Systematic review and meta-analysis of survival following extracorporeal liver support (Br J Surg 2011; 98: 623–631)

Meta-analysis

Systematic review and meta-analysis of survival followingextracorporeal liver support

B. M. Stutchfield1, K. Simpson2 and S. J. Wigmore1

Departments of 1Surgery and 2Hepatology, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UKCorrespondence to: Mr B. M. Stutchfield (e-mail: [email protected])

Background: Extracorporeal liver support (ELS) systems offer the potential to prolong survival in acuteand acute-on-chronic liver failure. However, the literature has been unclear on their specific role andinfluence on mortality. This meta-analysis aimed to test the hypothesis that ELS improves survival inacute and acute-on-chronic liver failure.Methods: Clinical trials citing MeSH terms ‘liver failure’ and ‘liver, artificial’ were identified by searchingMEDLINE, Embase and the Cochrane registry of randomized controlled trials (RCTs) between January1995 and January 2010. Only RCTs comparing ELS with standard medical therapy in acute or acute-on-chronic liver failure were included. A predefined data collection pro forma was used and study qualityassessed according to Consolidated Standards of Reporting Trials (CONSORT) criteria. Risk ratio wasused as the effect size measure according to a random-effects model.Results: The search strategy revealed 74 clinical studies including 17 RCTs, five case–control studiesand 52 cohort studies. Eight RCTs were suitable for inclusion, three addressing acute liver failure (198participants) and five acute-on-chronic liver failure (157 participants). The mean CONSORT score was14 (range 11–20). Overall ELS therapy significantly improved survival in acute liver failure (risk ratio0·70; P = 0·05). The number needed to treat to prevent one death in acute liver failure was eight. Nosignificant survival benefit was demonstrated in acute-on-chronic liver failure (risk ratio 0·87; P = 0·37).Conclusion: ELS systems appear to improve survival in acute liver failure. There is, however, no evidencethat they improve survival in acute-on-chronic liver failure.

Presented in part to a Joint Meeting of the European Society of Transplantation and American Society of Transplantation,Nice, France, October 2010

Paper accepted 8 December 2010Published online 24 February 2011 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.7418

Introduction

Liver transplantation is currently the only treatmentproven to improve survival in acute and acute-on-chronicliver failure1,2. Given the increasing demand for livertransplantation and the shortfall in organ supply, adevice capable of supporting the failing liver is required.Extracorporeal liver support (ELS) systems have been thesource of continued investigation for over 40 years, buttheir use remains restricted to a minority of specialistcentres. In comparison, extracorporeal renal, respiratoryand cardiac support systems have a well established rolein the management of critically ill patients. This disparitymay in part be attributed to the multitude of complex

functions the liver must perform in order to maintain life.A limited range of functions can be performed by ELSsystems, and both artificial and bioartificial systems havebeen developed.

Artificial liver support systems aim to replace thedetoxification functions of the liver, based on albumindialysis. Artificial systems consist of membrane separa-tion associated with columns or suspensions of sorbents,including charcoal and anion or cation exchange resins.Three artificial liver support system types have under-gone randomized controlled trials (RCTs), includingthe MARS device (Molecular Adsorbent RecirculatingSystem; Gambro, Stockholm, Sweden), Prometheus

(Fresenius Medical Care, Bad Homburg, Germany) and

2011 British Journal of Surgery Society Ltd British Journal of Surgery 2011; 98: 623–631Published by John Wiley & Sons Ltd

624 B. M. Stutchfield, K. Simpson and S. J. Wigmore

the BioLogic-DTTM

(now called the Liver Dialysis Device;HemoCleanse, Lafayette, Indiana, USA. This device iscurrently being redesigned). Bioartificial systems incor-porate either human hepatoblastoma cells or porcinehepatocytes into bioreactors that are intended to per-form both liver detoxification and synthetic functions.A porous barrier between the patient’s blood or plasmaisolates cells from immunoglobulins and leucocytes, avoid-ing immune rejection. Smaller particles such as toxins,metabolites and synthesized proteins are free to crossthe barrier. RCTs have been performed on two bio-artificial liver systems, the HepatAssist

