nouvelles techniques dʼépuration extra-hépatique · bioartificial liver support systems...
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Nouvelles Techniquesdʼépuration extra-hépatique
Pr Faouzi [email protected]
Centre Hépato-Biliaire, Réanimation HépatiqueHôpital Paul Brousse - Villejuif.
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CerveauEncéphalopathie
Œdème Cérébral
Insuffisancerénale
Oligurie
CirculationSyndrome hyperkinétique
Etat de choc
InsuffisanceRespiratoire
Ventilation
Défaillance MultiOrganes
Décès
S e p s i s
Cytolyse, Ictère, TP ,INR
Toxines, TNF, Cytokines, NO
Hépatite FulminanteFoie préalablement sain
Ou atteinte modérée
Décompensationaiguë d’une cirrhose
AoCLF
Autres situationsd’Ins. hépatique
Insuffisance hépatique aiguë dans différentescirconstances
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Extrahepatic Organ Failures in Patients WithCirrhosis and Severe Sepsis
Plessier et al. Liver Int 2003;23:440.
Prop
ortio
n of
Pat
ient
s(%
)
0
40
80
ARDS Shock RenalFailure
Thrombo-cytopenia
Acidosis
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Insuffisance hépatiqueAiguë / Aiguë- maladie chronique du foie
Support Hépatique
Transplantationhépatique
Régénération hépatique
Guérison/Survie
Pont
Traitement Médical optimal
Recompensation
AméliorationNeurologiqueHemodynamiqueBiologique Foie, reinInflammation/Sepsis
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Potential of Regeneration according tothe progression of the disease
F1F0 F2 F3 F4
ALF
DecompensationBleedingSBPInfection/sepsisEncephalopathy
years
LFT/INRProthrombine rate
- OLT(High-urgent)
- Death
- RegenerationRecovery
- Recompensate- Death- Progressive (AoCLF) worsening of LFT
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Liver support systems
Bioartificial Liver devices Artificial Liver devices Future Liver support
Other new type of liver support• Hybrid form• TiO2 photocatalytic membrane
Hepatocyte transplantation Stem cell therapy Molecules/Drugs that enhance regeneration
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Bioartificial Liver Support Systems
Definition BALs are essentially bioreactors with embedded hepatocytes that
perform the functions of a normal liver Aim
Replace the whole function of the hepatocytes Synthetic and metabolic functions
• Production of albumin and clotting factors• Regulation of carbohydrate homeostasis• Lipid and plasma lipoprotein synthesis
Detoxification Biliary excretion
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HepatAssist 2000 System(Circe biomedical)Phase II / III Clinical Trial
Days
Time to death within 30 days
Prop
ortio
n A
live
BAL
Control
147 patients : p = 0.11
Time to transplantation : 5 days
Time to transplantation : 3 days
59%
73%
Demetriou A. et al, Ann Surg 2004; 239:660-70
Etude randomisée multicentrique : FHF/SHF
Days
Time to death within 30 daysPr
opor
tion
Aliv
e
BAL
Control
83 patients : p = 0.009
FHF/SHF with known etiologyFHF/SHF whole population
Fibres creuses, 5 x 109 hépatocytes de pors cryopreservés
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HepatAssist 2000 System (Circe biomedical)Survie : Transplantés vs non-transplantés
0.3850%38%NontransplantésN = 77 (45%)
0.2289%80%Transplantésn= 94 (55%)
pBALControlGroupe
Demetriou A. et al, Ann Surg 2004; 239:660-70
HepatAssist-2® (ArbiosInc)
15 milliard hepatocytes
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Bioartificial Liver Support Systems Extracorporeal Liver Assist Device (ELAD®, Vitagen®)
In ALF Uncontrolled clinical trial 11 pts: 5/11 pts survived (4 with OLT) A pilot controlled trial 24 pts : No survival differences between treated and
controls, bilirubin and ammonia were higher than those before the ELADtreatment
Recently new version of ELAD modified membrane 70-120 kD Higher flow 200-500
In AoCLF: a randomised controlled trial (2 centers in China):preliminary data in 42 pts showed improvement in transplant freesurvival in the treated group
Sussman NL, Artif. Organs, 18, 1994. Ellis AJ, Hepatology 24, 1996.
