, creatinine, and ammonia.

daily chlorhexidine baths, is associated with a statisti-
cally significant decrease in bloodstream infections.(91)
The best approach to prevent catheter-associated infec-
tions is to avoid unnecessary catheterizations and to
remove them when no longer necessary.(78) In patients
with longterm indwelling catheters, antibiotic-coated
catheters could be considered. Consider antibiotic-
impregnated catheters in patients where central access is
required for >5 days if a comprehensive strategy to
reduce the rate of central line–associated bloodstream
infections has been implemented without success.
Replacement of central lines in the absence of infection
is not recommended.(79)
Severe sepsis is a common complication of patients
with cirrhosis with acute decompensation due to mul-
tiple immunological deficits/derangements and in
some cases can preclude successful LT.(92) Given that
the rates of antimicrobial prophylaxis are increasing in
cirrhosis, increasing rates of ACLF patients are pre-
senting with septic shock bacteremia from gram-
negatives (50%-60%) and multidrug resistant patho-
gens.(93,94) If severe sepsis is suspected, a thorough
evaluation should be promptly followed by antibiotic
administration because each hour delay impairs out-
come.(95) In patients with clinical improvement within
48-72 hours and a known pathogen, immediate tailor-
ing of antibiotics is recommended. In patients without
clinical improvement, the use of empiric antifungal
therapy and computed tomography scan are war-
ranted.(96) ACLF patients are at higher risk for fungal
infections likely because of significant immunologic
impairment, increased intestinal permeability, frequent
use of corticosteroids, malnutrition, and performance
of invasive procedures.(97,98) In patients with multifocal
candida colonization with clinical risk factors for infec-
tion but who remain in stable condition, preemptive
therapy is not indicated. Initial therapy for candiduria
should include Foley catheter removal or exchange.
Antifungal therapy should be considered in critically ill
patients with cirrhosis with 2 positive cultures from
different sites, isolated positive blood culture, and in
septic patients without improvement for 48 hours.(99)
Consider echinocandins (micafungin 50-100 mg IV
daily; caspofungin 70 mg then 50 mg IV daily; anidu-
lafungin 200 mg then 100 mg IV daily) as first-line
therapy in this setting.(100) Antifungal prophylaxis (flu-
conazole 400 mg IV daily) may be used in ACLF
patients without clinical improvement in high-
prevalence areas or in those with multiple risk factors
for infection (corticosteroid use, prolonged microbial
use, central venous catheter, total parenteral nutrition,
high acute physiology and chronic health evaluation
(APACHE) score, RRT, or malnutrition), particularly
while awaiting LT.(101)
Artificial Liver Support
Artificial (nonbiological) ECLS devices aim to preserve
hepatic function and mitigate or limit the progression of
multiorgan failure while either hepatic recovery or liver
transplant occurs. Current artificial ECLS devices differ
primarily in selectivity of the membrane used; dialysis-
based techniques molecular adsorbent recirculating sys-
tem (MARS) combine RRT with albumin dialysis
(MARS) and a highly selective (<50 kDa) filter in con-
trast to high volume plasmapheresis [HVP]/plasma sep-
aration and filtration (Prometheus) techniques, which
are less selective (250 kDa). Bioartificial ECLS sys-
tems incorporate a bioreactor containing various forms
of hepatocytes to provide synthetic functions. A sum-
mary of key ECLS trials are shown in Table 1. Artificial
and bioartificial ECLS devices have demonstrated bio-
chemical improvement in ACLF patients in small stud-
ies(102-104) and in those patients with HE,(105) but their
effects have failed to correlate with survival benefit
in larger methodologically robust studies.(106,107)

1472 | REVIEW ARTICLE

LIVER TRANSPLANTATION, Vol. 23, No. 11, 2017
We cannot recommend the routine use of ECLS as
standard of care in ACLF patients as a bridge to trans-
plant at this time.
