Epatite fulminante cause e gestione

Scuola di Specializzazione in Anestesia Rianimazione e Terapia IntensivaDirettore Prof G Della Rocca

Dott P ChiarandiniDottssa A Nigro

Dottssa A Ganss

Caso clinico

bullFC F 49 anni BMI 37 (100 kg 165 cm)

bullAnamnesi negativa non terapia domiciliare

bullNega allergie

bullRecente viaggio in Grecia

bullAbitudini sessuali riferite promiscue

PS

Pa

lma

no

va Astenia e dolore epigastrico da 2 gg per

cui non si egrave alimentata Dalla sera vomito

Ore 800

GB 13000mcL

PLT 147x103mcL

Ammonio 115 mcmolL

Glucosio 31 mgdL

Cr 152 mgdL

BR totdir 763557 mgdL

AST 12132 UIL

ALT 9767 UIL

PCR 102 mgL

12 set 13 set 14 set 15 set

h 1744GB 21000mcLPLT 178x103mcLGlucosio 26 mgdLCr 167 mgdLAST 13250 UILALT 10775 UUILPCR 845 mgLINR 701aPTTr 081

EGA artpH 723pCO2 156 mmHgpO2 855 mmHgFiO2 021PF 407HCO3

- 63 mmolLBE -202 mmolLLac 25 mmolL

Curr Op Crit Care 2009 15163-7

Acute liver failure (ALF) is a relatively uncommon disorder affecting onlyabout 2500 patients in the United States each year

The majority of cases of ALF are young (median age 38 years) and female(73)

Current Opinion in Critical Care 2009 15163ndash 167

GENERAL MANAGEMENT OF ACUTE LIVER FAILURE

Once recognized clinical care should occur in a critical care setting makingearly contact with a liver specialist centre

Determining cause is a priority because disease-specific therapies mayreverse or ameliorate liver injury

Management aims to rapidly identify cause and provide multisystem supportto facilitate hepatic regeneration preventing infection and othercomplications LT wait-listing can be performed expediently

Neuberger J et al Gut 2008 57252ndash257

PS

Pa

lma

no

va

HBsAg positivo

Ac Anti HBc totali positivo

Anti HBc IgM positivo

HBeAg positivo

Anti HBe negativo

12 set 13 set 14 set 15 set

Infezione acuta da

HBV

Acetaminophen39

Indeterminant17

Idiosyncratic drug reaction

13

Viral hepatitis11

Ischaemic hepatitis6

Autoimmune hepatitis4

Wilson disease3

Other7

Common causes of acute liver failure

Curr Op Crit Care 2009 15163-7

di cuiHBV 7

12 set 13 set 14 set 15 set

Peggioramento del quadro neurologico (stato confusionale e in seguito soporoso)

TC CAPO

NEG GCS 8 IOT

Centralizzata a Udine

bull lt 7 daysHyperacute

bull 7-28 daysAcute

bull 28 days ndash 26 weeksSubacute

Crit Care Med 2006 34 Ndeg 9 Suppl

Bernal W Wendon J Acute liver failure N Engl J Med 2013 3692525ndash 2534

PS

Ud

ine2225

AP 9050 mmHg HR 100 bpm FiO2 04 SpO2 99 GCS 8

TC torace-addome addensamenti polmonari probabili atelettasie a

livello addominale probabile colecistite e ispessimento della C duodenale

Posizionamento di SNG con fuoriuscita di materiale caffeano (600 mL)

12 set 13 set 14 set 15 set

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Caso clinico

bullFC F 49 anni BMI 37 (100 kg 165 cm)

bullAnamnesi negativa non terapia domiciliare

bullNega allergie

bullRecente viaggio in Grecia

bullAbitudini sessuali riferite promiscue

PS

Pa

lma

no

va Astenia e dolore epigastrico da 2 gg per

cui non si egrave alimentata Dalla sera vomito

Ore 800

GB 13000mcL

PLT 147x103mcL

Ammonio 115 mcmolL

Glucosio 31 mgdL

Cr 152 mgdL

BR totdir 763557 mgdL

AST 12132 UIL

ALT 9767 UIL

PCR 102 mgL

12 set 13 set 14 set 15 set

h 1744GB 21000mcLPLT 178x103mcLGlucosio 26 mgdLCr 167 mgdLAST 13250 UILALT 10775 UUILPCR 845 mgLINR 701aPTTr 081

EGA artpH 723pCO2 156 mmHgpO2 855 mmHgFiO2 021PF 407HCO3

- 63 mmolLBE -202 mmolLLac 25 mmolL

Curr Op Crit Care 2009 15163-7

Acute liver failure (ALF) is a relatively uncommon disorder affecting onlyabout 2500 patients in the United States each year

The majority of cases of ALF are young (median age 38 years) and female(73)

