Blood Depuration Methods in Liver

FailureFailure

Debbie ShawcrossSenior Lecturer & Consultant Hepatologist

Institute of Liver Studies

Liver Failure

1. Detoxification2. Biotransformation3. Excretion4. Synthesis

• Bilirubin• Ammonia• Glutamine• Lactate• Aromatic Amino Acids• Aromatic Amino Acids• Free Fatty Acids• Phenol• Mercaptans• Benzodiazepines• Proinflammatory

Cytokines

Complications of Liver Failure

�Hepatic encephalopathy�Coagulopathy� Jaundice�Cholestasis�Cholestasis�Pruritus�Ascites� Immune Dysfunction�Sepsis �Renal Dysfunction

Acute Liver Failure-Cerebral Oedema [24% Hyperacute; 23% Acute; 9% Sub-acute]

InflammatoryMediators (e.g. NO)NH3

Hepatocellular

ICP

Cerebral Blood Flow

Astrocyteswelling

necrosis and apoptosis

300

400

Ammonia is central in the pathogenesis of Hepatic Encephalopathy

0

100

200

µµ µµmol

/L

Olde Damink et al. Neurochem. Int. 2001

Acute Liver Failure

• 40% develop renal failure• Criteria for commencing RRT

• Hyperammonemia• Metabolic status…..HC03, lactate

• Treatment modes• Treatment modes

• Slow continuous HD, CVVHF/DF

• (Intermittent HD)

• Anticoagulation

• PGI2, low dose heparin,nil, citrate

CirrhosisAcute-on-chronic liver failure

–INFECTION

A precipitating factor that causes the cirrhotic liver to undergo ‘stress’ and fail (2nd Hit).

– GASTRO-INTESTINAL BLEEDING e.g. variceal

– Alcoholic Hepatitis– Metabolic (Pre-renal failure)– TIPS/surgery

MELD Score and Prognosis

Three Month Mortality

75%

100%

Remember that in any intervention study - this is what the control group should achieve

0%

25%

50%

75%

<9 10-19 20-29 30-39 >40

MELD score

Mor

talit

y

Kamath et al. Hepatology 2001

Outcome of Cirrhosis in Intensive CareSurvival Correlates with Number of Organs Failing

50

75

100

Observational Study n=146%

of

non-

surv

ivor

s in

eac

h gr

oup

0 n=47 1 n=36 2 n=30 3 or more n=300

25

50

Number of Organ Failures

% o

f no

n-su

rviv

ors

in e

ach

grou

p

Wehler et al. Hepatology 2001

Survival of cirrhotics admitted to ICU

Author NumberSurvival

ITU Hospital

Cholongitas et al 2006 (UK) 312 - 35%

Aggarwal A et al 2001 (USA) 240 63% 51%Aggarwal A et al 2001 (USA) 240 63% 51%

Wehler et al 2001 (Germany) 143 64% 54%

Arabi et al 2004 (Saudi Arabia) 129 - 26%

Zimmerman et al 1996 (USA) 117 - 37%

Tsai et al 2003 (Taiwan) 111 - 35%

Rabe et al 2004 (Germany) 76 41% -

SOFA is an excellent scoring system for predicting in-hospital mortality in patients with cirrhosis

SOFA

APACHE II

Child PughWehler et al. Hepatology 2001

King’s College ICU A-o-CLF Survival Data2000-2007 (n=563)

Survivors Non Survivors p value

Child-Pugh score 11 (10-12) 13 (11-13) <0.0001

MELD 17 (10-28) 31 (23-37) <0.0001MELD 17 (10-28) 31 (23-37) <0.0001

APACHE II 17 (14-23) 27 (21-31) <0.0001

SOFA 9 (7-11) 13 (10-16) <0.0001

Requirement for RRT 27% 73% <0.0001

Requirement for Vasopressors 20% 80% <0.0001

Requirement for Ventilation 44 % 56% <0.0001

Survival of patients with refractory ascites

Gines et al. NEJM 2004

Indications for a temporary ‘artificial liver’

• Bridge to Liver Transplantation.

• Time to allow native liver to recover.to recover.

• Primary non-function post Transplantation.

• Large hepatic resection leaves too little liver reserve.

Target Groups

• Acute Liver Failure– Intracranial hypertension– Stability to transplant– Delayed graft availability

• Critically ill cirrhotic (A-o-cLF)– To reverse organ failure– Stability on transplant waiting list– Stability on transplant waiting list

• Severe acute alcoholic hepatitis• Post Transplant

– Primary non-function– ‘Small for size’

• Post hepatic resection with poor liver reserve.• Drug removal• Severe cholestasis/pruritus/fatigue

European Liver Transplant Registry 1994-2005

Extracorporeal Liver Support Devices

• Non-living components to cleanse the blood or plasma of it’s ‘toxins’.