To Transplant or Not to
Transplant
Given the scarcity of organs and costs of prolonged
ICU support, being able to discriminate those ACLF
patients who will maximally benefit from LT following
ICU admission versus those where it would be futile is
important but remains a prognostic challenge. There-
fore, objective measures to score risk of death and
major morbidity based on accessible physiological and
laboratory values would be pragmatic to guide clinical
decision making for liver organ allocation and trans-
plantation among ACLF patients, but these are still
unavailable.(109) Model for End-Stage Liver Disease
has been validated for 3-month survival in patients
with cirrhosis (all etiologies) without transplant, but its
ability to prognosticate outcome with transplant in
ACLF is lacking.(110,111) Recently, Karvellas et al.
evaluated the Sequential Organ Failure Assessment
(SOFA) score in critically ill patients with cirrhosis
(ACLF) patients and concluded that although SOFA
differentiated between ACLF candidates who were
likely to receive LT from the ICU while on the waiting
list, it did not discriminate between good and poor
outcomes after LT.(112) This may reflect that LT cen-
ters are likely delisting patients thought to be “too sick”
for LT (selection bias), which may be appropriate.
Regardless, it is important to have frank discussions
with surrogate decision makers of ACLF patients
awaiting LT. Some patients may go on to be delisted
due to the severity of illness, and services such as pallia-
tive care appear to be underused in this setting.(113)
REFERENCES
1) Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of
chronic liver diseases: from the patient to the molecule. Hepa-
tology 2006;43:S121-S131.
2) Genecin P, Polio J, Groszmann RJ. Na restriction blunts
expansion of plasma volume and ameliorates hyperdynamic cir-
culation in portal hypertension. Am J Physiol 1990;259(pt 1):
G498-G503.
3) Møller S, Hove JD, Dixen U, Bendtsen F. New insights into
cirrhotic cardiomyopathy. Int J Cardiol 2013;167:1101-1108.
4) Møller S, Henriksen JH. Cirrhotic cardiomyopathy. J Hepatol
2010;53:179-190.
OLSON AND KARVELLAS
5) Monnet X, Teboul JL. Assessment of volume responsiveness dur-
ing mechanical ventilation: recent advances. Crit Care 2013;17:217.
6) McGowan JH, Cleland JG. Reliability of reporting left ventric-
ular systolic function by echocardiography: a systematic review
of 3 methods. Am Heart J 2003;146:388-397.
7) Biancofiore G, Critchley LA, Lee A, Yang XX, Bindi LM,
Esposito M et al. Evaluation of a new software version of the
FloTrac/Vigileo (version 3.02) and a comparison with previous
data in cirrhotic patients undergoing liver transplant surgery.
Anesth Analg 2011;113:515-522.
8) LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of
perfusion pressure on tissue perfusion in septic shock. Crit Care
Med 2000;28:2729-2732.
9) Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J,
Hofer C, et al. Consensus on circulatory shock and hemodynamic
monitoring. Task force of the European Society of Intensive Care
Medicine. Intensive Care Med 2014;40:1795-1815.
10) Ortega R, Ginès P, Uriz J, Cardenas A, Calahorra B, De Las
Heras D, et al. Terlipressin therapy with and without albumin
for patients with hepatorenal syndrome: results of a prospective,
nonrandomized study. Hepatology 2002;36(pt 1):941-948.
11) De Backer D, Biston P, Devriendt J, Madl C, Chochrad D,
Aldecoa C, et al.; for SOAP II Investigators. Comparison of
dopamine and norepinephrine in the treatment of shock. N
Engl J Med 2010;362:779-789.
12) O’Brien A, Clapp L, Singer M. Terlipressin for norepinephrine-
resistant septic shock. Lancet 2002;359:1209-1210.
13) Delmas A, Leone M, Rousseau S, Albanèse J, Martin C. Clini-
cal review: vasopressin and terlipressin in septic shock patients.
Crit Care 2005;9:212-222.
14) Fernandez J, Escorsell A, Zabalza M, Felipe V, Navasa M,
Mas A, et al. Adrenal insufficiency in patients with cirrhosis
and septic shock: effect of treatment with hydrocortisone on
survival. Hepatology 2006;44:1288-1295.
15) Tsai MH, Peng YS, Chen YC, Liu NJ, Ho YP, Fang JT, et al.
Adrenal insufficiency in patients with cirrhosis, severe sepsis
and septic shock. Hepatology 2006;43:673-681.
16) Annane D, Sebille V, Charpentier C, Bollaert PE, François B,
Korach JM, et al. Effect of treatment with low doses of hydro-
cortisone and fludrocortisone on mortality in patients with sep-
tic shock. JAMA 2002;288:862-871.