TMdevice (devel-

oped by Arbios Systems, Allendale, New Jersey, USA;now marketed as HepaMate by HepaLife Technologies,Boston, Massachusetts, USA), which uses porcine hepato-cytes, and the ELAD (Extracorporeal Liver Assist Device;Vital Therapies, San Diego, California, USA), which useshuman hepatoblastoma cells.

A Cochrane review of ELS systems for use in acuteand acute-on-chronic liver failure, reviewing articlespublished before September 2002, concluded that overallELS had no significant effect on mortality but thereappeared to be a survival advantage in acute-on-chronicliver failure3. Subsequent RCTs have provided differingviews, with one of the largest trials in acute-on-chronicliver failure (70 patients) showing no survival advantagewith ELS system use4. Conversely, a RCT involving147 patients with fulminant or subfulminant hepaticfailure demonstrated a significant survival benefit withELS when accounting for confounding factors5. Althoughsystematic reviews have provided descriptive analyses of theeffects of ELS since 2004, with others including systemsdating back to the 1970s6–8, meta-analysis examiningcontemporary ELS therapies has not been performed.It was therefore felt appropriate to re-evaluate the role ofELS therapies in improving survival in patients presentingwith acute and acute-on-chronic liver failure, especiallygiven the increasing demand on liver transplantationservices.

This systematic review explored the effect of ELSsystems on survival in both acute and acute-on-chronicliver failure by meta-analysis of RCTs, testing thenull hypothesis that ELS systems do not improvesurvival in acute or acute-on-chronic liver failure.A systematic review of the wider effects of ELSsystems on clinical and biochemical parameters was alsoundertaken.

Methods

A systematic review and meta-analysis were performedaccording to recommendations of the Preferred Report-ing Items for Systematic Reviews and Meta-analyses(PRISMA) statement9.

Literature search

Clinical trials citing the MeSH terms7 ‘liver failure’ AND‘liver, artificial’ were identified by searching MEDLINEand Embase databases and the Cochrane database of RCTsbetween January 1995 and January 2010. The search wascarried out by the principal researcher according to aprotocol agreed by all authors. A manual search of referencelists of published articles was also undertaken.

Study selection

Only RCTs were included in the meta-analysis; thesecondary analysis reviewed RCTs not included in themeta-analysis and case–control studies, excluding casereports. Publication language did not influence selection.Only RCTs comparing a single ELS therapy withstandard medical therapy were eligible for inclusion. Studypopulations included patients with acute liver failure andacute-on-chronic liver failure. Interventions (treatmentgroup) included artificial and bioartificial liver supportsystems. The comparison intervention (control group) wasstandard medical therapy.

Trial assessment

A predefined data collection form was used to extractrelevant trial information. RCTs were assessed forquality according to the Consolidated Standards ofReporting Trials (CONSORT) criteria by three reviewersindependently10. A point was awarded for each criterionmet. The mean CONSORT score was calculated foreach trial. Potential study bias was assessed accordingto Cochrane Collaboration guidelines, with consensusreached following discussion by all authors11. The primaryoutcome measure was all causes of death at maximumfollow-up. Separate analyses were performed for acute andacute-on-chronic liver failure. Where possible, short-termsurvival at specified time points, 7 and 10 days, was alsoassessed. Secondary outcome measures included effectson hepatic encephalopathy, biochemical parameters andadverse events.

