critical care in acute liver failure || plasmapheresis and extracorporeal liver support

162 © 2013 Future Medicine162162 www.futuremedicine.com

Roger WilliamsRoger Williams is Director of the Institute of Hepatology (London, UK) and of the Foundation for Liver Research. Before that, he had established, over a period of 30 years, the world-renowned Institute of Liver Studies at King’s College Hospital (London, UK). He is a Fellow of the Academy of Medical Sciences and is the recipient of numerous honorary fellowships, medals and prizes, including the American Society of Transplantation Senior Achievement Award in 2004, a Hans Popper Lifetime Achievement Award in 2008 and in 2011 the Distinguished Service Award of the International Liver Transplant Society. His main clinical and research interests are in acute liver failure, liver transplantation, complications of cirrhosis and management of viral hepatitis.

Julia WendonJulia Wendon trained in internal medicine before specializing in liver intensive care and hepatology, and has been a consultant within the Institute of Liver Studies, King’s College Hospital (London, UK) since 1992. Her focus is in liver intensive care incorporating encephalopathy, hepatorenal failure, haemodynamic failure, sepsis and immune function, liver support systems, liver function assessment and management of acute liver failure.

About the Authors

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© 2013 Future Medicine 163

doi:10.2217/EBO.12.374

Plasmapheresis and extracorporeal liver support

Roger Williams & Julia WendonThis chapter will cover the two main types of extracorporeal device for temporary liver support based on adsorbents and dialysis plus additional biological cell module in the bioartificial devices. The nature of ‘plasma toxemia’ in acute liver failure and the rationale for temporary liver support will also be discussed, along with the results of controlled clinical trials of the current devices MARS™ and Prometheus™ in acute liver failure and acute-on-chronic liver failure. The chapter concludes with a look at the implications of reduced albumin binding capacity for toxins in advanced liver disease in the context of temporary liver support.

Exchange transfusion & high-volume plasmapheresis 164

Extracorporeal artificial & bioartificial devices 165

Controlled trials of bioartificial & artificial devices 166

Artificial devices 167

Functionality of albumin in liver failure & in commercial preparations 171

Timing & use of TLS in ALF 172

Chapter 12

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In acute liver failure (ALF) on which this book is focused, the aim of temporary liver support (TLS) is to provide time for a spontaneous recovery from the injurious processes causing the liver to fail and allow regeneration. In addition, it could be argued that in improving the clinical condition of patients who fulfil poor prognostic criteria,

TLS may improve their chances of a good outcome, both by providing extra time for an organ to be obtained and by the patient being physiologically more stable at the time of an organ becoming available and thus decreasing the risk of other organ failure and complications in the post-transplant period. Unlike the toxemia of kidney failure, the toxins that are retained in the blood when the function of the liver becomes severely deranged comprise many protein-bound as well as water-soluble toxins. The build-up of these toxins occurs in relation to decreased clearance and production from the necrotic liver. These include small-molecular-weight toxins (e.g., ammonia, phenol, false neurotransmitters, free bile acids) but also mediators of inflammation (e.g., cytokines, chemokines), vasoactive substances, cell growth inhibitors (e.g., TGF-b1) and endotoxin [1]. Their exact role in the neurological, ongoing hepatic and other organ impairment in ALF remains to be determined. The balance of these agents in regard of liver regeneration versus ongoing injury to the liver is an essential component of recovery and regeneration; the aim of any liver support system is to facilitate the balance in favor of regeneration.

Exchange transfusion & high-volume plasmapheresisThe beneficial effects of clearing the blood of the toxins accumulating in ALF were shown very early on in the history of TLS. The use of exchange transfusion was first reported from Sydney, Australia, in 1958, in a 13-year-old boy with presumed fulminant viral hepatitis [2]. Two exchange transfusions were followed by marked improvements in conscious level and he was discharged from hospital fully recovered 37 days after admission. Successful outcomes were similarly reported from Cape Town, South Africa, in 1966, with plasma exchange [3]. This approach was further developed in 1994 by Fin Stolze Larsen of the Copenhagen Liver Unit [4] in the technique

of high volume plasmapheresis. In total, 16% of the bodyweight is exchanged with fresh frozen plasma (FFP) once a day for 3 sequential days. The case series he reported showed improvement in neurological and

Acute liver failure: onset of jaundice usually followed by encephalopathy within 8 weeks of

first symptom of illness and with no preceding liver disease.

Temporary liver support: term used to cover techniques usually based on extracorporeal devices for removal of plasma toxins in failing liver until spontaneous recovery occurs.