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Bioartificial Liver Support Systems
3. Other BAL, currently under phase I or II clinical trials Bioartificial Liver Support System (Pittsburgh, BLSS®, Excorp Medical Inc Mineapolis;
Mazariegos 2001); Porcine hepatocytes
Modular Extracorporeal Liver System (LSS+MARS=MELS®, Charite Virchow Clinic,Berlin; Sauer IM 2002); Human hepatocytes
The Radial Flow Bioreactor (RFB-BAL, University of Ferrara Italy; Morsiani 2002);Porcine hepatocytes
The Academic Medical Center Bioartificial liver (AMC-BAL, Amsterdam; Van DeKekhove 2002); Porcine hepatocytes
LiverX2000 System (Algenix Inc Minesota, Hu WS 1997)
Others: (Xue YL 2001, Ding YT 2003, Donini A 2000)
Preclinical or in vitro test: seven others (Park JK and Lee DH 2005)
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Bioartificial Liver devices Limitations
Most systems are based on hollow fibers which anatomically do notreproduce physiological blood flow and cell arrangement in the liver.
The mass exchange between the patients blood and the extracorporealliver cells is limited
Do not incorporate non-parenchymal liver cells (hepatic stellate cells) The liver mass cells incorporated in the devices (< 5% of the liver mass)
not sufficient (lessons learned from LDT): The synthetic function isextremely poor
The inability to maintain highly functional hepatocytes in vitro.
The viability of the cells is limited in time
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The risk of transmission of porcine endogenous retroviruses (PERV)from pig hepatocyes
The risk of cancer cell lines to transmit some portions of DNA orRNA that could promote cancer growth in the patient.
Many questions about Biochemical Immunological Metabolical incompatibilities The risk of xenozoonosis
Bioartificial Liver devices Safety issues
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Artificial Liver Support
Aim : Detoxification Devices
Hemodialysis (Opolon 1976, Knell and Dukes 1976, Silk 1978, Denis and Opolon 1978, Opolon
1981)
Hemofiltration/Hemodiafiltration (Matsubara 1990, Rakela 1988, Sadamori 2002)
Hemoperfusion charcoal (Silk 1978, Gimson 1982, OʼGrady 1988, He 2000)
Hemoperfusion on anion and cation resin exchange Blood and Plasma Exchange (Iwai 1998, Singer 2001)
Plasma Exchange + CVVHDF (Matsubara 1990, Soeda 1991,Yoshiba 1996, Sadahiro 2001,
Sadamori 2002, Nakae 2002, Nakanishi 2005)
High volume plasmapheresis (Inoue 1981, Yamazaki 1988, Soeda 1991, Kondrup 1992, Larsen
1994, Clemmesen 1999)
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The Liver Dialysis UnitTM(formerly BioLogic-DT)
FDA approved Liver Dialysis Unit Uses a cation exchange resin in addition to charcoal. A randomized controlled trial, 56 patients with acute hepatic
encephalopathy (grade II-IV) Acute on chronic liver disease versus controls
• significant improvement of the incidence of positive outcome (recovery ofhepatic function or improvement for liver transplantation): 71.5% vs. 35.7 %, p=0.036).
Fulminant hepatitis• No significant improvement of the outcome versus the control group. Overall
survival: 51.6%
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The SEPETTM Liver Assist Device (ArbiosSystems)
A SElective Plasma Exchange Therapy Use a single cartridge containing hollow fibers capable of sieving
substances with molecular weight of up to 100 kDa. The patientʼs blood plasma is expressed through the micropores,
thereby cleansing the blood from toxins (Ammonia, mediators ofinflammation, inhibitors of hepatic regeneration).
The system can be connected with most available kidney dialysis unit. Phase I clinical trial.
