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Bridge therapy to liver transplantation in fulminant hepatic failure

William T. Merritt

The management of patients with fulminant hepatic failure is a

major clinical endeavor. Early intensive care at an institution able
to perform liver transplantation is essential. It is recognized that
therapy focused solely on attempts at preventing/reversing
increased intracranial pressure, and the treatment of other
failing organs as they occur falls well short of ideal. This review
covers the non-biological and biological techniques utilized in
efforts to support liver function. The goal is to foster recovery, or
to buy enough time for successful liver transplantation.
Prospective, controlled trials are beginning to acknowledge
subgroups of fulminant hepatic failure and properly randomize
therapy. Our understanding of the essential elements of liver
support is improving, but no single device has yet proved
indispensable. Curr Opin Anaesthesiol 14:713719. # 2001 Lippincott
Williams & Wilkins.

Department of Anesthesiology/CCM, Johns Hopkins Hospital, Baltimore, Maryland,

Correspondence to William T. Merritt, MD, MBA, Department of Anesthesiology/
CCM, Johns Hopkins Hospital, Baltimore, MD, USA
Tel: +1 410 955 5615; fax: +1 410 955 0994; e-mail:
Current Opinion in Anaesthesiology 2001, 14:713719

acute liver failure

central nervous system
Food and Drug Administration
fulminant hepatic failure
intracranial hypertension
molecular adsorbent recycling system
orthotopic liver transplantation
porcine endogenous retrovirus

# 2001 Lippincott Williams & Wilkins



Acute hepatic failure, recognized as a clinical syndrome

for over 40 years, is a devastating condition that quickly
results in multi-organ dysfunction, with death rates
consistently falling between 70 and 90% [1], depending
upon etiology and patient age. Central nervous system
(CNS) effects occur early, and in severe cases, lead to
death from cerebral edema and brainstem herniation [2].
With the emergence in the 1970s of liver transplantation
as a genuine form of `cure' in severe acute liver disease,
intensive care in fulminant hepatic failure (FHF) and
referral for specialized care pending transplantation have
become modern necessities. The shortage of donor
organs, however, results in only approximately 10% of
FHF patients undergoing transplantation.
Survival in FHF varies quite widely between centers,
with spontaneous (i.e. without liver transplant) aggregate
survival being not more than 2530% [3]. Survival is
higher in patients with acetaminophen overdose and
viral A hepatitis (57 and 40%, respectively) than in those
with other drug-related hepatitis, cryptogenic or non-A,
B, or C hepatitis (425%). Spontaneous survival in
hepatitis B has been reported as being between 13 and
39%. Spontaneous survival in the acute liver failure
(ALF) associated with Wilson's disease was 0% in a
recent review from the United States [4].
Because the non-uniformity of criteria for judging which
patients with FHF will only survive with orthotopic liver
transplantation (OLT) is one of the major dilemmas in
treating FHF patients and in comparing spontaneous
survival and OLT rates among centers, retrospective
criteria have been developed. Those from King's
College are based on prothrombin time, arterial pH,
hepatic encephalopathy grade and serum creatinine in
ALF caused by acetaminophen, and age, duration of
jaundice before onset of encephalopathy, etiology,
prothrombin time, and serum bilirubin level in those
patients with FHF with a non-acetaminophen cause [5].
Whereas these criteria predicted 77% of deaths in the
acetaminophen group, 11% of those not meeting the
criteria also died. In the non-acetaminophen group, 96%
of fatal cases were predicted, with 18% dying who did
not full the criteria. An alternative scale developed in
Clichy, based prognosis in FHF caused by viral hepatitis
on age-related factor V levels and the presence of coma
or confusion [6]. Meeting the Clichy criteria predicted
90% of deaths, but unfortunately an additional 18% died
who did not satisfy their conditions. Although these
predictive criteria have been generally validated in other