Artificial and bioartificial devices: the main types of extracorporeal device for temporary

liver support consisting of adsorbents and dialysis with or without as additional module of functioning liver cells.

Plasmapheresis & extracorporeal liver support

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cardiovascular parameters. These encouraging data resulted in the setting up of a controlled clinical trial in patients with ALF, which closed in 2009 with 182 patients entered. The results shortly to be published have been reported in abstract form to show a 20% survival benefit in the group of patients who were not transplanted but treated with plasma exchange.

Extracorporeal artificial & bioartificial devicesThe two pathways of development in extracorporeal liver support devices, namely, entirely artificial systems based on dialysis membranes and perfusions through absorbents, and the bioartificial devices incorporating a module of functioning liver cells in addition to adsorbents/dialysis components, are based on different premises (Figure 12.1). For both the objective is the effective as well as safe removal of toxins accumulating in the blood and in those with a biological liver cell component, replacement of the liver’s failing metabolic and synthetic functions.

Whether there is a need to provide supplementary metabolic and synthetic functions in addition to an efficient removal of toxic substances in improving survival is to-date unanswered. Major reductions in circulatory and tissue toxin load alone may be sufficient to enable spontaneous recovery of tissue and organ functions. Furthermore, evidence that blood levels of plasma albumin and coagulation factors are

Figure 12.1. Different and common objectives of artificial and bioartificial devices.

Key functions of liver devices

ArtificialEfficient removal of accumulatedtoxins allowing natural processes

of recovery

BioartificialSynthetic and metabolic functionfrom heptaocyte module along

with toxin removal

Improvement in survival rate(including bridge to liver transplant)

With permission from [20], Jaypee Brothers Medical Publishers Ltd.

Good toxin removal by adsorption and dialysis components of devices, such as MARS™ and

Prometheus™.

Williams & Wendon


i n c r e a s e d o r m e t a b o l i c a n d biotransformatory functions improved by the bioartificial-based devices trialed to date has not been convincingly shown. This is despite the apparent demonstration in vitro of an adequately functioning liver

cell module [5]. Many of the liver cell lines used in the biological devices whether porcine, primary human, tumor cell subclones or immortalized human hepatocyte preparations have significant limitations in terms of functional capacity (Box 12.1).

Controlled trials of bioartificial & artificial devicesBioartificial The first large major controlled clinical trial of a bioartificial device based on a module of living pig-derived hepatocytes gave disappointing results in a series of patients with fulminant hepatic failure or primary graft failure. Overall, a statistically significant improvement in survival was not obtained although some benefit was demonstrated in certain defined subgroups [6]. The study, which included 171 patients with both ALF and primary graft nonfunction, showed how difficult it is to conduct controlled trials in ALF because of the removal of patients for transplantation at varying times after randomization. The profound impact of transplantation on survival in ALF also makes analysis of a possible beneficial effect from an extracorporeal device extraordinarily difficult. Furthermore, it needs to be recognized that liver failure is a very heterogenous disease and any trial requires patients to be matched for etiology and severity and the time of entry to any study protocol.

Techniques for endotoxin and other mediator removal from the plasma to decrease

susceptibility to infective episodes and or improve outcome are not yet clinically available, nor have a clearly defined role.

Box 12.1. Hepatocyte module of bioartificial device.

Primary culture�� Porcine�− Good function and cryopreservation

�� Human�− Limited availability and rapid de-differentiation

Tumor cell line: C3A subclone Hep G2�� Oncogenic potential�� Incomplete function

Immortalized cell lines: telomerase reconstitution of human fetal cells�� Limited functions

Source of living liver cells in biological component of bioartificial temporary liver support devices.



More encouraging results with respect to an improvement in survival were reported, in abstract form, in a recently conducted trial of a device known as ELAD™ (extracorporeal liver assist device), which is based on a clone of a human hepatoblastoma tumor cell line. The device has been greatly improved over the years in terms of oxygenation of the cells and use of plasma instead of blood for perfusion. The randomized controlled trial carried out in two centers in China included 80 chronic HBV or HCV patients with episodes of acute decompensation [7]. Continuous ELAD perfusion was used for periods of 43–119 h. Interim results showed 30 days transplant-free survival was 86 vs 47% in the controls. Biochemical improvement was said to support the increase in survival. These encouraging results led the manufacturers: Vital Therapies Inc. (CA, USA), to set up a multicenter controlled clinical trial initially in the USA. Early findings from this trial on the safety and efficacy of the device in patients with a sequential organ failure assesment (SOFA) score ≥9, a Meld score ≥32 or 24 if grade 3/4 hepatic encephalopathy or hepatorenal syndrome (HRS) were reported at the 2010 European Association for the Study of the Liver (EASL) meeting in Vienna [8]. At 30 days, more patients achieved transplant-free survival in the ELAD-treated group although overall survival was similar to randomized controls (46 vs 50%).