Liver Assist Device ( Liver Assist Device ( Liver Assist Device ( Liver Assist Device (ArbiosArbiosArbios
Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving
Liver Assist Device ( Liver Assist Device (ArbiosArbiosArbiosArbiosArbiosArbiosArbiosArbiosArbiosArbios
Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sievingSEPET™ Microscopic Filter
Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Microscopic Filter Microscopic Filter Microscopic Filter Microscopic Filter Microscopic Filter
Use a single cartridge containing hollow fibers capable of sieving Use a single cartridge containing hollow fibers capable of sieving Microscopic Filter Microscopic Filter
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MARS® : (Gambro-Hospal, ex Teraklin)Molecular Adsorbent Recirculating System
PROMETHEUS (Fresenius)
SPAD : Single Pass Albumin Dialysis
La Dialyse hépatique à lʼalbumine
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Le concept de dialyse à l’albumine
MARS® (Molecular Adsorbents Recirculating System)
Prometheus (Fresenius)
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Substances toxiques épurés par leMARS®
- Bilirubine totale et conjuguée- Acides biliaires- Ammoniac- Acides aminés aromatiques- Tryptophane- Acides gras à chaînes courtes et moyennes- Prostacyclines- Urée- Créatinine- Lactates- Cuivre- Benzodiazépines et substances dérivées- Digoxines- NO- Paracétamol- TNF-alpha- Cytokines pro-inflammatoires
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Hémodiafiltration continue au cours de l’insuffisancehépatique et rénaleVariabilité de la bilirubine et du TP (séances 12-24h)
0
0,5
1
1,5
2
2,5
3
12 12
12,8 13
13,3
13,5
14,3
14,5 15
15,3
15,5 16
16,3
17,5 18
18,1 19
19,4 20 20
,3
21 21
21,5
21,7 22
22,5
22,5 23
Durée des séances (en h)
Bilirubine totale Bilirubine conjuguée Taux de Prothrombine
Moyenne de la bilirubine totale : 236 + 256,8 µmol/l (5-833 µmol/l)
Moyenne de la bilirubine conjugu ée : 159,3 – 168,9 µmol/l (7-660 µmol/l)
Expérience de Paul Brousse : 62 patients (2000-2002)
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Bilirubine totale Bilirubine conjuguée Bilirubine non conjuguée5 5 0
200 150 60SD=40 SD=36 SD=14
SD=1 SD=1 SD<1n=10 n=10 n=10n=12 n=12 n=12
HFMARS
0
50
100
150
200
µmol
/ h
250
MARS®HF
MARS® vs. Hémodiafiltration
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0
50
100
150
200
µmol
/ h
Acides Biliaires Acides gras libres
MARSHF n = 8 : 2 + 3
n = 8 : 160 + 40n = 12 : 10 + 2 n = 12 : 150 + 120
MARS®HF
MARS® vs. Hémodiafiltration
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Treatment sessions in acute on chronicliver failure
Chui Liver Intern 2006
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Main Indications of MARS® (1)
Acute / Fulminant Liver Failurea) King’s College criteria
b) Clichy criteria
MARS® should be started immediately (within few hours)as soon as the criteria above are met
Liver transplantation should remain the aimed treatment
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Effets du MARS® au cours des HépatitesFulminantes
Amélioration de l’encéphalopathie hépatique
Amélioration du score de Glasgow
Augmentation de la pression artérielle moyenne
Augmentation de la pression de perfusion cérébrale
Diminution de la pression intracrânienne et de l’œdème cérébral
Epuration de certains cytokines augmentées au cours de l’HF:
TNF- æ, Interleukine 6, interleukine ßSchmidt LE et al, Scand J Gastroenterol. 2004;39(10):974-80.
Schmidt LE et al, Liver Transpl 2003;9(3):290-7.
Abraham RB etal, Transplant Proc 2001;33(6):2897-9.
Schmidt LE et al, Liver Transpl 2001 ;7(8):709-12.
Auth MKet al, J Pediatr Gastroenterol Nutr. 2005;40(1):54-9.
Awad SS et al, ASAIO J 1999;45(1):47-9. Camus C, Intensive Care Med 2006;32:1817-25
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Effects of MARS® on ICP: controversial?