2011 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2011; 98: 623–631Published by John Wiley & Sons Ltd

Survival following extracorporeal liver support 625

Statistical analysis

Meta-analyses were carried out with RevMan 511, and thesoftware package Comprehensive Meta-analysis (Biostat,Englewood, New Jersey, USA) was used to assess studybias statistically. Effectiveness was estimated accordingto a random-effects model. The effect was calculatedas a risk ratio with 95 per cent confidence intervals. A‘number needed to treat’ calculation was used as anadditional measure of potential clinical impact. Cochran’sQ statistic was used to test for heterogeneity in effect size.Clinical heterogeneity was assessed by reviewing patientcharacteristics and study design. Potential for publicationbias was investigated by visual inspection of funnel plots.Further assessment of publication bias was made by the fail-safe N method if appropriate12. The level of significancewas set at P < 0·050.

Results

The search strategy revealed 74 clinical trials including17 RCTs, five case–control studies and 52 cohort studies.Fig. 1 shows the trial flow diagram for study selection.Eight RCTs investigating the effects of ELS in acute liver

failure (3 studies, 198 participants)5,13,14 and acute-on-chronic liver failure (5 studies, 157 participants)4,15–18

were suitable for inclusion. Study characteristics areshown in Table 1. In addition to survival, included studiesalso assessed hepatic encephalopathy, liver metabolicfunction, liver synthetic function and effects on haemo-dynamics. Results for these outcomes are summarizedin Table 2. None of the included trials reported asignificant difference in adverse events between theELS and standard medical therapy groups. No specificbiocompatibility issues were raised by any of thetrials. Sample size calculations were provided by twostudies4,16 and sufficient recruitment was achieved in these.Randomization and sequence generation procedures wereadequately reported by three of the eight studies4,5,17.Details of allocation concealment were reported by five ofthe eight included studies4,5,15–17. None of the studies wasblinded.

Effect of ELS on mortality in acute andacute-on-chronic liver failure at maximumfollow-up

Overall ELS therapy significantly improved survival inacute liver failure (risk ratio 0·70; Z = 1·95; P = 0·05),

Potentially relevant abstractsidentified and screened for retrieval

n = 74

Articles retrieved for more detailedevaluation

n = 17

Potentially appropriate RCTs to beincluded in the meta-analysis

n = 15

RCTs included in meta-analysisn = 10

RCTs with usable information, byoutcome

n = 8

Excluded as abstract or title unsuitable n = 57

Excluded n = 2 Survival data not reported n = 2

RCTs withdrawn, by outcome n = 2 Same patient group as another included study n = 2

RCTs excluded from meta-analysis n = 5 No SMT group n = 1 Inconsistent management (including additional therapies) of SMT group n = 1 Single treatment assessing haemodynamic/clinical parameters n = 2 Small sample size including patients with ALF and AoCLF n = 1

Fig. 1 Trial flow diagram according to PRISMA statement9. RCT, randomized controlled trial; SMT, standard medical therapy; ALF,acute liver failure; AoCLF, acute-on-chronic liver failure



Table 1 Characteristics of randomized controlled trials assessing the use of artificial and bioartificial liver support systems in acute andacute-on-chronic liver failure included in the meta-analysis

Reference ELS type

Primaryoutcomemeasure Follow-up

Aetiology ofliver failure

No. ofpatients

(ELS : SMT)

Recruitmentperiod

(months)No. of

centresTreatmentregimen

CONSORTscore

Acute liver failureElliset al.13

1996

ELAD

(bioartificial)Survival 31 days Paracetamol

overdose 17,viral hepatitis5, anti-TBchemotherapy2

12 : 12 12 1 Median 62 h ofELS therapy

14

ElBanayosyet al.14

2004

MARS

(artificial)Survival Discharge from

ICU (mean42 days ELS;27 daysSMT)

Acute hypoxicliver failure(cardiogenic)

14 : 13 16 1 8 h/day for 3days; treatmentcontinued ifbilirubin < 6mg/dl

11

Demetriouet al.5

2004

HepatAssist(bioartificial)