The role of hepatocyte transplantation has been explored and reported in case series. Hepatocytes may be deposited into the liver or peritoneum. In adults, there are difficulties in respect of cell volume delivered. In neonates, case reports are encouraging.

Artificial devicesAlbumin dialysis with MARSThe concept of albumin dialysis and the development of the device known as MARS (Molecular Adsorbent Recycling System) by Stanger and Mitzner from the University of Rostock between 1993 and 1997 marked an important step forward in the development of extracorporeal devices. The patient’s blood is dialysed across a high flux polysulfone membrane impregnated with albumin. The pore size of 50 kDa prevents the loss of valuable hormones, growth factors and albumin. Toxins in the circulating blood are thought to pass from the patients plasma into the extracorporeal circuit (albumin rich [20%] dialysate) and thence be bound to the albumin and subsequently detoxified on the adsorbent columns (charcoal and ion exchange resins). The circuit can also include a standard hemodialysis or filtration membrane to facilitate fluid balance and removal of water soluble toxins (Figure 12.2).

Albumin functionality: capacity of albumin to bind toxins in plasma impaired when liver

disease is advanced and reduced by preservatives in commercial albumin preparations.

Williams & Wendon


More than 15,000 patients from 45 countries have now been treated by a p p r o x i m a t e l y 5 0 , 0 0 0 M A R S perfusions [Torner J, Pers. Comm.]. Clinical studies have shown improvement in some

of the pathophysiological manifestations of liver failure including encephalopathy, circulatory dysfunction and renal impairment in parallel with reductions in measured blood parameters. In the carefully controlled clinical trial of the device in cirrhotic patients with advanced encephalopathy carried out in the USA, a statistically significant improvement in encephalopathy was demonstrated accompanied by significant decreases in ammonia, bilirubin, creatinine and aromatic amino acids [9].

The anticipation was that these improvements in clinical manifestations and in biochemical abnormalities would translate through to improvements in overall survival. This, however, was not found in the recently completed

Complexity of liver failure in respect of measured putative toxins (water and protein

bound) and the breadth of pathophysiological disturbances seen in the clinical setting.

Figure 12.2. Diagrammatic representation of MARS device showing principles of toxin removal through membrane and adsorption cycle.

Blood albuminwith toxicmolecules

Dialysate albuminwith toxicmolecules

Dialysate albuminwith free binding sites

Blood albuminwith freebinding sites

Blood Dialysate

Membrane

Albumincoating with binding sites

1 2 3 4

With permission from Wiley.



controlled clinical trial of MARS known as the RELIEF Study, which was carried out in acute-on-chronic liver failure (AoCLF). In this trial of 189 unselected patients, randomization was to MARS or to standard medical therapy alone [10]. The perfusions proved to be safe with a similar frequency of adverse events in both groups. Twenty-eight day survival in the intention to treat population was similar in the two groups 60.7 versus 58.9%. Even after adjusting for confounding factors, a significant beneficial effect of MARS was not observed. An improvement in encephalopathy was, however, seen with more frequent improvement in encephalopathy from grade 2–4 to grade 0–1 (62.5 versus 38.2%) on day 4. Bilirubin was also lower in the MARS group compared with the control group on day 4.

Another recently finished multicenter controlled clinical trial of MARS – this time in ALF, was undertaken in France [11]. Overall survival was not increased. However, the majority of patients were transplanted within 24 h and thus only had one treatment. In a subgroup analysis, there was a tendency to improved survival in those of acetaminophen etiology (85 vs 68.5%). Transplant-free survival was significantly longer in those having at least three MARS sessions. The only other substantial data in ALF, excluding many published case reports showing benefit, is that of Kantola and colleagues from Finland, in which 113 ALF patients were treated with MARS over the period 2001–2007 and compared with findings in 47 historical controls seen during 1995–2001 [12]. Spontaneous survival was 20% in the treated group compared with 8% in controls and the 6-month survival in those transplanted was higher in the cases treated with MARS pretransplant (91 vs 69%). Although these data would suggest potential benefit the changes seen may be consequent on improvements in critical care management, surgical and anesthetic techniques over this period.