714 Anaesthesia and medical disease

studies, the ability to foretell survival without OLT has

been less than in the original papers [7,8].
Complementing these criteria is a working denition of
ALF proposed by the King's College group from their
own data collected between 1972 and 1985 [9] (Table 1).
Patients with a previous history of symptomatic liver
disease are excluded, but patients with an underlying
condition revealed by acute liver decompensation (e.g.
Wilson's disease) are not. This scheme recognizes,
paradoxically, that hyperacute liver failure has the `best'
prognosis. Encephalopathy is a mandatory clinical
characteristic. Subtleties of early encephalopathy and
overlap with other causes (renal, drug-induced, etc.) do
not lessen the importance of this indicator of the severity
of the liver disease. The use of such denitions allows a
comparison of treatment and survival between centers
and facilitates the organization and analysis of controlled
trials for new therapies.
In addition to the ongoing imprecision in deciding who
is likely to live or die without liver transplantation are
the difculties in separating process and outcome effects
of treatment. The pathogenesis of liver failure remains
incompletely understood, the range of etiologies is
broad, and the best measures of the progression of
failure and recovery are a matter of debate and fall short
of ideal. The liver is a complex organ with many
metabolic tasks inter-related with other organ systems
(Fig. 1). There is no universal agreement concerning
which functions need to be supported and which
chemicals/toxins need to be removed. Concurrent
dysfunction of other organs, especially the brain and
kidneys, affects the clinical picture and necessary
therapy. Within the context of these dilemmas have
arisen various technologies in an effort to support the
patient with an acutely failing liver [10] (Fig. 2).

tation centers at an early phase, before CNS function

deteriorates or the gravity of their condition threatens
their ability to be safely transported. Early (within a few
hours) identication of the etiology is potentially
important, especially with acetaminophen toxicity because therapy includes the early use of N-acetylcysteine
or methionine. Cerebral blood ow is believed to be
increased in ALF, an important feature of the intracranial hypertension (:ICP) that develops [11,12]. As
clinical signs and imaging can be insensitive indicators
of the presence of or potential for :ICP/cerebral edema,
intracranial pressure monitoring allows an assessment of
cerebral perfusion pressure. The prevention/treatment of
:ICP can become an exasperating dilemma. The
avoidance of fever and agitation are desirable. Elevation
of the head not higher than 208, mild hyperventilation,
diuretics (osmotic and loop), barbiturate-induced coma,
and an assessment of brain blood ow and oxygenation

Figure 1. Liver functions

Metabolism synthesis/degradation
Fatty acids
Porphyrin, Heme, Bilirubin
Glycogen synthesis and glycogenolysis
Lipoprotein and cholesterol
Plasma proteins
Albumin, Globulin
Coagulation factors
Biotransformation of drugs
Bile formation
Storage of nutrients/vitamins
Receptor-mediated endocytosis
Immune modulation

General supportive care

Aggressive and intensive supportive care is essential in

the treatment of patients with acute forms of hepatic
failure. Patients should be transferred to liver transplan-

Table 1. Acute liver failure subgroups

Interval: jaundice to encephalopathy
Cerebral edema
Prothrombin time
Dominant etiologies
(King's College)







Prolonged as acute
Least increased
All acetaminophen
Hepatitis A, B, NANB
Other drug

Prolonged as hyperacute
Increased as in subacute
NANB hepatitis
Hepatitis A, B
Halothane, other drug

Least prolonged
Increased as in acute
NANB hepatitis
Hepatitis A, B

NANB, Non-A, non-B. Adapted from O'Grady et al [9], with permission.

Bridge therapy to liver transplantation Merritt 715

Figure 2. `Bridge' to liver transplantation

Non-biological/Physical Chemical Mechanical (PCM)

Blood detoxification
Dialysis like
Varying membrane surfaces
Albumin impregnated
Activated charcoal
Ionic and non-ionic resins
Plasmapheresis/plasma exchange
Total body washout
Molecular adsorbent recycling system (MARSTM)
Blood dialysis HEMOTherapiesTM
Biological whole organ/Cellular activity
Auxiliary ex-vivo liver perfusion
Extracorporeal hepatocyte based [ hybrid (PCM) technology]
HepatAssist (Circe biomedical bioartificial liver)
ELAD (extracorporeal liver assist device)
MELS (modular extracorporeal liver system)
Hepatocyte implantation
PCM, Physicalchemicalmechanical.