Survival 30 days Fulminant andsubfulminanthepatic failure

73 : 74 36 20 6 h/day,maximum 14days; stoppedif significantclinical changeor transplanted

18

Acute-on-chronic liver failureHassaneinet al.4

2007

MARS

(artificial)Encephalopathy;

adverseevents

180 days Cirrhosis +deteriorationto HE grade 3or 4

39 : 31 36 8 6 h/day until 5treatments orimprovement inencephalopathy

20

Heemannet al.15

2002

MARS

(artificial)Serum bilirubin 30 days Cirrhosis

(predominantlyalcoholic) +acutedeterioration

12 : 11 NS 2 Average 6 h/dayuntilimprovement inbilirubin

17

Sen et al.16

2004MARS

(artificial)Cytokine profile

and survival3 months Alcoholic

cirrhosis +acutedeterioration

9 : 9 NS 1 4 sessions of 8 hover 7 days

15

Mitzneret al.17

2000

MARS

(artificial)30-day survival 30 days Cirrhosis and

deteriorationwithhepatorenalsyndrome

8 : 5 2 2 6–8 h/day;maximum of 10treatments perpatient

16

Elliset al.18

1999

BioLogic-DT

TM*

(artificial)

Survival todischarge

33 days Alcoholic liverdisease

5 : 5 NS 1 6 h/day for 3 days 11

*BioLogic-DTTM has been renamed Liver Dialysis Device. ELS, extracorporeal liver support; SMT, standard medical treatment; CONSORT,Consolidated Standards of Reporting Trials; ELAD, Extracorporeal Liver Assist Device; TB, tuberculosis; MARS, Molecular Adsorbent RecirculatingSystem; ICU, intensive care unit; HE, hepatic encephalopathy; NS, not stated.

although the risk ratio was not significant in any individualtrial. The forest plot of risk ratio and summary statisticsare shown in Fig. 2. Visual inspection of the funnel plotdid not suggest publication bias but interpretation waslimited by the small number of studies. As no individualtrial demonstrated significant survival benefit, calculationof fail-safe N was not relevant. The Q statistic didnot demonstrate significant heterogeneity in effect size

(Q = 0·09; P = 0·95). The number needed to treat toprevent one death was eight.

In acute-on-chronic liver failure there was no reductionin mortality with ELS compared with standard medicaltherapy (risk ratio 0·87; Z = 0·89; P = 0·37). The forestplot of risk difference and summary statistics are shownin Fig. 3. The Q statistic did not demonstrate significantheterogeneity in effect size (Q = 6·20; P = 0·18).



Table 2 Outcomes of randomized controlled trials included in the meta-analysis according to significant benefit

ReferenceOverallsurvival

Subgroupsurvival

Survival totransplant

Hepaticencephalopathy Bilirubin

Prothrombinactivity Haemodynamics

Acute liver failureEllis et al.13 No No NA No No (at 48 h) No NAEl Banayosy et al.14 No No NA NA Reduced serum

bilirubinNo NA

Demetriou et al.5 No Yes (in FHF/SHFfailure accountingfor confoundingfactors)

NA NA Reduced serumbilirubin

NA No

Acute-on-chronic liverfailureHassanein et al.4 No NA NA Yes No NA NAHeemann et al.15 Yes NA NA Yes Reduced serum

bilirubinNo Yes (increased MAP

with ELS)Sen et al.16 No NA NA Yes No No NoMitzner et al.17 No NA NA NA Reduced serum

bilirubinYes (increased) Yes (increased MAP

with ELS)Ellis et al.18 No NA NA No No No No

No, no significant benefit; NA, not assessed; Yes, significant benefit demonstrated; FHF, fulminant hepatic failure; SHF, subfulminant hepatic failure;MAP, mean arterial pressure; ELS, extracorporeal liver support.