17) Mandorfer M, Bota S, Schwabl P, Bucsics T, Pfisterer N, Kruzik
M, et al. Nonselective beta blockers increase risk for hepatorenal
syndrome and death in patients with cirrhosis and spontaneous
bacterial peritonitis. Gastroenterology 2014;146:1680-1690.
18) Serste T, Melot C, Francoz C, Durand F, Rautou PE, Valla D,
et al. Deleterious effects of beta-blockers on survival in patients
with cirrhosis and refractory ascites. Hepatology 2010;52:1017-
1022.
19) Krag A, Bendtsen F, Henriksen JH, Møller S. Low cardiac out-
put predicts development of hepatorenal syndrome and survival
in patients with cirrhosis and ascites. Gut 2010;59:105-110.
20) Mookerjee RP, Pavesi M, Thomsen KL, Mehta G,
Macnaughtan J, Bendtsen F, et al.; for CANONIC Study
Investigators of the EASL-CLIF Consortium. Treatment with
non-selective beta blockers is associated with reduced severity of
systemic inflammation and improved survival of patients with
acute-on-chronic liver failure. J Hepatol 2016;64:574-582.
21) Brower RG, Matthay MA, Morris A, Schoenfeld D,
Thompson BT, Wheeler A; for Acute Respiratory Distress Syn-
drome Network. Ventilation with lower tidal volumes as com-
pared with traditional tidal volumes for acute lung injury and
the acute respiratory distress syndrome. N Engl J Med 2000;
342:1301-1308.
REVIEW ARTICLE | 1473
OLSON AND KARVELLAS
22) Plataki M, Hubmayr RD. The physical basis of ventilator-
induced lung injury. Expert Rev Respir Med;4:373-385.
23) Cordoba J, Mınguez B. Hepatic encephalopathy. Semin Liver
Dis 2008;28:70-80.
24) Nadim MK, Durand F, Kellum JA, Levitsky J, O’Leary JG,
Karvellas CJ, et al. Management of the critically ill patient with
cirrhosis: a multidisciplinary perspective. J Hepatol 2016;64:
717-735.
25) Cordoba J, Ventura-Cots M, Simon-Talero M, Amoros A,  ment and mortality in patients with cirrhosis and spontaneous
Pavesi M, Vilstrup H, et al.; for CANONIC Study Investi-
gators of EASL-CLIF Consortium. Characteristics, risk factors,
and mortality of cirrhotic patients hospitalized for hepatic
encephalopathy with and without acute-on-chronic liver failure
(ACLF). J Hepatol 2014;60:275-281.
26) Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P.
Cerebral herniation in patients with acute liver failure is corre-
lated with arterial ammonia concentration. Hepatology 1999;29:
648-653.
27) Ong JP, Aggarwal A, Krieger D, Easley KA, Karafa MT, Van
Lente F, et al. Correlation between ammonia levels and the
severity of hepatic encephalopathy. Am J Med 2003;114:188-
193.
28) Bakti G, Fisch HU, Karlaganis G, Minder C, Bircher J. Mech-
anism of the excessive sedative response of cirrhotics to benzo-
diazepines: model experiments with triazolam. Hepatology
1987;7:629-638.
29) Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs
polyethylene glycol 3350--electrolyte solution for treatment of
overt hepatic encephalopathy: the HELP randomized clinical
trial. JAMA Intern Med 2014;174:1727-1733.
30) Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy
CB, et al. Rifaximin treatment in hepatic encephalopathy. N
Engl J Med 2010;362:1071-1081.
31) Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R,
Sarin SK. A randomized, double-blind, controlled trial compar-
ing rifaximin plus lactulose with lactulose alone in treatment of
overt hepatic encephalopathy. Am J Gastroenterol 2013;108:
1458-1463.
32) Sanyal AJ, Boyer T, Garcia-Tsao G, Regenstein F, Rossaro L,
Appenrodt B, et al.; for Terlipressin Study Group. A random-
ized, prospective, double-blind, placebo-controlled trial of terli-
pressin for type 1 hepatorenal syndrome. Gastroenterology
2008;134:1360-1368.
33) Tsien CD, Rabie R, Wong F. Acute kidney injury in decom-
pensated cirrhosis. Gut 2013;62:131-137.