have become useful tools to assess continued brain

viability. Moderate hypothermia is emerging as a
potentially useful component of :ICP management
[13 . .]. Intravascular volume assessment and cardiovascular support may require the presence of a pulmonary
artery catheter or echocardiogram for the judicious use of
uids and pressors. Oliguric renal failure complicates
FHF in 3070% of cases; acute hemodialysis can be
associated with an abrupt increase in intracranial
pressure; continuous arteriovenous or venovenous hemoltration is not associated with these changes and is
preferred. The systemic inammatory response syndrome [13 . .], sepsis and severe infection, both bacterial
and fungal, eventually occur in many ALF patients [14].
Although liver transplantation is the therapy of choice in
those patients whose liver failure is not reversing,
bridging therapy has been studied for several decades;
both non-biological and biological systems have been
developed, as well as hybrid systems that combine
elements of both.

Non-biological systems

Initial attempts at improving patients with deteriorating

liver disease began with technologies successfully used
in the management of renal failure. Blood detoxication
techniques have been tried since the 1950s. Variations
on the theme of renal hemodialysis (solute removal by
solvent drag or solute gradient) with novel membrane
surfaces and various pore sizes, have added some form of
sorption system incorporating charcoal or resins. Such a

therapy can be effective in removing the `middle

molecules' of of 515 kDa, thought to be important in
the evolution of many of the symptoms of FHF.
Numerous small studies have been performed, with
encouraging results. Controlled studies, however, have
not been so enthusiastic. Hemoltration, potentially
capable of removing protein-bound, non-dialysable
components from the plasma efciently, has been tried,
but is unfortunately efcient at removing clotting factors,
and has been associated with hypotension, thrombocytopenia, leukopenia and bleeding. Plasma exchange
modalities have been tried but with varied results, with
complications that have included allergic reactions,
citrate toxicity, hypernatremia, metabolic alkalosis, a
sharp decrease in colloid osmotic pressure and pulmonary microemboli. Some have asserted that plasma
exchange may be useful in the treatment of druginduced liver failure, restoring stability for a number of
days [15], and others that plasma exchange removes
inammatory mediators not removable with hemodialysis
[16]. A recent retrospective review [17] suggested that
plasma exchange combined with hemoltration alleviates/attenuates many of the problems associated with
plasma exchange alone, and a recent animal study [18 .]
suggested that hemoltration is associated with improvement in oxygenation in endotoxin-induced lung injury.
Although each of these therapies may result in
presumably benecial biochemical changes with clinical
correlates, the results are often transient, of unclear
relationship to the outcome, and have not been
adequately studied in a randomized fashion. Other
exchange/washout therapies have involved replacement
of plasma with fresh frozen plasma, or exsanguination
with albumin/electrolyte/fresh blood replacement. Again,
resulting in short-term improvements, such treatments
are poorly correlated with outcome, and have not been
submitted to randomized trials.
Two commercially available non-biological systems are
worth mention. The molecular adsorbent recycling
system (MARS) [19] is a blood purication treatment
based on blood dialysis. This system uses selective
hemodialtration with countercurrent albumin dialysis
aimed at selectively removing both water-soluble and
protein-bound hepatic toxins in the low and middle
molecular weight range (560 kD). This closed-loop
dialysate circuit allows the transfer of albumin-bound
toxins from plasma to the membrane and continuous
deligandization and water-soluble toxin removal by
means of charcoal columns, exchange resins and
continuous venovenous hemoltration. Essential hormones bound to carrier proteins and growth factors (i.e.
molecules larger than 50 00060 000 Da) are not thought
to be removed by this process. Both water-soluble (e.g.
ammonia, urea, lactate, creatinine, etc.) and fat-soluble