Reference

Demetriou et al.5

El Banayosy et al.14

Ellis et al.13

Total

Heterogeneity: τ2 = 0·00; χ2 = 0·09, 2 d.f., P = 0·95, I2 = 0%Test for overall effect: Z = 1·95, P = 0·05

20 of 73

7 of 14

4 of 12

31 of 99 44 of 99

30 of 74

9 of 13

5 of 12

Weight (%)

57·8

30·7

11·5

100·0

0·68 (0·42, 1·08)

0·72 (0·38, 1·37)

0·80 (0·28, 2·27)

0·70 (0·49, 1·00)

ELS SMT Risk ratio Risk ratio

0·2 0·5 1 2 5

Favours ELS Favours SMT

Acute liver failure

Fig. 2 Forest plot showing risk ratio with 95 per cent confidence interval for individual studies comparing extracorporeal liver support(ELS) with standard medical therapy (SMT) in acute liver failure. The Mantel–Haenszel random-effects method was used

Reference

Ellis et al.18

Hassanein et al.4

Heemann et al.15

Mitzner et al.17

Sen et al.16

Total

Heterogeneity: τ2 = 0·04; χ2 = 6·20, 4 d.f., P = 0·18, I2 = 35%Test for overall effect: Z = 0·89, P = 0·37

5 of 5

19 of 39

1 of 12

36 of 73 39 of 61

5 of 5

17 of 31

7 of 11

Weight (%)

34·7

26·3

2·5

100·0

1·00 (0·71, 1·41)

0·89 (0·56, 1·40)

0·13 (0·02, 0·90)

6 of 8 5 of 5 25·1 0·79 (0·49, 1·26)

5 of 9 5 of 9 11·4 1·00 (0·44, 2·29)

0·87 (0·64, 1·18)

ELS SMT Risk ratio Risk ratio

Acute-on-chronic liver failure

0·1 0·2 0·5 1 2 5 10

Favours ELS Favours SMT

Fig. 3 Forest plot showing risk ratio with 95 per cent confidence interval for individual studies comparing extracorporeal liver support(ELS) with standard medical therapy (SMT) in acute-on-chronic liver failure. The Mantel–Haenszel random-effects method was used



Effect of ELS on short-term mortality in acute andacute-on-chronic liver failure

It was possible to extract short-term mortality data at aspecified time point for only one of the three studies inacute liver failure5. In this study, there was no significantdifference in mortality at 7 days (risk ratio 0·69; Z = 1·27;P = 0·20).

Mortality data at a specified time point could be extractedfor only four of the five trials assessing acute-on-chronicliver failure. Survival data could be calculated at 10 days forthree trials4,15,17 and at 7 days for one study16. There wasno difference in mortality between ELS and control groupsat 10 or 7 days (risk ratio 0·70; Z = 1·29; P = 0·20). TheQ statistic did not demonstrate significant heterogeneity ineffect size (Q = 3·83; P = 0·28).

Secondary analysis: case–control studies andexcluded randomized controlled trials

Extending the search criteria to include case–controlstudies assessing the efficacy of ELS therapies revealedtwo case–control studies in acute liver failure19,20 andthree in acute-on-chronic liver failure21–23. None showedan overall survival benefit with ELS therapy in acuteliver failure, but all three studies in acute-on-chronicliver failure showed significant benefit in favour of ELS.Characteristics of these studies are shown in Table S1(supporting information).

Excluded RCTs were one study in acute liver failure24,six in acute-on-chronic liver failure25–30, and two thatincluded patients with both acute and acute-on-chronicliver failure31,32. The results of these studies aresummarized in Table S2 (supporting information).