Sen S, Crit Care Med 2006;34:158-64; Lai WK, Intensive Care Med 2005;31:1544-9
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Albumin Dialysis and cytokines controversial? Albumin dialysis has no clear effect on cytokine levels in patients
with life-threatening liver insufficiency. Transplant Proc. 2006
The effect of albumin dialysis on cytokine levels in acute liver failureand need for liver transplantation. Transplant Proc. 2005
The decrease in cytokine concentration during albumin dialysiscorrelates with the prognosis of patients with acute on chronic liverfailure. Transplant Proc. 2005
Effect of extracorporeal liver support by MARS and Prometheus onserum cytokines in acute-on-chronic liver failure. Crit Care 2006
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Etude FULMAREtude FULMAR (FulminantMARS®)
PHRC* National*Projet Hospitalier de Recherche Clinique
16 Centres
Promoteur : - DRCD / AP-HPDirection de Recherche CliniqueAssistance Publique-Hôpitaux de Paris
- Gambro/Hospal - Laboratoires LFB
Ile de France
Lille
StrasbourgRennes
Lyon
Bordeaux
ToulouseMontpellier Nice
Besançon
Etude prospective, contrôlée, randomisée, multicentrique évaluant letraitement par le système d’épuration extra-hépatique MARS® despatients atteints d’hépatite aiguë fulminante ou subfulminante
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Etude FULMAR: Fin du recrutement110 patients (31/12/07)
First patient19/08/2004
(Actual vs Projected)
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Indications du MARS®
Hépatite Fulminante ou subfulminante
Décompensation aiguë chez le cirrhotique (Acute on Chronic LiverDisease)
Ictère cholestatique sévère / Hépatite alcoolique aigue
Syndrome hépato-rénal
Encéphalopathie/Coma Hépatique
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Hemodynamic Effects of MARS® inAcute on Chronic Hepatic Failure(Review of reported effect)
Increased Mean arterial Pressure (MAP) Decrease cardiac output Increased Vascular systemic resistance
Decrease in NO
Increased Hepatic Blood flow (HBF) Increased Hepatic delivery of O2 (HDO2) No change in Hepatic venous oxygen consumption
(HvO2)
Decrease of Portal Pressure
Decrease Renin Decrease Aldosterone Decrease Norepinephrine Increased Atrial natriuretic peptide
Aim of the therapy :Return the circulatory function to the pre-precipitating events
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Mitzner S, Liver Transpl 2000 May;6(3):277-86
MARS® improves Survival in patients with AoCLF
13 cirrhotic pts: 8 CVV-HDF+MARS, 5 CVV-HDF
Hepato-renal syndrome type 1
0
0,2
0,4
0,6
0,8
1
0 10 20 30Su
rviv
alC
umul
ativ
edays
SMT
SMT + MARS
P < 0.05
Heemann et al., Hepatology 2002;36:949-58
Acute on Chronic liver failureprogressive jaundice failing 5 days of SMT23 cirrhotic patients
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Rationnel du MARS pour le traitementde lʼencéphalopathie hépatique
Le MARS améliore significativement lʼencépahalopathie hépatique Le profil des acides aminés neuro-actifs
GABA (p = 0.04) Glutamate (p = 0.03) Glutamine (p = 0.0006) Tryptophane (p < 0.0001) Histidine (p = 0.0001) Tyrosine (p < 0.001) Quotient de Fischer : AAB/AAA (p < 0.001)
Isoniemi et al, AASLD 2005, Abs N°227
Étude prospective 51 patients consécutifs avec IHC sévère en attente de transplantation
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Change of Fisher-Index
HDF MARS®
Chan
ge o
f in
itial
Blo
od le
vel
(%)
-60
100
80
60
40
20
0
-20
-40
Increase
Decrease
p = 0,05
Fischer-Index:BCAA - Branched-chain Amino AcidsAAA - Aromatic Amino Acids
MARS® vs. Hémodiafiltration
Ratio : BCAA /AAA
Ratio of BCAA/AAA
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Efficacité du MARS® chez les patients atteints dʼunecirrhose avancée avec une encéphalopathie hépatique
stade III et IV
Randomisation: Traitement Médical Standard (TMS) MARS + TMS
Durée de l’étude: 5 jours Encéphalopathie hépatique évaluée 2 fois/j (10 X)
Objectif principal Amélioration de l’encéphalopathie > 2 stades par rapport à l’inclusion
Etude prospective contrôlée randomisée multicentrique: 70 pts
T.Hassanein et al, Hepatology 2007; 46:1853-62.