716 Anaesthesia and medical disease

(e.g. bile acids, bilirubin, aromatic amino acids, short and

medium chain fatty acids, etc.) toxins seem to be
effectively removed. The system appears to be safe,
without the logistical problems of supplying functional
cells in a biological based system. Although effective in a
very small, randomized, controlled study of patients with
hepatorenal syndrome [20], encouraging uncontrolled
[21 .] and anecdotal information is available for `acute'
forms of liver failure. Although it is unresolved whether
cerebral blood ow is increased or decreased in acute-onchronic liver failure, a recent study [22,23 .] suggesting
increased cerebral blood ow velocity during MARS
treatment (as measured by transcranial Doppler over the
middle cerebral artery) in patients with acute-on-chronic
liver failure, may have important implications during
attempts to treat the failed liver/cerebral hyperdynamic
state in FHF.
`Liver dialysis' is offered by HEMOtherapies [24] as the
only liver-support technology market cleared by the
Food and Drug Administration (FDA) [25]. Utilizing a
cellulosic membrane with a cutoff of 5000 Da, capable of
removing the putative toxins of liver failure (55000 Da),
but not bilirubin, cytokine or endotoxin protein-bound
complexes. On the system side of the membrane is a
sorbent suspension of powdered charcoal and a cationexchange resin of powdered polystyrene sulfonate. It has
been trialled in many groups of patients with acute and
chronic liver disease. Benecial effects have been noted
in acute-on-chronic liver failure, drug overdose (e.g.
acetaminophen, tricyclic antidepressants, etc.) and `benets' have been noted in neurological and physiological
parameters, but outcomes were not changed in FHF
[26]. A new `add-on' plasma lter, in trials for use in
patients with FHF, utilizes a suspension of activated
charcoal and silica to remove the protein-bound cytokines, endotoxins and bilirubin known to be high in
these patients. However, the initial results of this
therapy have yet to be reported.
The questions to be answered by detoxication technologies are several. Should the various systems be
compared solely on their detoxication ability, or do
actual improvements in liver metabolic/synthetic function also occur and lead to an improvement in the
biochemical derangements? The effects of this therapy
on splanchnic, renal, systemic and CNS hemodynamics
are poorly understood and require examination. Is overall
survival improved, and what are the costbenet

Biological systems

Hepatologists and intensivists have long sought to

develop a treatment that not only removes harmful
substances, but also provides some of the biotransformation and synthetic functions of the liver. As the essential

elements of liver function become better understood,

new methods are being developed. Many of these
systems utilize some non-biological components, such as
dialysing membranes or charcoal perfusion (from which
the designation `hybrid' has arisen), a heat exchanger
and the ability to deliver oxygen to living cells.
One biological therapy is cross-hemodialysis, during
which a patient's blood is dialysed against blood from a
healthy animal or against biologically active hepatocyte
tissue (homogenates, slices, freeze-dried granules).
Benecial effects have been reported in glucose, lactate
and ammonia handling, but no major studies have been
performed. Whole liver perfusion ex-vivo has been
performed with livers harvested from pigs, dogs, calves,
baboons and human cadavers. Although some short-term
success has been noted, survival rates have not been
Extracorporeal hepatocyte-based systems have received
considerable attention for over 10 years. Not only must
functional hepatocytes be readily isolated, cell lines
established and kept viable, but the quantity must be
sufcient to provide enough liver function to allow
recovery or survival until transplantation. Isolated
hepatocytes have been tested in a number of settings,
including a centrifuge, perfusion chambers, dialysers and
`bioreactors'. Cells have been cultured on a variety of
surfaces, membranes and three-dimensional geometries
[27 .]. However, the level of detoxication and liver
function noted in animal models of liver function was not
signicant. A major dilemma is the functional number of
hepatocytes needed to support the essential activities of
the liver. Based on hepatic resection experience in
humans, approximately 1030% of liver mass is necessary to support life. If approximately 90% of a liver
weight of 1500 g represents actual parenchymal cells, the
minimum number of hepatocytes appears to be in the
range of 100400 g [28]. In the USA, the FDA has
determined that the extracorporeal use of hepatocytes is
to be considered as a drug, not as a mechanical device.
A number of centers are working internally, jointly, or
with industry support, actively pursuing cell-based/
assisted liver support systems. They are doggedly
searching for the best source of cells, better cell isolation
techniques, the best mix of biological function and nonbiological capabilities, with an eye towards cell growth,
storage, portability, reactivation and robust function in the
clinical setting. It is anticipated that this will eventually
become a very successful medical industry [29].
There is clinical experience using animal cells, a human
line of hepatoblastoma cells and human liver cells
isolated from discarded cadaveric organs [30]. Because
of their morphological and functional similarity to human