• Cell-housing bioreactor to replace the most important liver functions.

Artificial Bioartificial

plasma of it’s ‘toxins’. – Oxidative Detoxification– Biotransformation– Excretion– Synthesis

Schematic principles of extracorporeal systems for the treatment of Liver Failure

Treatment Units in parallel or series in an extracorporeal circuit.Carpentier et al. Gut 2009

Treatment Units Used in Liver Support DevicesEach extracorporeal circuit is made up of 3 or more units in series or parallel within the

circuit.

Artificial Liver Support Devices

Plasma-pheresis Plasma

FractionationHemofiltration Hemodialysis

Albumin Dialysis

Aided Transfer Adsorption

Liver Dialysis

MARS

Prometheus

Carpentier et al. Gut 2009

Liver Support Device Trials

• Evidence Base is poor– Uncontrolled studies/historical control groups

• Effects of standard therapy

– Few RCT• Heterogenous patient groups

– ALF– A-o-CLF

• Small patient samples• Single centre studies / variable standard care in the

multicentre studies

– Cost

First Liver Dialysis Studies: Charcoal Haemoperfusion

Charcoal HaemoperfusionGimson A et al. Lancet 1982Uncontrolled study– 75 patients with ALF and grade III encephalopathy– 10 hrs of charcoal haemoperfusion– 65% survival in treated patients– 15% survival in historical controls

O’Grady JG et al. Gastroenterology 1988Controlled study– 62 patients with ALF and grade IV encephalopathy– No perfusion vs 10 hrs perfusion daily– Survival 39.3% vs 34.5% (non-significant)– No survival benefit

Effect of improved overall management package

Liver DialysisHemoCleanse, Indiana, USA – originally called Biologic DT – Ash et al.

++

5 kDa Cellulosic Membrane

Liver Dialysis – Biologic DT

• Largest prospective RCT• n=56 [Only 15 cases published]• ALF/A-o-CLF• Liver Dialysis vs SMT• Treated for 8-12 hrs/day• Average 4 treatments (range 1-12)• Average 4 treatments (range 1-12)• Significantly improved neurological status and

MAP.• Increased bleeding in patients with active

bleeding• DIC – activation and aggregation of platelets in

the circuit and clotting of circuit during treatment.

Ash et al. Int J Artif Organs 1992; ASAIO Trans 199 2

MARSMolecular Adsorbant Recirculating System; Gambro Sweden

• Developed by Stange and Mitzner.• Toxins (both albumin-bound and soluble) are transferred to the

counter-current human albumin-enriched dialysate.• Albumin dialysate is regenerated against a conventional bicarbonate

–buffered dialysate and adsorption through charcoal and anion-exchange resin columns.

MARS Therapy Mitzner et al. Liver Transpl. 2000

MARS (n=8) HDF (n=5)

Pre Post Pre Post

Creat (mg/dL)3.8+1.6 2.3+1.5 ** 4.4+1.3 3.8+0.5

Bilirubin (mg/dL)

26.8+11.6 17.3+7.5 * 24+18.6 22.2+12

PT (%)32+13 44+12 ** 36+19 42+22

Sodium (mmol/L)

130+8 139+7 124+8 131+7

Survival: MARS mean 25 days, 5 days controls (p<0.05)

Long term survival (30 days) in MARS group (8%)

MARS Heemann et al. Hepatology 2002

24 patients with ‘decompensated’ cirrhosis • Randomised to SMT with MARS (6 hour sessions; 2 weeks up to 10

sessions) or SMT alone (RRT for life threatening electrolyte abnormalities)

• MARS group: reduced bile acids, bilirubin, encephalopathy, renal dysfunction.

• No difference in albumin or prothrombin• No difference in albumin or prothrombin

• Controls: no change in biochemistry, worsening encephalopathy

• Improved 30 day Survival

– MARS 11/12 , SMT 6/12 (P<0.05) ITT p =0.069, PP p=0.02

– 6 month survival 6/12 MARS and 4/11 in control group

• Trial stopped early due to benefit in treatment group.

MARS in A-o-CLF (alcohol): A RCTSen et al. Liver Transplant 2004.

•Significant fall in bilirubin in MARS group.•Significant fall in NOx levels in MARS group.•No significant change in plasma cytokines and ammonia.•No change in MAP and renal function.•MELD score decreased significantly in both groups.