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Système MARS®
Séances de 6h / jour x 5 jours 1 à 5 séances Arrêt si amélioration de lʼEH de 2 stades, décès, retrait du
consentement.
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Caractéristiques des patients
NS15 H16 F
24 H15 F
Sexe
0.01356 + 1050 + 11Age (ans)
NS1219EH stade 4
NS1920EH stade 3
pTMSn=31
MARSn=39
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Pathologie initiale
10Cirrhose médicamenteuse
23Cirrhose autoimmune, CSP
34Cirrhose cryptogénétique
36Cirrhose mixte (virus+alcool)
1011Cirrhose virale (HCV/HBV)
1215Cirrhose alcoolique
TMSn=31
MARSn=39
T.Hassanein et al, Hepatology 2007; 46:1853-62.
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Gravité de la cirrhose
NS1.9 + 1.12.1 + 1.0INR
0.0043.0 + 0.72.4 + 0.7Albumine g/dL
NS17 + 1620 +14Bilirubine totalemg/dL
NS2.3 + 1.42.1 + 1.5Créatinine mg/dL
NS3 non8 sévères
5 non12 sévèresAscite
pTMSn=31
MARSn=39
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Scores de Gravité
NS81%88%SOFA Score >9
NS3 (10%)5 (13%)Sédation Propofol +benzodiazépines
NS35,5%51,3%Ventilationmécanique
NS8(3 -15)
6(3 -12)GCS
NS28(15 - 50)
33(11- 49)MELD Score
NS12(10 -15)
13(10 -15)CTP Score
pTMSn=31
MARSn=39
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Objectif primaire (ITT)
MARS
SMT
Temps (médiane) d’amélioration 72 h (MARS®) vs 108 h (TMS®)
T.Hassanein et al, Hepatology 2007; 46:1853-62.
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Objectif primaire (ITT)
MARS
SMT
T.Hassanein et al, Hepatology 2007; 46:1853-62.
Amélioration de l’EH/Répondeurs: 62% (MARS®) vs 40% (TMS®)
Aucun des patients qui a amélioré de 2 stades l’EH a rechuté
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Objectifs secondairesParamètres biologiques Amélioration significative en faveur du groupe MARS®
de l’ammoniémie (p < 0,01) du rapport AA branché/AA aromatique (p < 0,01) Bilirubine totale (p < 0,01) Acides biliaires (p < 0,01) Urée (p < 0,01) Créatinine (p < 0,01)
Taux comparable dans les deux groupes de L’INR Plaquettes
T.Hassanein et al, Hepatology 2007; 46:1853-62.
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Tolérance
86 ± 51 x10/mm3)
70 ± 43 x10/mm3)
Réduction de 21% après chaque traitement
Transfusions de Plaquettes
%
T.Hassanein et al, Hepatology 2007; 46:1853-62.
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Séances de MARS®
108 séances de MARS (médiane 3) 94% (102/108) des patients > 4 h de traitement 6 séances < 4h
Instabilité hémodynamique: 2 Hémorragie digestive : 1 Malfonctionnement cathéter: 1 Malfonctionnement machine : 1 Greffon disponible /transplantation: 1
Anticoagulation Héparine était seulement utilisée dans 26% (28/108) des
séancesT.Hassanein et al, Hepatology 2007; 46:1853-62.
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Effets indésirables graves
NANANA35SMT
694756MARS
Insertion ducathéter
Possible relationavec le MARS
Sans relationavec le MARS
EIGtotal
T.Hassanein et al, Hepatology 2007; 46:1853-62.
Thrombopénie 31000: 1 pt Neutropénie < 0,8 g/dL : 1 pt
Instabilité hémodynamique: 3 pts Tachycardie supraventiculaire: 1 pt Hémorragie digestive: 1pt
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Devenir des patients de lʼétude
71%
64%
TotalDécès
23%
26%
TotalTransp-lantés
65%6 (23%)16%1/26 (4%)TMS
61%8 (24%)13%3/33 (9%)MARS
Décèsde 6 à 180
jours
Transplantésde 6 à 180
jours
Décès dansles 5 jours
Transplantésdans les 5
jours
T.Hassanein et al, Hepatology 2007; 46:1853-62.