Bridge therapy to liver transplantation Merritt 717

liver cells, porcine hepatocytes may become good

candidates for testing. Ensuring that infectious and
immunological concerns are met are signicant hurdles
before useful clinical trials can be undertaken. There are
biosafety issues using tumor cells in immunosuppressed
patients. Three devices are discussed.
One device in active FDA-approved clinical trials since
1994 is the HepatAssist 2000 (Circe Biomedical,
Lexington, MA, USA) [31 .]. This bioarticial liver
utilizes cryopreserved porcine hepatocytes as its primary
source of specic liver support. Blood is separated into
its cellular and plasma components, with plasma entering
the bioarticial liver circuit consisting of a reservoir, a
column charged with cellulose-coated activated charcoal
(to enhance detoxication and possibly remove `toxic'
elements from patient plasma before it reaches the
system's hepatic cells), an oxygenator, a heat exchanger
and nally the hollow-ber hepatocyte bioreactor.
Sodium citrate is used to prevent thrombosis. Plasma
and cellular components are reconstituted before their
return to the patient. In the setting of care in a Liver
Support Unit and `standard' supportive therapy including hyperventilation, mannitol, and lactulose, over 39
patients with acute liver dysfunction have been studied.
Each bioarticial liver treatment lasts 6 h, with the
charcoal units replaced after 3 h. In their FHF group, 26
patients met the criteria for liver transplantation.
Eighteen out of 26 were bridged to transplantation,
and six out of 26 (ve with acetaminophen FHF)
recovered sufcient liver function while on bioarticial
liver that OLT was not needed. Two patients died
before liver transplantation; both had `remarkable
neurologic recovery', but died of multi-organ failure.
Liver function tests, blood urea nitrogen, creatinine
level, intracranial pressure, cerebral perfusion pressure,
and measures of cerebral function showed statistically
signicant improvements, but liver function tests, blood
urea nitrogen, and creatinine levels did not return to
normal. Lactate levels and the prothrombin time were
not improved by the therapy. Patients were hemodynamically stable during treatments. There was no evidence
that treatment with the HepatAssist device had an
adverse effect on subsequent allograft function, and
retroviral testing showed no evidence of transmission of
the porcine endogenous retrovirus (PERV) [31 .].
The extracorporeal liver assist device (ELAD; Vitagen,
La Jolla, CA, USA) utilizes a human hepatoblastoma cell
line (C3A cells) seeded into and allowed to grow in two
hemodialysis-like cartridges, resulting in approximately
200 g of liver cells. These cartridges are transported to
the bedside and placed into a whole-blood circuit for
continuous treatment (longest treatment to date is
168 h). Although an early trial suggested benecial
neurological changes, ve out of six deaths were

associated with cerebral edema [32]. A subsequent

controlled trial involved two groups of FHF patients:
those expected to require liver transplantation and those
not expected to require transplantation. Patients were
randomly assigned to treatment and control in both
groups. For those not expected to require liver
transplantation, 78% survived with treatment, whereas
75% survived in the control group. In the group
expected to require transplantation, 33% survived with
treatment, whereas 25% survived in the control group
[33]. A second-generation extracorporeal liver assist
device, which incorporates a greater liver cell mass and
improved ow circuitry, with plasma rather than wholeblood perfusion, is currently undergoing clinical trials.
The modular extracorporeal liver system (MELS;
Hybrid Organ GmbH, Berlin, Germany) is being
developed in Europe, with initial human trials that
began in 1996. Although initially using porcine cells, the
current system uses immortalized human liver cells
grown from rejected cadaveric organs. Utilizing plasma
separation and heparin for continuous treatments, the
therapy has been used successfully in an uncontrolled
group of patients with ALF. The system contains up to
650 g of liver cells, both parenchymal and non-parenchymal, in a three-dimensional culture. Oxygen supply and
carbon dioxide removal is possible using direct membrane contact oxygenation. An uncontrolled phase 1
study with eight patients in ALF enabled bridging to
liver transplantation utilizing porcine cells [34], with
eight out of eight survival to 3 years. Ongoing clinical
studies are utilizing a bioreactor with human liver cells.