34) Barreto R, Fagundes C, Guevara M, Sola E, Pereira G,
Rodrıguez E, et al. Type-1 hepatorenal syndrome associated
with infections in cirrhosis: natural history, outcome of kidney
function, and survival. Hepatology 2014;59:1505-1513.
35) Piano S, Rosi S, Maresio G, Fasolato S, Cavallin M, Romano
A, et al. Evaluation of the Acute Kidney Injury Network criteria
in hospitalized patients with cirrhosis and ascites. J Hepatol
2013;59:482-489.
36) Wong F, O’Leary JG, Reddy KR, Patton H, Kamath PS,
Fallon MB, et al.; for North American Consortium for Study
of End-Stage Liver Disease. New consensus definition of acute
kidney injury accurately predicts 30-day mortality in patients
with cirrhosis and infection. Gastroenterology 2013;145:1280-
1288.
37) Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis,
prevention and treatment of hepatorenal syndrome in cirrhosis.
Gut 2007;56:1310-1318.
38) Moreau R, Durand F, Poynard T, Duhamel C, Cervoni JP,
Icha€ı P, et al. Terlipressin in patients with cirrhosis and type 1
1474 | REVIEW ARTICLE
LIVER TRANSPLANTATION, November 2017
hepatorenal syndrome: a retrospective multicenter study. Gastro-
enterology 2002;122:923-930.
39) Nadim MK, Genyk YS, Tokin C, Fieber J, Ananthapanyasut W,
Ye W, Selby R. Impact of the etiology of acute kidney injury on
outcomes following liver transplantation: acute tubular necrosis
versus hepatorenal syndrome. Liver Transpl 2012;18:539-548.
40) Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-
Arbol L, et al. Effect of intravenous albumin on renal impair-
bacterial peritonitis. N Engl J Med 1999;341:403-409.
41) Cavallin M, Piano S, Romano A, Fasolato S, Frigo AC,
Benetti G, et al. Terlipressin given by continuous intravenous
infusion versus intravenous boluses in the treatment of hepa-
torenal syndrome: a randomized controlled study. Hepatology
2016;63:983-992.
42) Nassar Junior AP, Farias AQ, D’ Albuquerque LA, Carrilho
FJ, Malbouisson LM. Terlipressin versus norepinephrine in the
treatment of hepatorenal syndrome: a systematic review and
meta-analysis. PloS One 2014;9:e107466.
43) Keller F, Heinze H, Jochimsen F, Passfall J, Schuppan D,
B€uttner P. Risk factors and outcome of 107 patients with
decompensated liver disease and acute renal failure (including
26 patients with hepatorenal syndrome): the role of hemodialy-
sis. Ren Fail 1995;17:135-146.
44) Karvellas CJ, Farhat MR, Sajjad I, Mogensen SS, Leung AA,
Wald R, Bagshaw SM. A comparison of early versus late initia-
tion of renal replacement therapy in critically ill patients with
acute kidney injury: a systematic review and meta-analysis. Crit
Care 2011;15:R72.
45) Arroyo V. Acute kidney injury (AKI) in cirrhosis: should we
change current definition and diagnostic criteria of renal failure
in cirrhosis? J Hepatol 2013;59:415-417.
46) Martın-Llahı M, Guevara M, Torre A, Fagundes C, Restuccia T,
Gilabert R, et al. Prognostic importance of the cause of renal failure
in patients with cirrhosis. Gastroenterology 2011;140:488-496.
47) Follo A, Llovet JM, Navasa M, Planas R, Forns X, Francitorra
A, et al. Renal impairment after spontaneous bacterial peritoni-
tis in cirrhosis: incidence, clinical course, predictive factors and
prognosis. Hepatology 1994;20:1495-1501.
48) Eason JD, Gonwa TA, Davis CL, Sung RS, Gerber D, Bloom RD.
Proceedings of Consensus Conference on Simultaneous Liver Kid-
ney Transplantation (SLK). Am J Transplant 2008;8:2243-2251.
49) Tripodi A, Primignani M, Chantarangkul V, Dell’Era A,
Clerici M, de Franchis R, et al. An imbalance of pro- vs anti-
coagulation factors in plasma from patients with cirrhosis. Gas-
troenterology 2009;137:2105-2111.