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Impact de lʼamélioration de lʼencéphalopathiesur la survie
Survie corrélée à l’amélioration de l’EH
0
0,2
0,4
0,6
0,8
1,0
50 100 150 180Jours
Surv
ie
Non-répondeurs
Répondeurs
p < 0,05
3 /13 Facteurs étaient déterminants d’une réponse de 2 stades de l’EH:- Le MARS® augmente significativement la réponse- Le score de Child diminue la réponse (OR: 0.56)- Le score de Glasgow diminue la réponse (OR: 0.18)
T.Hassanein et al, Hepatology 2007; 46:1853-62.
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The RELIEF* Study: Impact of MARS® inseverely decompensated chronic liver disease
A prospective randomised multicentre studyCurrent state of recruitment
* Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or renal Failure
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Après transplantation :Précoce : PNF, dysfonctionnement du greffonTardive : récidive de la maladie initiale, rejet chronique
Après chirurgie hépatique majeure
Insuffisance hépatique secondaire
Autres indications du MARS®
Prurit réfractaire au cours des maladies chroniques cholestatiques
Intoxications médicamenteuses (médicaments liés à l’albumine)
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Le Registre de l'AP-HP de la dialyse à l'albumine par leMARS® chez les patients atteints d'une insuffisance
hépatique aiguë grave sur une maladie chronique du foie
Rapport 2004 - 2007Rapport 2004 - 2007Résultats préliminairesRésultats préliminaires
Pr Faouzi [email protected]
Assistance Publique Hôpitaux de Paris,Hôpital Paul Brousse, CentreHépato-Biliaire, Réanimation, Villejuif - France
Université Paris Sud, Unité INSERM 785 France
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Patients traités par le système MARS®à lʼAP-HP (Janvier 2004 - Juillet 2007)
148 Patients traités par le MARS®
PHRC FULMAR : 30 patients (bras MARS®) 118 Patients:
Exclus de l’analyse CEDIT 8 patients traités pour hépatite fulminante /IHA (hors étudeFULMAR) 4 patients (Protocole RELIEF) 2 patients (absence de renseignements) 2 patients post chirurgie cardiaque majeure
IHA/maladie chronique du foie: Inclus dans l’analyse 102 patients
Registre AP-HP: Résultats préliminaires
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Patients : Répartition par Hôpital des 102patients102 patients CEDIT (117 séjours) (HEGP +2 pts)
Registre AP-HP: Résultats préliminaires
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Paul-Brousse
Beaujon Cochin Mondor Saint-Antoine
Total
0
25
50
75
100
125
150
175
200
225
250
275
300
325
350
200
82
18 16 10
326
Nb séances par patient
Nb séances
Hop i ta l Paul Brousse Beau jon Coch in Mondo r Sa i n t -Anto i neMed iane 3 3 3 2 3I n t e r v a l l e 1 - 9 1 - 9 2 - 4 1 - 3 1 - 3
Nombre et durée des sessions deMARS® par Centre
Moyenne: 3,19 ± 1,7 sessions/patient Durée médiane des sessions: 8 h (min=1, max=9)
Registre AP-HP: Résultats préliminaires
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Indications de traitement par le MARS®(Groupe 1)
Patients Médicaux : 62 patients, 65 séjours, Cirrhose alcoolique: 27 pts/ 28 séjours (dont 21pts/22 séj avec
HAA) Cirrhose biliaire: 12/13 (CBP 3/3, CSP 4/4, CB autre 5/6) Cirrhose virale: 8/8 pts (VHB 5, coinfection B,C,VIH 2, VHC 1) Cirrhose autoimmune: 1 Cirrhose métabolique: 3 Cirrhose dʼétiologie indéterminée: 1 Cirrhose médicamenteuse: 2 Autres: 8 pts /9 séjours
• IHA sur Drépanocytose 1, allogreffe de moelle 2 pts, maladie de Crohn 1pt, HNR 1pt, Budd Chiari 1 pt, Foie hypoxique 1
Registre AP-HP: Résultats préliminaires
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Indications de traitement par le MARS®(2)
Patients après Transplantation hépatique (Groupe 2) 31 pts / 38 séjours
• Précoce (dysfonctionnement primaire du greffon) : 7 pts/7 séjours• Tardive : 24 pts/31 séjours