Hepatocyte transplantation

Awareness of the considerable proliferative capacity of

the differentiated hepatocyte has led to attempts at
hepatocyte transplantation for over three decades.
Whereas fewer than one out of 20 000 hepatocytes
divide each day in the natural state, in the setting of liver
injury cells become mitotically active and undergo cell
division until the liver mass is restored. This metamorphosis is not fully understood, but presumably occurs in
response to cytokines and growth factors.
Hepatocyte transplantation entails the infusion of
normal hepatocytes into the splanchnic/liver bed by
injection of isolated hepatocytes into the splenic artery
or spleen or directly into the portal vein. Experimental
work in animals and in small groups of patients
demonstrates that such cell transfer can lead to viable
cells, which can have sufcient metabolic activity, for
example, to treat the CriglerNajjar syndrome [35]. In a
protocolized study of ve patients deemed unacceptable for liver transplantation [36], with rigorous examination for the presence of the cells in the target organ, the
presence of living donor cells in the recipients was not

718 Anaesthesia and medical disease

only demonstrated, but improvement in the grade of

hepatic encephalopathy, international normalized ratio,
arterial ammonia, computed tomography of the brain,
electroencephalogram, and clearance function was
noted, with short-term survival beyond expectation,
but death eventually occurred from infection and multisystem organ failure.
Whereas the optimal liver mass to maintain liver function
remains a matter of debate, hepatocyte transplantation
should eventually be much less expensive than liver
transplantation, and there is the potential to treat more
than one patient from a single donor. Transgene therapy
may allow `autologous' cell transplantation obviating the
need for immunosuppression. It may even be possible to
manipulate cells genetically to develop `super hepatocytes' capable of enhanced proliferation, protein synthesis and metabolism, and even cells less susceptible to
ongoing liver injury and apoptosis [37 . .]. There are no
commercially available options for this therapy for the
near future.


The insufcient numbers of human livers, both cadaveric and living, to meet the needs for OLT, and the
continued inadequacy of liver support devices to
support/reverse liver failure reliably has led to ongoing
efforts to nd suitable animal organs for the short and
long-term therapy of patients with failing livers [38 . .].
Potential uses include permanent and bridge transplantation, auxiliary transplantation, hepatocyte transplantation, ex-vivo organ perfusion and hepatic assist devices.
Although non-human primates (e.g. chimpanzees, baboons, etc.) have been used successfully as a source of
both kidneys and livers, with survival up to several
months, largely because hyperacute rejection does not
occur (see below) with these `concordant' organs,
enthusiasm has not been maintained for a number of
reasons. These animals are in short supply, their
reproductive life cycle is slow, the organ size is not
suitable for many adults, they may harbor viral infection,
primate genetic manipulation is in its infancy, and there
is considerable opposition to the use of non-human
primates for lethal experimentation/therapy, even to
benet humans.
Most investigators have focused on lower animals,
including dogs, calves and especially the pig. Pigs could
be available in large numbers and can be genetically
manipulated to express desirable genes. Although a risk
of PERV exists, the pig liver may resist infection by
agents known to cause viral hepatitis in humans.
Signicant hurdles exist to xenotransplantation of the
liver. Hyperacute rejection may occur because of

naturally occurring xenoreactive antibodies in all immunocompetent individuals, even without a history of
sensitization. When this occurs, it is usually also
accompanied by thrombocytopenia, and the liver has
an effective use of just 26 h. Depletion of these
antibodies, and transgenic manipulation to inhibit the
certain antigen expression or manipulate human complement regulation are among the techniques under
study. There may be proteinprotein reactions between
species, e.g. thrombin and protein C and complement
inhibitory proteins, which may impair graft survival.
Animal cells in continuity with a recipient's own cells
heightens the possibility of the acquisition of varied
unusual infectious agents and zoonoses, e.g. PERV.
Genetic engineering may be able to resolve the PERV
problem. The use of animal cells in liver assist devices
attenuates many of these concerns because of the
presence of some form of `membrane' surface between
a patient's cells and the animal liver cells. There are 12
reports of human liver xenotransplantation: four chimpanzee, seven baboon, and one pig. Such therapy is not
clinically useful at this time in the treatment of FHF.