50) Caldwell SH, Hoffman M, Lisman T, Macik BG, Northup
PG, Reddy KR, et al.; for Coagulation in Liver Disease Group.
Coagulation disorders and hemostasis in liver disease:
pathophysiology and critical assessment of current management.
Hepatology 2006;44:1039-1046.
51) Colucci M, Binetti BM, Branca MG, Clerici C, Morelli A,
Semeraro N, Gresele P. Deficiency of thrombin activatable
fibrinolysis inhibitor in cirrhosis is associated with increased
plasma fibrinolysis. Hepatology 2003;38:230-237.
52) Lisman T, Porte RJ. Rebalanced hemostasis in patients with
liver disease: evidence and clinical consequences. Blood 2010;
116:878-885.
53) Montalto P, Vlachogiannakos J, Cox DJ, Pastacaldi S, Patch D,
Burroughs AK. Bacterial infection in cirrhosis impairs coagula-
tion by a heparin effect: a prospective study. J Hepatol 2002;37:
463-470.
54) Noris M, Remuzzi G. Uremic bleeding: closing the circle after
30 years of controversies? Blood 1999;94:2569-2574.
LIVER TRANSPLANTATION, Vol. 23, No. 11, 2017
55) Lisman T, Bongers TN, Adelmeijer J, Janssen HL, de Maat
MP, de Groot PG, Leebeek FW. Elevated levels of von Wille-
brand Factor in cirrhosis support platelet adhesion despite
reduced functional capacity. Hepatology 2006;44:53-61.
56) Tripodi A, Primignani M, Chantarangkul V, Clerici M,
Dell’Era A, Fabris F, et al. Thrombin generation in patients
with cirrhosis: the role of platelets. Hepatology 2006;44:440-
445.
57) Villanueva C, Colomo A, Bosch A, Concepcion M,
Hernandez-Gea V, Aracil C, et al. Transfusion strategies for
acute upper gastrointestinal bleeding. N Engl J Med 2013;368:
11-21.
58) Rijken DC, Kock EL, Guimar~aes AH, Talens S, Darwish
Murad S, Janssen HL, Leebeek FW. Evidence for an enhanced
fibrinolytic capacity in cirrhosis as measured with two different
global fibrinolysis tests. J Thromb Haemost 2012;10:2116-
2122.
59) Krzanicki D, Sugavanam A, Mallett S. Intraoperative hyperco-
agulability during liver transplantation as demonstrated by
thromboelastography. Liver Transpl 2013;19:852-861.
60) Ben-Ari Z, Panagou M, Patch D, Bates S, Osman E, Pasi J,
Burroughs A. Hypercoagulability in patients with primary bili-
ary cirrhosis and primary sclerosing cholangitis evaluated by
thrombelastography. J Hepatol 1997;26:554-559.
61) Hincker A, Feit J, Sladen RN, Wagener G. Rotational throm-
boelastometry predicts thromboembolic complications after
major non-cardiac surgery. Crit Care 2014;18:549.
62) Gulley D, Teal E, Suvannasankha A, Chalasani N,
Liangpunsakul S. Deep vein thrombosis and pulmonary embo-
lism in cirrhosis patients. Dig Dis Sci 2008;53:3012-3017.
63) Wu H, Nguyen GC. Liver cirrhosis is associated with venous
thromboembolism among hospitalized patients in a nationwide
US study. Clin Gastroenterol Hepatol 2010;8:800-805.
64) Francoz C, Belghiti J, Vilgrain V, Sommacale D, Paradis V,
Condat B, et al. Splanchnic vein thrombosis in candidates for
liver transplantation: usefulness of screening and anticoagula-
tion. Gut 2005;54:691-697.
65) Villa E, Camma C, Marietta M, Luongo M, Critelli R, Colopi
S, et al. Enoxaparin prevents portal vein thrombosis and liver
decompensation in patients with advanced cirrhosis. Gastroen-
terology 2012;143:1253-1260.
66) Englesbe MJ, Schaubel DE, Cai S, Guidinger MK, Merion
RM. Portal vein thrombosis and liver transplant survival benefit.
Liver Transpl 2010;16:999-1005.