• Complications du greffon : rejet chronique, Complications biliaires,Cirrhose
Patients après Chirurgie de Foie (Groupe 3) Hépatectomie majeure : 14 pts/ 14 séjours
Registre AP-HP: Résultats préliminaires
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Gravité des patients avant le traitementpar le MARS®
Hémodynamique instable (nécessitant des drogues inotropes):
36 pts 37 séjours
Dopamine (médiane) : 7,1 ± 3,5 (méd 8, int: 2-12) µg/Kg/mn
Noradrénaline : 2,8 ± 2,9 (méd 2,1, int: 0,2-15) mg/h
Adrénaline : 1,16 ± 1,11 (méd 1, int: 0,3-3) mg/h
Ventilation mécanique : 35 pts / 37 séj
Insuffisance rénale: 77 pts / 85 séj
Encéphalopathie hépatique : 67 pts / 71 séj Médiane: stade 3
Coma hépatique : 47 pts /49 séj Médiane : stade 3
Ascite réfractaire: 23 pts / 23 séj
Sepsis probable : 31 pts / 31 séjRegistre AP-HP: Résultats préliminaires
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Gravité des patients avant le traitementpar le MARS®
Score IGS II: 42,9 + 17,8 Médiane: 39,5 (27 DM)
Score de GLASGOW 10,5 + 5 Médiane: 13
Score de Child-Pugh (groupe 1) Child-Pugh A: 7 pts Child-Pugh B: 4 pts Child-Pugh C: 53 pts Médiane: 12
Score de MELD (exclusion groupe 3) Médiane: 35Registre AP-HP: Résultats préliminaires
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Paramètres biologiquesdʼefficacité avec une différence significative
µmol/l µmol/l
p< 0,0001
p< 0,0001P< 0,0001
P< 0,0001
Moyenne avant et après dernière séance de MARS®
Pas de différence avant et après dernière séance de MARS® pour les paramètres suivants : ASAT,ALAT, Phosphatases alcalines, Lactates, Hémoglobine, hématocrite, CO2 total, Protéines, AlbumineRegistre AP-HP: Résultats préliminaires
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• Inotropes : réduction des doses (35%)
p= NS
PAm (Médiane) avant et après chaque séance de MARS®
Tolérance : Hémodynamique
p= NS p= NS p= NS
Registre AP-HP: Résultats préliminaires
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Paramètres de coagulationavant et après dernière séance de MARS®
p= 0,0002*
p= NS p< 0,0001
p= 0,034*
Médiane
Médiane
* Significatifs seulement dans le groupe 1Registre AP-HP: Résultats préliminaires
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Survie Globalepost bilan pré MARS® : n =101
Registre AP-HP: Résultats préliminaires
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Survie par Groupepost bilan pré MARS®
Registre AP-HP: Résultats préliminaires
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Facteurs de risque prédictifs de la survieRésultats de lʼanalyse univariée
Variable p (LogRank)* Groupe médical
Hémodynamique instable 0,00000002
IGS2 0,000002
Glasgow 0,000002
Sepsis probable 0,000034
Groupe 0,0002
Encéphalopathie 0,0004
Meld 0,0004
Ventilation mécanique 0,0005
Coma 0,001
Age 0,002
Insuffisance rénale 0,015
Cirrhose alcoolique/HAA 0,122 0,002
*Test du score dans un modèle de Cox Registre AP-HP: Résultats préliminaires
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Conclusion (1)
Amélioration importante de la prise en charge desmaladies graves du foie
La transplantation hépatique demeure le traitementde référence
Développement plus accéléré des supportshépatiques bioartificiels et artificiels (beaucoup sonten phase 1 et 2)
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Conclusion (2) La dialyse à lʼalbumine est un nouveau concept et doit être
intégré dans la prise en charge des maladies graves du foie: En cas dʼéchec du TMS Avant le stade de défaillance multiorgane
Malgré le potentiel important de malades existants, la dialyseà lʼalbumine est encore limitée par: Initiation des équipes (hépatologues et réanimateurs) Expérience limité et coûts
Dʼautres évaluations et études randomisées sont encorenécessaires