It is quite clear that patients with acute, fulminant forms

of hepatic failure must be transferred at an early stage to
institutions with appropriate levels of intensive care and
the ability to perform liver transplantation. However,
even when this is rigorously carried out, the increasing
numbers of liver transplant centers results in few
patients with acute and FHF being cared for at any
single institution. Only with collaborative, multi-center
investigation will our understanding of the variations of
ALF, response to therapy, and the likelihood of
spontaneous recovery without OLT continue to advance. Such studies must be controlled, randomized and
organized around the best current denitions/understanding of disease pathophysiology. In our enthusiasm
to test new treatments and devices, we must remember
that demonstrating relative safety does not prove this or
that useful or benecial result as having a signicant
effect on overall liver function, or patient symptoms and
Support for the failing liver is still very much a work in
progress; each of the treatments discussed has benets
and shortcomings and risks that must be better understood; none has an incontrovertible hold on the ultimate
path to success. During this process there are many
opportunities for those in the critical care and anesthesiaoriented community to study the varied effects of these
therapies on cardiovascular, CNS and pulmonary function, systemic and regional hemodynamics, coagulation,
drug disposition and metabolism, and the assessment of
liver function and general metabolism, to list some of the

Bridge therapy to liver transplantation Merritt 719

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

20 Mitzner S, Stange J, Klammt S, et al. Improvement of hepatorenal syndrome

with extracorporeal albumin dialysis MARS: results of a prospective,
randomized, controlled clinical trial. Liver Transplant 2000; 6:277286.
21 Awad S, Swaniker F, Magee J, et al. Results of a phase I trial evaluating a liver
support device utilizing albumin dialysis. Surgery 2001; 130:354362.
Nine patients in an uncontrolled study suggesting improvement in encephalopathy
score and intracranial pressure.

Hoofnagle JF, Carithers RL, Shapiro C, Ascher N. Fulminant hepatic failure:

summary of a workshop. Hepatology 1995; 21:240252.

D'Agostino A, Combes B. Cerebral edema: a major complication of massive

hepatic necrosis. Gastroenterology 1971; 61:877884.

Riordan SM, Williams R. Cause and prognosis in acute liver failure. Liver
Transplant Surg 1999; 5:8689.

Schiodt F, Atillasoy E, Shakil O, et al., and the Acute Liver Failure Group.
Etiology and outcome for 295 patients with acute liver failure in the United
States. 1999; 5:2934.

23 Jalan R, Williams R. Improvement in cerebral perfusion after MARS therapy:

further clues about the pathogenesis of hepatic encephalopathy? Liver
Transplant 2001; 7:713715.
An editorial discussing the relevance of the findings in the study by Schmidt et al.
[22] in patients with FHF.

O'Grady JG, Alexander G, Hayliar KM, Williams R. Early indicators of

prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439445.

24 HEMOtherapies Company, 11975 El Camino Real, Suite 104, San Diego,

CA 92130, USA.

Bernuau J, Samuel D, Durand F, et al. Criteria for emergency liver

transplantation in patients with acute viral hepatitis and factor V below
50% of normal: a prospective study [Abstract]. Hepatology 1991; 14:49A.

Pauwels A, Mostefa-Kara N, Florent C, Levy VG. Emergency liver

transplantation for acute liver failure. J Hepatol 1993; 17:124127.

Anand AC, Nightingale P, Neuberger JM. Early indicators of prognosis in

fulminant hepatic failure: an assessment of the King's criteria. J Hepatol
1997; 26:6268.

O'Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the
syndromes. Lancet 1993; 342:273275.