Fractionated plasma separation & adsorption: the Prometheus devicePrometheus is the other artificial-based device that has recently been subjected to a multicenter controlled clinical trial in AoCLF patients. In contrast to MARS, it is based on an albumin-permeable membrane and the separated plasma fraction is cleared of protein bound toxins by passage through columns of adsorbents, before being returned to the patient (Box 12.2). A comparison study with MARS showed a better reduction in bile acids, plasma bilirubin level and particularly of the unconjugated fraction. Correction of the characteristic hyperdynamic circulatory disturbance of liver failure was found only with MARS in association with

High-volume plasmapheresis (reported in abstract form only) is thus far the only form of

temporary liver support to show statistically significant survival benefit in acute liver failure.

Williams & Wendon


decreased levels of vasoactive substances, including plasma renin activity and nitric oxide [13].

The results of the controlled clinical trial with the Prometheus system in AoCLF (Helios study) reported initially at the 2010 EASL meeting, were recently published [14]. The patients had eight to 11 rounds of TLS (minimum of 4 h each). As with the RELIEF study, no statistically significant difference in overall survival from the control group was demonstrated. The 66% probability of survival on day 28 in the device-treated group is to be compared with 63% for standard medical care – very similar survival figures, interestingly, as in the MARS device trial. Analysis of predefined subgroups showed that one of them, namely, those patients with a high MELD score and type I HRF score had a significant survival advantage after adjustments for independent prognostic baseline parameters.

Possible explanations why overall survival is not increased despite improvements in various components of the AoCLF syndrome, particularly encephalopathy, circulatory derangements and the hepatorenal syndrome, include inadequacy of the perfusion regime with insufficient duration and number of treatments. Another possibility relates to the case mix of the patients entered into the trial with inclusion of cases without the potential for recovery. Failure to control infective episodes: increasingly recognized as an important component of the syndrome of AoCLF and of ALF both in the development of multiorgan dysfunction and as the final cause of death, is a further explanation. Appropriate dosing of antimicrobials in patients receiving extracorporeal support systems needs to be addressed. Removal

of endotoxin released into the plasma from gut microbial translocation may be critical and the efficacy of such removal by different adsorbents in new systems for extracorporeal liver support is currently the subject of ongoing research.

There is good theoretical basis for temporary liver support in the context of improving liver

regenerative capacity and thus survival following onset of acute liver failure.

Little evidence to date of significant synthetic function or of biotransformatory function from living liver cell components.

Box 12.2. Basis of Prometheus™ temporary liver support system and comparison with MARS device.

Principles of the Prometheus system: fractionated plasma separation.Separation through albumin-permeable membrane (300 kDa), perfusion through neutral resin and anion exchanger. Purified plasma returned to blood via standard dialysis to remove water soluble toxins.�� Compared with MARS�− No dissociation of albumin and diffusion necessary�− No need for exogenous albumin infusion



Functionality of albumin in liver failure & in commercial preparationsRelevant to the use of extracorporeal systems for the removal of albumin bound toxins that accumulate in liver failure, is the increasing evidence that the functional capacity of albumin for binding to toxins is impaired in patients with advanced liver disease (Figure 12.3) [15,16]. The defect does not appear to be corrected by passage through the adsorbent columns of the devices and removal of the toxins. This would suggest that the recycled albumin being returned to the patients’ circulation in the MARS and Prometheus devices will have a poor capacity for taking up further toxins released from damaged tissues.

Figure 12.3. Reduced albumin binding capacity in liver failure and of commercial preparations and in the latter correction by Hepalbin® device.

Alb

um

in b

ind

ing

cap

acit

y (%

)

Healthydonor

Liverfailure

Commercialalbumin

Bed-sidefiltration albumin(Hepalbin)

0

10

20

30

40

50

60

70

80

90

100

110

Reproduced with permission from Albutec GmbH.

Decreased albumin functionality in binding toxins is potentially of importance in design of

future temporary liver support systems.

Williams & Wendon


It has also been shown that the commercially available preparations of albumin for intravenous use that may be infused to supplement albumin levels during the course of extracorporeal perfusion, or indeed as part of standard of care also have impaired binding capacity for toxins. The preservatives caprylate and N-acetyltryptophan, which are added for virus inactivation and storage, overload the benzodiazepine binding site on the albumin molecule. This results in a 30–40% reduction of albumin binding capacity.

Furthermore, these substances are poorly metabolized in patients with impaired liver function and may exacerbate clinical manifestations of encephalopathy and circulatory vasodilatation. This needs to be considered, however, in the face of the large body of clinical evidence, which has shown benefit of albumin infusions in patients with liver disease. A case can be made however for considering removing them from albumin preparations prior to infusion into patients with liver failure. This can be achieved using the bedside Hepalbin-Adsorbent device. In decompensated cirrhotic patients, albumin binding capacity was increased with an improvement in renal and circulatory hemodynamics function. A controlled trial comparing commercial versus cleaned albumin has not yet been undertaken.