67) Senzolo M, Rodriguez-Castro KI, Rossetto V, Radu C,
Gavasso S, Carraro P, et al. Increased anticoagulant response
to low-molecular-weight heparin in plasma from patients
with advanced cirrhosis. J Thromb Haemost 2012;10:1823-
1829.
68) Youssef WI, Salazar F, Dasarathy S, Beddow T, Mullen KD.
Role of fresh frozen plasma infusion in correction of coagulop-
athy of chronic liver disease: a dual phase study. Am J Gastro-
enterol 2003;98:1391-1394.
69) Nascimento B, Goodnough LT, Levy JH. Cryoprecipitate ther-
apy. Br J Anaesth 2014;113:922-934.
70) Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeu-
tic target for bleeding: a review of critical levels and replacement
therapy. Transfusion 2014;54:1389-1405.
71) Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J,
Fernandez-Mondejar E, et al. Management of bleeding and
coagulopathy following major trauma: an updated European
guideline. Crit Care 2013;17:R76.
72) Lang T, Johanning K, Metzler H, Piepenbrock S, Solomon C,
Rahe-Meyer N, Tanaka KA. The effects of fibrinogen levels on
OLSON AND KARVELLAS
thromboelastometric variables in the presence of thrombocyto-
penia. Anesth Analg 2009;108:751-758.
73) Friedman LS. The risk of surgery in patients with liver disease.
Hepatology 1999;29:1617-1623.
74) del Olmo JA, Flor-Lorente B, Flor-Civera B, Rodriguez F,
Serra MA, Escudero A, et al. Risk factors for nonhepatic sur-
gery in patients with cirrhosis. World J Surg 2003;27:647-652.
75) McCluskey SA, Karkouti K, Wijeysundera DN, Kakizawa K,
Ghannam M, Hamdy A, et al. Derivation of a risk index for
the prediction of massive blood transfusion in liver transplanta-
tion. Liver Transpl 2006;12:1584-1593.
76) Massicotte L, Denault AY, Beaulieu D, Thibeault L, Hevesi Z,
Nozza A, et al. Transfusion rate for 500 consecutive liver trans-
plantations: experience of one liver transplantation center.
Transplantation 2012;93:1276-1281.
77) McPhail MJ, Shawcross DL, Abeles RD, Chang A, Patel V,
Lee GH, et al. Increased survival for patients with cirrhosis and
organ failure in liver intensive care and validation of the chronic
liver failure-sequential organ failure scoring system. Clin Gas-
troenterol Hepatol 2015;13:1353-1360.
78) Carbonell N, Pauwels A, Serfaty L, Fourdan O, Levy VG,
Poupon R. Improved survival after variceal bleeding in patients
with cirrhosis over the past two decades. Hepatology 2004;40:
652-659.
79) Fortune BE, Garcia-Tsao G, Ciarleglio M, Deng Y, Fallon
MB, Sigal S, et al.; for Vapreotide Study Group. Child-Tur-
cotte-Pugh Class is best at stratifying risk in variceal hemor-
rhage: analysis of a US multicenter prospective study. J Clin
Gastroenterol 2016;in press.
80) Levacher S, Letoumelin P, Pateron D, Blaise M, Lapandry C,
Pourriat JL. Early administration of terlipressin plus glyceryl tri-
nitrate to control active upper gastrointestinal bleeding in cir-
rhotic patients. Lancet 1995;346:865-868.
81) Nadler J, Stankovic N, Uber A, Holmberg MJ, Sanchez LD,
Wolfe RE, et al. Outcomes in variceal hemorrhage following
the use of a balloon tamponade device. Am J Emerg Med
2017;35:1500-1502.
82) Escorsell A, Pavel O, Cardenas A, Morillas R, Llop E,
Villanueva C, et al.; for Variceal Bleeding Study Group. Esoph-
ageal balloon tamponade versus esophageal stent in controlling
acute refractory variceal bleeding: a multicenter randomized,
controlled trial. Hepatology 2016;63:1957-1967.
83) Azoulay D, Castaing D, Majno P, Saliba F, Icha€ı P, Smail A,
et al. Salvage transjugular intrahepatic portosystemic shunt for
uncontrolled variceal bleeding in patients with decompensated
cirrhosis. J Hepatol 2001;35:590-597.