10 Arkadopoulos N, Detry O, Rozga J, Demetriou A. Liver assist systems: state

of the art. Int J Artif Organs 1998; 21:781787.
11 Blei A, Larsen F. Pathophysiology of cerebral edema in fulminant hepatic
failure. J Hepatol 1999; 31:771776.
12 Jalan R, Olde Damink S, Deutz N, et al. Treatment of uncontrolled intracranial
hypertension in acute liver failure with moderate hypothermia. Lancet 1999;
13 Rolando N, Wade J, Davalos M, et al. The systemic inflammatory response
. . syndrome in acute liver failure. Hepatology 2000; 32:743739.
An examination of the effect of the systemic inflammatory response syndrome on
outcome in 887 patients in a single center over 11 years.
14 Sussman N, Lake J. Treatment of hepatic failure 1996: current concepts
and progress towards liver dialysis. Am J Kidney Dis 1996; 27:605621.
15 Kondrup J, Almdal T, Vilstrup H, Tytgstrup N. High volume plasma exchange
in fulminant hepatic failure. Int J Artif Organs 1992; 15:669676.
16 Iwai H, Nagaki M, Naito T, et al. Removal of endotoxin and cytokines by
plasma exchange in patients with acute hepatic failure. Crit Care Med 1998;
17 Sadahiro T, Hirasawa H, Oda S, et al. Usefulness of plasma exchange plus
continuous hemodiafiltration to reduce adverse effects associated with
plasma exchange in patients with acute liver failure. Crit Care Med 2001;
18 Ulrich R, Roeder G, Lorber C, et al. Continuous venovenous hemofiltration
improves arterial oxygenation in endotoxin-induced lung injury in pigs.
Anesthesiology 2001; 95:428436.
An animal study showing improvement in arterial oxygenation utilizing a nonspecific blood purification device. Suggests implications for FHF patients.
19 Teraklin AG. Molecular adsorbent recycling system (MARS). FriedrichBarnewitz-Strasse 4, D-18119, Rostock, Germany.

22 Schmidt L, Svendsen L, Sorensen V, et al. Cerebral blood flow velocity

increases during a single treatment with the molecular adsorbents recirculating systems in patients with acute on chronic liver failure. Liver Transplant
2001; 7:709712.

25 Liver dialysis. In: The physician resource center for liver dialysis.
26 Ash S, Kuczek T, Foster D, et al. Liver dialysisTM in treatment of hepatic
failure and hepatorenal failure: randomized clinical trials and clinical
experience. Int J Artif Organs 2000; 23:534.
27 Khalil M, Shariat-Panahi A, Tootle R, et al. Human hepatocyte cell lines
proliferating as cohesive spheroid colonies in alginate markedly upregulate both
synthetic and detoxificatory liver function. J Hepatol 2001; 34:6877.
An interesting study covering many of the issues important in hepatocyte culture
and functional assessment.
28 Nyberg S, Misra S. Hepatocyte liver-assist systems a clinical update. Mayo
Clin Proc 1998; 73:765771.
29 Parker-Pope T. Health journal new kind of dialysis could help patients with
liver diseases. Wall Street Journal 2001; March 9th Section B page 1.
30 Liver cell culture for hybrid liver support.
31 Hui T, Rozga J, Demetriou AA. Topics: basic science and clinics in
pathophysiology of liver failure bioartificial liver support. J Hepatobil Pancreat
Surg 2001; 8:115.
A review of extracorporeal liver support for ALF, with a discussion of the authors'
hollow fiber system using porcine hepatocytes.
32 Sussman N, Gislason G, Conlin C, Kelly J. The Hepatix extracorporeal liver
assist device: initial clinical experience. Int J Artif Organs 1994; 18:390396.
33 Ellis A, Hughes R, Wendon W, et al. Pilot-controlled trial of the extracorporeal
liver assist device in acute liver failure. Hepatology 1996; 24:14461451.
34 Gerlach J. Development of a hybrid liver support system a review. Int J Artif
Org 1996; 19:645655.
35 Fox I, Chowdhury J, Kaufman S, et al. Treatment of the CriglerNajjar
syndrome type I with hepatocyte transplantation. N Engl J Med 1998;
36 Bilir B, Guinette D, Karrer F, et al. Hepatocyte transplantation in acute liver
failure. Liver Transplant 2000; 6:3240.
37 Lee L. Advances in hepatocyte transplantation: a myth becomes reality. J Clin
. . Invest 2001; 108:367369.
A succinct discussion of the issues associated with hepatocyte transplantation in
38 Kanai N, Platt J. Xenotransplantation of the liver. Clin Liver Dis 2000; 4:731
. . 746.
A complete discussion of the issues involved with xenotransplantation of livers in