Discussion

This meta-analysis has demonstrated that ELS systems cansignificantly improve survival in acute liver failure, with thepotential for clinical benefit demonstrated by the overallnumber needed to treat of eight. Although no individualincluded RCT showed overall survival significance,Demetriou and colleagues5 conducted further analysis oftheir survival data (the largest randomized trial to date),taking into account confounding factors, such as severity ofillness and disease aetiology, revealing a significant survivaladvantage in favour of ELS in fulminant/subfulminanthepatic failure. Owing to the additional informationrequired for such analysis, accounting for confoundingfactors was not possible in this meta-analysis. Analysisaccording to disease aetiology was not provided by anyof the studies included here, but others have shown that

patients with paracetamol-related liver failure are at greaterrisk of death while awaiting transplantation than thosewith other aetiologies (survival rate 68 versus 84 per cent),perhaps indicating that this group may derive most benefitfrom ELS therapy33. Neither the Cochrane review3

evaluating ELS use (published in 2004) nor the meta-analysis by Kjaergard and colleagues34 (published in 2003)demonstrated a significant survival advantage in acuteliver failure. These previous reviews included publishedabstracts and full papers dating back to the 1970s andpredate the trial of Demetriou and co-workers5. The morestringent selection criteria in the present meta-analysis mayprovide a more accurate reflection of contemporary ELSsystem use.

There was no evidence that ELS improved survivalin acute-on-chronic liver failure in this meta-analysis.It should be noted that the largest two trials in thisgroup by Hassanein et al.4 and Heemann and co-workers15

used encephalopathy and serum bilirubin respectively asprimary outcome measures rather than survival. Despiteoverall non-significance, Heemann and colleagues15 didshow a significant survival benefit in favour of ELSin acute-on-chronic liver failure. The reason for thediscrepancy in outcome compared with other includedRCTs is not clear, although the range of results was notsignificantly heterogeneous. The findings of the presentmeta-analysis are in agreement with a previous meta-analysis looking specifically at the MARS

TMsystem35, but

contrasts with previous reviews suggesting a survival benefitwith ELS in acute-on-chronic liver failure3,34. Theseprevious favourable reviews predate the largest trial ofELS use in acute-on-chronic liver failure, which showed nodifference between ELS use and standard medical therapy4.Despite this, benefit for ELS in acute-on-chronic liverfailure should not be discounted. The disease trajectorymay show considerable variation in acute-on-chronic liverfailure owing to diverse underlying aetiology and extentof cirrhosis, and subgroup analysis may therefore be ofparticular relevance. All studies assessed ELS use in atime-limited manner, which in the setting of chronic liverfailure may complicate assessment of survival beyond thetreatment period. Among the case–control studies, thethree investigating acute-on-chronic liver failure showed asignificant survival benefit with ELS. All three of these trialswere open to considerable selection bias and so these resultsshould be interpreted with caution. The excluded RCTsadded little to the survival data, owing to considerablevariation in trial design and quality.

In this meta-analysis a short-term survival endpoint wascalculated to assess the potential role of ELS systemsas a ‘bridge to transplantation’. In severe acute liver



failure, death while on the transplant waiting list is mostprevalent during the first 5 days33. Short-term support ofliver function before transplantation is therefore highlydesirable. None of the included studies had directlyassessed this. Given the presentation of survival data inthese studies, it was possible only to specify a short-termsurvival endpoint of either 7 or 10 days. There was nosignificant difference between groups, in either acute oracute-on-chronic liver failure, although it should be notedthat only one trial in acute liver failure could be includedin this analysis5.

There appeared to be a reduction in serum bilirubin andhepatic encephalopathy associated with ELS in severalof the studies included in the secondary analysis. Areduction in bilirubin level should perhaps be expectedgiven that most ELS systems included an albumin dialysiscomponent. The clinical significance of this is not clear.Reduced hepatic encephalopathy may in part be attributedto reduced serum ammonia levels, although confirmationof the specific underlying mechanism was not demonstratedby any of the studies.