Mortality 5/9 in each group

MARS in A-o-CLFSchmidt et al. Liver Transpl. 2001

Pathophysiological effects of a single 10 hour session of MARS treatment

•Significant decrease in HR•20% reduction in CI•Increase in SVRI•Increase in SVRI•DO2 decreased

621±198 to 486±141•VO2 decreased

142±31 to 112 ±21•No change in lactate

Effect of MARS treatment on portal pressure in patients with acute alcoholic hepatitis

Sen et al. J Hepatol. 2005

•n=9 with alcoholic hepatitis•DF > 32; MELD 24±4•6 discharged home •No difference in ammonia

Pares A et al. Critical Care 2009

Fischer’s Ratio

Ratio between the branched Ratio between the branched chain amino acids and

phenolic aromatic amino acids and has been

suggested to correlate with hepatic encephalopathy.

Koivusalo et al. Metab Brain Dis. 2008

MARS: a futile tool in centres without active liver

transplant support.•ALF n=50; A-o-CLF n=26•Median 4 (1-10) treatments•ALF group [HBV and drug-induced]

•1 recovered•1 transplanted (cadaveric)•Remainder died

Wai et al. Liver International 2007

Coagulopathy and MARS treatment in A-o-CLFDoria et al. Clinical Transplantation 2004

• MARS treatment undertaken in 9 A-o-CLF: 4-7 Rx each• Factors at time of Evaluation: INR < 2.5; platelets >50

• Pre and post MARS measures of Platelets, PT, Thromboelastograms Factors II,V,VII,VIII, IX,X,XI and XII Factors II,V,VII,VIII, IX,X,XI and XII Von Willibrand factor, protein C and S

• Significant worsening of PT, all TEG variables, Factor VIII, von WBF ,D-DimersRisk of bleeding

MARS: activation of coagulation and bleeding complications

Bachli E et al. Liver International 2007

Decrease in platelets and fibrinogen but no evidence of fibrinolysis.

MARS and hemostasis in patients at high risk of bleeding: an observational study

Faybik P et al. Critical Care 2006

•Largest prospective controlled multicentre study published to date.•Patients with advanced cirrhosis and grade 3/4 hepatic encephalopathy.•MARS (6 hrs per day; 5 days) + SMT or SMT alone.•Responder : 1 or more episode of 2 grade improvement•n=70 enrolled; GCS 6/15•Platelets decreased in 21% - Rx needed in 49% MARS group versus 32% SMT.•During follow up 7 episodes GI bleeding MARS versus 1 in SMT.

Hassanein T et al. Hepatology 2007.

Higher, earlier and more frequent improvement in HE with MARS compared to SMT.

Hassanein T et al. Hepatology 2007.

• 10 patients with ALF grade III/IV coma.

• Treated for 8 hours on 2 consecutive days.• Increase SVRI on first treatment 1114±196 to 1432±2 45.

• Changes not significant by end of second treatment.

• No change in ICP 14.5 (7-25) to 14 (3-25).

MARS in Acute Liver Failurein Acute Liver FailureLai W et al. Int Care Med 2005; Schmidt et al. Liver Transplant 2003

MARS in Fulminant Hepatic FailureCamus et al. Ther Apher. Dial. 2009

• 18 patients with FHF listed for Liver Tx.• Treated with MARS whilst on list.• 9/18 avoided Liver Tx (cf 19.3% in a

French Control Group).French Control Group).• A minimum of 15 hours of MARS was

necessary to produce significant improvement in liver function.

Summary of MARS Studies

• Effect of MARS is encouraging in ALF and A-o-CLF is not yet proven.

• RCTs in ALF [FULMAR Trial] and A-o-CLF [MARS Relief Trial] are ongoing.

• Adverse effects of thrombocytopenia, DIC and significant bleeding are concerning.

• Should be used with caution in patients with coagulopathy.

PrometheusFresenius Medical; Germany.

• Blood is drawn to an albumin-permeable polysulfone filter (250 kDa) generating an albumin-containing filtrate.

• Albumin filtrate then passes through a neutral resin and anion exchanger in series.

• Blood leaving the Albu-Flow is then dialysed with a conventional high-flux polysulphone dialyser.

Prometheus Studies

• Improves levels of conjugated bilirubin, bile acids, ammonia, creatinine, urea and blood pH.

• Albumin, fibrinogen, coagulation factors, • Albumin, fibrinogen, coagulation factors, and cytokines remain unchanged.

• Multicentre RCT (Helios Study) ongoing.• Decreased BP, clotting of secondary

circuit and slight increase in leucocyte count have been reported.

Prometheus versus MARSKrisper et al. J Hepatology 2005

AmmoniaUrea

High efficiency of toxin clearance and delivered dose with Prometheus but this was not responsible for significant differences in plasma levels.

Total bilirubin

Unconjugated bilirubin

Effect of MARS & Prometheus on systemic haemodynamics and vasoactive agents in A-o-CLF

Laleman et al. Critical Care 2006

Sauer et al Hepatology 2004.