84) Garcıa-Pagan JC, Caca K, Bureau C, Laleman W, Appenrodt
B, Luca A, et al.; for Early TIPS (Transjugular Intrahepatic
Portosystemic Shunt) Cooperative Study Group. Early use of
TIPS in patients with cirrhosis and variceal bleeding. N Engl J
Med 2010;362:2370-2379.
85) Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila F,
Soares-Weiser K, Mendez-Sanchez N, Gluud C, Uribe M.
Meta-analysis: antibiotic prophylaxis for cirrhotic patients with
upper gastrointestinal bleeding - an updated Cochrane review.
Aliment Pharmacol Ther 2011;34:509-518.
86) de Franchis R; for Baveno V Faculty. Revising consensus in
portal hypertension: report of the Baveno V consensus work-
shop on methodology of diagnosis and therapy in portal hyper-
tension. J Hepatol 2010;53:762-768.
87) Pauwels A, Mostefa-Kara N, Debenes B, Degoutte E, Levy
VG. Systemic antibiotic prophylaxis after gastrointestinal hem-
orrhage in cirrhotic patients with a high risk of infection. Hepa-
tology 1996;24:802-806.
REVIEW ARTICLE | 1475
OLSON AND KARVELLAS
88) Soriano G, Guarner C, Tomas A, Villanueva C, Torras X,
Gonzalez D, et al. Norfloxacin prevents bacterial infection in
cirrhotics with gastrointestinal hemorrhage. Gastroenterology
1992;103:1267-1272.
89) Wu CK, Wang JH, Lee CH, Wu KL, Tai WC, Lu SN, et al.
The outcome of prophylactic intravenous cefazolin and ceftriax-
one in cirrhotic patients at different clinical stages of disease
after endoscopic interventions for acute variceal hemorrhage.
PLoS One 2013;8:e61666.
90) Loomba R, Wesley R, Bain A, Csako G, Pucino F. Role of flu-
oroquinolones in the primary prophylaxis of spontaneous bacte-
rial peritonitis: meta-analysis. Clin Gastroenterol Hepatol 2009;
7:487-493.
91) Huang SS, Septimus E, Kleinman K, Moody J, Hickok J,
Avery TR, et al.; for CDC Prevention Epicenters Program;
AHRQ DECIDE Network and Healthcare-Associated Infec-
tions Program. Targeted versus universal decolonization to pre-
vent ICU infection. N Engl J Med 2013;368:2255-2265.
92) Gustot T, Durand F, Lebrec D, Vincent JL, Moreau R. Severe
sepsis in cirrhosis. Hepatology 2009;50:2022-2033.
93) Karvellas CJ, Pink F, McPhail M, Austin M, Auzinger G,
Bernal W, et al. Bacteremia, acute physiology and chronic
health evaluation II and modified end stage liver disease are
independent predictors of mortality in critically ill nontrans-
planted patients with acute on chronic liver failure. Crit Care
Med 2010;38:121-126.
94) Karvellas CJ, Abraldes JG, Arabi YM, Kumar A; for Coopera-
tive Antimicrobial Therapy of Septic Shock (CATSS) Database
Research Group. Appropriate and timely antimicrobial therapy
in cirrhotic patients with spontaneous bacterial peritonitis-
associated septic shock: a retrospective cohort study. Aliment
Pharmacol Ther 2015;41:747-757.
95) Arabi YM, Dara SI, Memish Z, Al Abdulkareem A, Tamim
HM, Al-Shirawi N, et al.; for Cooperative Antimicrobial Ther-
apy of Septic Shock (CATSS) Database Research Group. Anti-
microbial therapeutic determinants of outcomes from septic
shock among patients with cirrhosis. Hepatology 2012;56:2305-
2315.
96) Lau A, Chen S, Sleiman S, Sorrell T. Current status and future
perspectives on molecular and serological methods in diagnostic
mycology. Future Microbiol 2009;4:1185-1222.
97) Panasiuk A, Wysocka J, Maciorkowska E, Panasiuk B,
Prokopowicz D, Zak J, Radomski K. Phagocytic and oxidative
burst activity of neutrophils in the end stage of liver cirrhosis.
World J Gastroenterol 2005;11:7661-7665.
98) Cheruvattath R, Balan V. Infections in patients with end-stage
liver disease. J Clin Gastroenterol 2007;41:403-411.
99) Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr,
Calandra TF, Edwards JE Jr, et al.; for Infectious Diseases
Society of America. Clinical practice guidelines for the manage-
ment of candidiasis: 2009 update by the Infectious Diseases
Society of America. Clin Infect Dis 2009;48:503-535.
100) Cornely OA, Bassetti M, Calandra T, Garbino J, Kullberg BJ,
Lortholary O, et al.; for ESCMID Fungal Infection Study
Group. ESCMID* guideline for the diagnosis and management
1476 | REVIEW ARTICLE
LIVER TRANSPLANTATION, November 2017
of Candida diseases 2012: non-neutropenic adult patients. Clin
Microbiol Infect 2012;18(suppl 7):19-37.
101) Dimopoulos G, Karabinis A, Samonis G, Falagas ME. Candi-
demia in immunocompromised and immunocompetent critically
ill patients: a prospective comparative study. Eur J Clin Micro-
biol Infect Dis 2007;26:377-384.
102) Heemann U, Treichel U, Loock J, Philipp T, Gerken G,
Malago M, et al. Albumin dialysis in cirrhosis with superim-
posed acute liver injury: a prospective, controlled study. Hepa-
tology 2002;36(pt 1):949-958.
103) Laleman W, Wilmer A, Evenepoel P, Elst IV, Zeegers M,
Zaman Z, et al. Effect of the molecular adsorbent recirculating
system and Prometheus devices on systemic haemodynamics
and vasoactive agents in patients with acute-on-chronic alco-
holic liver failure. Crit Care 2006;10:R108.
104) Mitzner SR, Stange J, Klammt S, Risler T, Erley CM, Bader
BD, et al. Improvement of hepatorenal syndrome with extracor-
poreal albumin dialysis MARS: results of a prospective, ran-
domized, controlled clinical trial. Liver Transpl 2000;6:277-286.
105) Hassanein TI, Tofteng F, Brown RS Jr, McGuire B, Lynch P,
Mehta R, et al. Randomized controlled study of extracorporeal
albumin dialysis for hepatic encephalopathy in advanced cirrho-
sis. Hepatology 2007;46:1853-1862.
106) Ba~ nares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger
M, et al.; for RELIEF study group. Extracorporeal albumin
dialysis with the molecular adsorbent recirculating system in
acute-on-chronic liver failure: the RELIEF trial. Hepatology
2013;57:1153-1162.
107) Kribben A, Gerken G, Haag S, Herget-Rosenthal S, Treichel U,
Betz C, et al.; for HELIOS Study Group. Effects of fractionated
plasma separation and adsorption on survival in patients with acute-
on-chronic liver failure. Gastroenterology 2012;142:782-789.
108) Sen S, Davies NA, Mookerjee RP, Cheshire LM, Hodges SJ,
Williams R, Jalan R. Pathophysiological effects of albumin dial-
ysis in acute-on-chronic liver failure: a randomized controlled
study. Liver Transpl 2004;10:1109-1119.
109) Tsai MH, Chen YC, Ho YP, Fang JT, Lien JM, Chiu CT,
et al. Organ system failure scoring system can predict hospital
mortality in critically ill cirrhotic patients. J Clin Gastroenterol
2003;37:251-257.
110) Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau
TM, Kosberg CL, et al. A model to predict survival in patients
with end-stage liver disease. Hepatology 2001;33:464-470.
111) Wiesner R, Edwards E, Freeman R, Harper A, Kim R,
Kamath P, et al.; for United Network for Organ Sharing Liver
Disease Severity Score Committee. Model for End-Stage Liver
Disease (MELD) and allocation of donor livers. Gastroenterol-
ogy 2003;124:91-96.
112) Karvellas CJ, Lescot T, Goldberg P, Sharpe MD, Ronco JJ,
Renner EL, et al.; for Canadian Liver Failure Study Group.
Liver transplantation in the critically ill: a multicenter Canadian
retrospective cohort study. Crit Care 2013;17:R28.
113) Poonja Z, Brisebois A, van Zanten SV, Tandon P, Meeberg G,
Karvellas CJ. Patients with cirrhosis and denied liver transplants
rarely receive adequate palliative care or appropriate manage-
ment. Clin Gastroenterol Hepatol 2014;12:692-698.