It is well recognized that meta-analysis of small RCTscan produce unreliable results36. The limited number ofstudies and relatively small number of patients suitablefor inclusion in this meta-analysis leads to a risk ofunderpowered analysis. The selection criteria for thepresent review have resulted in the exclusion of a numberof trials that have been included in other analyses. Despitethese more stringent criteria, many of the included trialswere of questionable methodological quality, reflected bya low CONSORT score in some instances. Althoughsignificant publication bias did not appear to be present,several studies did not report randomization methods andallocation concealment, or provide sample size calculations.There was considerable variation in length of follow-upacross the included RCTs and survival was not the primaryoutcome measure in several studies.

Recruiting sufficient numbers of patients to powerstudies adequately has clearly been a challenge. The largestRCT in acute liver failure involved 20 centres over 3 years,thereby recruiting a mean of 2·5 patients per centre per year(individual centre recruitment not provided). Althoughthese low single-centre numbers are likely to relate to unitvolume, the contraindications for ELS use may also restrictpatient numbers. To be eligible for ELS, patients mustbe haemodynamically stable, aseptic and have sufficientcardiac reserve to tolerate extracorporeal circulation of aquantity of blood. Although these may be justified on thegrounds of similarity to pretransplant criteria, extendingthe use of ELS to patients unsuitable for transplantation

(perhaps owing to co-morbidities) may offer these patientsa chance of survival.

Acute and acute-on-chronic liver failure were analysedseparately in this meta-analysis. Such division was thoughtappropriate given the differences in disease aetiology,management and outcome between these liver failure types.Including both artificial and bioartificial ELS systems inthe meta-analysis is a limitation. However, the conceptof providing ELS remains the same. It is not possibleto suggest the most efficacious type of ELS systemfrom this analysis, rather that ELS as a concept maybe beneficial. A similar methodology has been used byprevious reviewers3,34,35. Even among individual types ofartificial or bioartificial support system there is considerableheterogeneity (charcoal filtration, anion/cation exchangeresins, human hepatoblastoma cells, porcine hepatocytes).Although bioartificial systems contain a biologically activeelement, their major function is likely to be detoxificationwith little evidence conclusively to demonstrate clinicallyrelevant synthetic function. Few trials have assessedbioartificial system use, perhaps reflecting the greatercomplexities in the development, production and deliveryof hepatocyte-based systems.

Investigations to assess efficacy further and establishthe most appropriate indications for artificial and bio-artificial systems should continue. Hepatic resection isa well established treatment for liver metastases andhepatocellular cancer, with an increasing role in the multi-disciplinary oncological approach. Extended resectionis often necessary, risking small-for-size syndrome andpostoperative liver failure37. There is currently no otherliver-specific supportive treatment available and a ‘rescuetherapy’ is required. Significant hypoxic liver insult, as candevelop in the context of cardiac surgery, warrants furtherinvestigation14. Supporting the failing liver during the waitfor transplantation, the effect of pretransplant ELS therapyon postoperative outcome, and the potential for ELS tofacilitate hepatic regeneration in acute and chronic liverfailure, should also be explored.

There is currently no way of predicting the waitingtime in patients with acute or acute-on-chronic liverfailure listed for transplantation. It would therefore seemappropriate to start all patients who meet the criteria forurgent liver transplantation on ELS therapy if available. Incountries where an urgent liver transplantation service isnot available, ELS therapies may offer the only chance ofsurvival in supporting liver regeneration. In such situationsit would seem reasonable that patients with a significantpredicted risk of death be commenced on ELS therapy.

The present evidence suggests that ELS systems canimprove survival in acute liver failure. The available data



from RCTs do not suggest a significant survival benefitfor ELS use in acute-on-chronic liver failure. Given theincreasing demand for liver transplantation and risk of liverfailure following extended liver resection, the developmentof effective ELS systems is necessary.

Acknowledgements

This paper was awarded the BJS prize in August 2010 forthe best scoring e-dissertation of the Edinburgh SurgicalSciences Qualification (ESSQ). The prize is awarded annu-ally to students of the ESSQ Masters in Surgical Sciencesdistance learning programme (www.essq.rcsed.ac.uk) whosubmit an adapted version of their masters research projectfor publication in the BJS. The authors declare no conflictof interest.