Timing & use of TLS in ALFWhatever technique of TLS used, it is likely to be of greatest value in initiating/enhancing spontaneous recovery if started early in the course of ALF when as progressive biochemical deterioration with a rising serum bilirubin and INR level and deterioration in encephalopathy to deep levels of coma become evident. In cases of acetaminophen hepatotoxicity from a single overdose, this is likely to be approximately days 3–4 following ingestion. In the staggered (often unintentional) type of overdose, which according to a recent publication from Edinburgh (UK), accounts for over 24% of their cases currently (48% in the USA), low-grade hepatic encephalopathy is often already present by the time of presentation [17]. This is a group where standard prognostic models are less likely to predict outcome effectively and use of SOFA score should be considered as suggested by the Edinburgh group. TLS systems may be considered in such patients once a given SOFA score is achieved.

Later on in the clinical course of ALF, once transplant criteria has been fulfilled and the patient is on the waiting list for an organ, TLS could be of benefit in improving the clinical state and thereby outcome after transplantation. This will be particularly relevant when an organ is not immediately available over the first 24–48 h after listing and in the subacute type of ALF where transplantation remains the main, and indeed the only



option in most cases, for obtaining a survival result. Further studies will need to address etiology and severity stratification in addition to the compounding effect of transplantation.

As to which form of TLS is used will revolve around availabilities and practicalities of use. High-volume plasmapheresis: the only technique currently available that has shown statistical significance in improving survival outcome in those not proceeding to transplantation, can be achieved in critical care units but is dependent upon an adequate supply of fresh frozen plasma. However, one of the effects of this system is loss of coagulation as a prognostic marker. This is not an issue if the decision regarding transplantation has been made but if not may compound difficulty in deciding that transplantation is the appropriate management. The MARS device at least in Europe is likely to be available in many of the larger regional centers. Its good safety record and its beneficial effects on cardiovascular and neurological parameters in AoCLD make this technique attractive but there is as yet no proven survival benefit with it. An established background of liver expertise in the intensive care unit is essential for successful and safe use of extracorporeal devices. In turn, this should lead to early referral of ALF cases to such centers for treatment, which again should lead to a better overall outcome. Availability of expertise in all the different facets of liver intensive care has to be the basis on which standard medical care for these patients is developed and is also the basis for the successful additional use of TLS and liver transplantation.

The rarity of ALF and the difficulty in conducting controlled clinical trials because of the confounding influence of liver transplantation quite apart from the costs involved for a small commercial market will all mitigate against the setting up of further controlled trials in ALF. For example, the accrual of patients for the high-volume plasmapheresis controlled trial took 8 years. Some extrapolation of findings from trials of TLS in chronic liver disease is inevitable particularly as the main pathophysiological changes of encephalopathy, circulatory disturbance and renal impairment are common to both forms of liver failure.

Finally, it is to be stressed that this review is restricted to techniques that are in current use in Western countries and for which there is a substantial evidence base available from controlled clinical trials in humans. Beyond the scope of this chapter are the many different liver support systems that are being used in China and Japan based on various combinations of dialysis, adsorption and plasma exchange. Much research is also ongoing into bioartificial devices in terms of improving bioreactor designs with

Williams & Wendon


better oxygenation and removal of excretory products. Of these the AMC (Academic Medical Centre) BAL, and the MELS (Modular Extracorporeal Liver Support) bioreactors have shown initial promise in a limited number of patients as well as in experimental animal models. New liver cell sources under trial include immortalized fetal and adult hepatocytes and human stem cell-derived hepatocytes. The potential of scaffold systems for promoting adhesion growth function of hepatocytes and of culturing cells in microfluids represent other important research areas [18,19]. All of this may yet result in an effective bioartificial system providing significant quantitative biochemical and metabolic function when used in humans.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organi-zation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, con-sultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Summary.

�� Considerable progress has been made in the development of safe devices for extracorporeal temporary liver support (TLS) over the past 20 years. �� Mounting evidence is available for the efficacy of the artificial-based systems in removal of

toxins that accumulate in liver failure.�� Associated with toxin removal is improvement in encephalopathy and other manifestations of

multiorgan failure, notably renal and circulatory disturbances. �� Attainment of overall survival benefit may be beyond what can be reasonably expected from

TLS because of lack of potential for spontaneous recovery of liver cell function. �� Specific adsorption requirements in TLS need to be related to greater knowledge of the early

cellular mechanisms underlying liver damage.�� Critical to the use of TLS is removal of endotoxin to reduce susceptibility of acute liver failure

patients to infective episodes and their effect on exacerbating multiorgan failure.

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