In vitro work4.1 litres of toxin loaded sera.Plasma obtained fromplasmapheresis and thenSpiked.Processed for 6.5 hrs.Processed for 6.5 hrs.

MARS in CVVHDF or CVVHD mode hadsimilar decreases in bilirubin, bile acids. CVVHDF mode was more efficient at removing ammonia.

Sauer et al Hepatology 2004.

Sauer et al Hepatology 2004.

PDR ICG is superior to bilirubin and PT to determine the gr aft function in patients with primary non-function and graft dysfunction und ergoing MARS therapy

Scheingraber S et al. Clin. Transplant 2007

MARS and Hypoxic Liver Failure after Cardiogenic ShockBanayosy A et al. ASAIO Journal 2004.

Interim analysis of 27 cases with hypoxic hepatitis following

cardiogenic shock and cardiac surgery.

MARS SMT

MARS and Hypoxic Liver Failure after Cardiogenic ShockBanayosy A et al. ASAIO Journal 2004.

7 survivors in MARS group compared to 4 in the SMT.

MARS and ECMO in multiorgan failurePeek GJ et al. Liver 2002.

• ECMO and MOF associated with poor prognosis

• In 41 cases Bilirubin > 300µmol/L predicted death with 87% sensitivity and 90% specificity (1998-1999).

•MARS used in 5 patients with Bilirubin > 300µmol/L; 1-8 treatments.

• Fall in Bilirubin 30 -162 µmol/L

• 2 patients survived

Plasmapheresis in Liver Failure

Advantages:• Removes all molecules• Substitutes plasma products

– coagulation factors• Is well tolerated

– Improves HE– Increases CPP and CBF– No effect upon ICP– No effect upon ICP– Increases MAP & SVRI– Decreases CI/DO2 but not

VO2– Increases splanchnic

removal of ammonia.

Disadvantages:• Limited transport of water-

soluble substances• Unselective removal substances• Requires donor plasma

Transport: filtration/convection

Membrane: plasma-filter

Replacement: donor plasma

Toxins: all; entire plasma phase

High Volume Plasmapheresis in Liver FailureClemmesen et al. Hepatology 1999.

•Membrane filtration (0.65 mm pore size, Gambro)

•8-10L FFP per treatment (15% body weight)

•Improvement in encephalopathy CBF increased (40 to 62 cm/sec)** CBF increased (40 to 62 cm/sec)** CPP (59 to 72 mmHg)** ICP unchanged at 14 mmHg

•Haemodynamic effects:MAP 80+18 to 94+15* mmHg CO 6.7+2.5 to 6.6+2.2 l/min SVR increased*

•HBF 1.67+0.7 to 2.1+1.1* HVO2 3.7+0.9 to 4.3+1.3 (NS)

Does High Volume Plasmapheresis improve survival in ALF?

Preliminary findings of interim analysis after 61 p atients (trial now closed 120 patients enrolled)

Bioartificial Liver Systems

Bioartificial Liver Systems

Carpentier et al. Gut 2009

Bioartificial Liver Systems

Carpentier et al. Gut 2009

RCTs Bioartificial LiversHepatAssist (porcine) and ELAD (human tumour cell l ine)

are the only BAL systems on which RCTs have been perfomed

ELAD•200g of C3A human hepatoblastoma cells located in hollow fibre cartridges.

•RCT performed at King’s in 24 patients with ALF (7 listed for Liver Tx).

•Encephalopathy grade worsened in 58% SMT cf to 25% of those treated with ELAD.

•No improvement in chemical parameters or clinical outcome.

•After $50,000,000 investment Vitagen went into liquidation.•After $50,000,000 investment Vitagen went into liquidation.

•Has been redeveloped by Vital Therapies.

ELAD Phase 2 Studies in US/Europe

•Phase 2 RCT Multicentre Trials in 15 US/European Centres in patients with ALF ongoing since Jan 2009.

•A RCT in China in 2006/7 enrolled 69 patients with ALF secondary to HBV/HCV.

�30 day transplant free survival was significantly improved.

Market status of major bioartificial liver devices

• HepatAssist – now HepaMate – 14 x 109

cryopreserved hepatocytes –phase 3 clinical trials in USA.

• ELAD – Vital Therapies –Phase 2 Clinical Trial USA/Europe.Phase 2 Clinical Trial USA/Europe.

• Excorp Medical – BLSS –Phase 1/2 Clinical Trials in China/USA.

• Hep-Art Medical Devices –Spin off of AMC-BAL- human cell lines being developed.

We need to continue to work with industry and bio-engineers todevelop systems that are applicable for various disease states and areadaptable.adaptable.

Support systems need to be assessed inwell designed studiesthat reflect clinical reality.

In the management of liver failure, attention to detail and team working is imperative to improve outcomes.

Thank you