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Supporting information

Additional supporting information may be found in the online version of this article:

Table S1 Case–control studies assessing extracorporeal liver support in acute and acute-on-chronic liver failure(Word document)

Table S2 Excluded randomized controlled trials assessing extracorporeal liver support in acute and acute-on-chronicliver failure. Studies including patients with both acute and acute-on-chronic liver failure are also shown (Worddocument)

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Commentary

Systematic review and meta-analysis of survival following extracorporeal liversupport (Br J Surg 2011; 98: 623–631)

Many biological and non-biological liver support therapies based on detoxification of the patient’s blood have beendeveloped and tested in patients with acute liver failure and those with cirrhosis, mainly patients with hepaticencephalopathy. This meta-analysis by Stutchfield and colleagues has tried to answer a crucial question about thereal impact of these devices on patient survival. Whether survival should be the only surrogate marker is still a matter ofconsiderable debate; other markers, such as improvement in neurological status, haemodynamics, cholestasis, markers ofliver regeneration and quality of life, are still questionable. The ideal clinical endpoint on the patient side is transplant-freesurvival, thereby avoiding liver transplantation and death. On the other hand, liver transplantation remains the besttreatment for these patients today. The recent improvement in liver transplantation results, reaching a 1-year survivalrate of 90 per cent, makes the evaluation of liver support therapies mainly in the acute setting extremely difficult. Themeta-analysis reported here, despite some methodological biases (small trials, different aetiologies, different devices andtechniques, non-homogeneity of patient recruitment), provides an accurate basis for the future development of thesetechniques. The better outcome observed in patients with acute liver failure well reflects the clinical reality and mainlythe fact that, in this clinical setting, the liver is more prone to regenerate and transplant-free survival is more likely thanin patients with end-stage chronic liver disease.

Could we consider all available devices equivalent? The synthetic functional capacity of the currently availablebioartificial devices is hardly noticeable and clinically insufficient by far. Based on recent experimental and preclinical data,improvements in this field are awaited. Meanwhile, the results from new trials of non-biological liver support therapiesusing high-volume plasma exchange, the molecular adsorbent recirculating system MARS (Gambro, Stockholm, Sweden)and Prometheus (Fresenius Medical Care, Bad Homburg, Germany) are expected1–3.

F. SalibaCentre Hepato-Biliaire, Assistance Publique–Hopitaux de Paris Hopital Paul Brousse, Universite Paris-Sud, Unite Mixte de Recherche en

Sante 785 and Unite Institut National de la Sante et de la Recherche Medicale 785, Villejuif, France(e-mail: [email protected])

DOI: 10.1002/bjs.7428

References

1 Saliba F, Camus C, Durand F, Mathurin P, Delafosse B, Barange K et al.; FULMAR study group. Randomized controlledmulticenter trial evaluating the efficacy and safety of albumin dialysis with MARS in patients with fulminant and subfulminanthepatic failure. Hepatology 2008; 48: Abstract LB4.

2 Banares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger M; Relief Study Group. Extracorporeal liver support with themolecular adsorbent recirculating system (MARS) in patients with acute-on-chronic liver failure (AoCLF). The Relief Trial.J Hepatol 2010; 52(Suppl 1): S459.

3 Rifai K, Kribben A, Gerken G, Haag S, Herget-Rosenthal S, Treichel U et al. Extracorporeal liver support by fractionated plasmaseparation and absorption (Prometheus) in patients with acute-on-chronic liver failure (HELIOS study): a prospective randomizedcontrolled multicenter study. J Hepatol 2010; 52(Suppl 1): S3.

2011 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2011; 98: 632Published by John Wiley & Sons Ltd

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Systematic review and meta-analysis of survival following extracorporeal liver support (Br J Surg 2011; 98: 623–631)