Current Opinion in Critical Care 2009 15163ndash 167

GENERAL MANAGEMENT OF ACUTE LIVER FAILURE

Once recognized clinical care should occur in a critical care setting makingearly contact with a liver specialist centre

Determining cause is a priority because disease-specific therapies mayreverse or ameliorate liver injury

Management aims to rapidly identify cause and provide multisystem supportto facilitate hepatic regeneration preventing infection and othercomplications LT wait-listing can be performed expediently

Neuberger J et al Gut 2008 57252ndash257

PS

Pa

lma

no

va

HBsAg positivo

Ac Anti HBc totali positivo

Anti HBc IgM positivo

HBeAg positivo

Anti HBe negativo

12 set 13 set 14 set 15 set

Infezione acuta da

HBV

Acetaminophen39

Indeterminant17

Idiosyncratic drug reaction

13

Viral hepatitis11

Ischaemic hepatitis6

Autoimmune hepatitis4

Wilson disease3

Other7

Common causes of acute liver failure

Curr Op Crit Care 2009 15163-7

di cuiHBV 7

12 set 13 set 14 set 15 set

Peggioramento del quadro neurologico (stato confusionale e in seguito soporoso)

TC CAPO

NEG GCS 8 IOT

Centralizzata a Udine

bull lt 7 daysHyperacute

bull 7-28 daysAcute

bull 28 days ndash 26 weeksSubacute

Crit Care Med 2006 34 Ndeg 9 Suppl

Bernal W Wendon J Acute liver failure N Engl J Med 2013 3692525ndash 2534

PS

Ud

ine2225

AP 9050 mmHg HR 100 bpm FiO2 04 SpO2 99 GCS 8

TC torace-addome addensamenti polmonari probabili atelettasie a

livello addominale probabile colecistite e ispessimento della C duodenale

Posizionamento di SNG con fuoriuscita di materiale caffeano (600 mL)

12 set 13 set 14 set 15 set

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

PS

Pa

lma

no

va Astenia e dolore epigastrico da 2 gg per

cui non si egrave alimentata Dalla sera vomito

Ore 800

GB 13000mcL

PLT 147x103mcL

Ammonio 115 mcmolL

Glucosio 31 mgdL

Cr 152 mgdL

BR totdir 763557 mgdL

AST 12132 UIL

ALT 9767 UIL

PCR 102 mgL

12 set 13 set 14 set 15 set

h 1744GB 21000mcLPLT 178x103mcLGlucosio 26 mgdLCr 167 mgdLAST 13250 UILALT 10775 UUILPCR 845 mgLINR 701aPTTr 081

EGA artpH 723pCO2 156 mmHgpO2 855 mmHgFiO2 021PF 407HCO3

- 63 mmolLBE -202 mmolLLac 25 mmolL

Curr Op Crit Care 2009 15163-7

Acute liver failure (ALF) is a relatively uncommon disorder affecting onlyabout 2500 patients in the United States each year

The majority of cases of ALF are young (median age 38 years) and female(73)

Current Opinion in Critical Care 2009 15163ndash 167

GENERAL MANAGEMENT OF ACUTE LIVER FAILURE

Once recognized clinical care should occur in a critical care setting makingearly contact with a liver specialist centre

Determining cause is a priority because disease-specific therapies mayreverse or ameliorate liver injury

Management aims to rapidly identify cause and provide multisystem supportto facilitate hepatic regeneration preventing infection and othercomplications LT wait-listing can be performed expediently

Neuberger J et al Gut 2008 57252ndash257

PS

Pa

lma

no

va

HBsAg positivo

Ac Anti HBc totali positivo

Anti HBc IgM positivo

HBeAg positivo

Anti HBe negativo

12 set 13 set 14 set 15 set

Infezione acuta da

HBV

Acetaminophen39

Indeterminant17

Idiosyncratic drug reaction

13

Viral hepatitis11

Ischaemic hepatitis6

Autoimmune hepatitis4

Wilson disease3

Other7

Common causes of acute liver failure

Curr Op Crit Care 2009 15163-7

di cuiHBV 7

12 set 13 set 14 set 15 set

Peggioramento del quadro neurologico (stato confusionale e in seguito soporoso)

TC CAPO

NEG GCS 8 IOT

Centralizzata a Udine

bull lt 7 daysHyperacute

bull 7-28 daysAcute

bull 28 days ndash 26 weeksSubacute

Crit Care Med 2006 34 Ndeg 9 Suppl

Bernal W Wendon J Acute liver failure N Engl J Med 2013 3692525ndash 2534

PS

Ud

ine2225

AP 9050 mmHg HR 100 bpm FiO2 04 SpO2 99 GCS 8

TC torace-addome addensamenti polmonari probabili atelettasie a

livello addominale probabile colecistite e ispessimento della C duodenale

Posizionamento di SNG con fuoriuscita di materiale caffeano (600 mL)

12 set 13 set 14 set 15 set

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Curr Op Crit Care 2009 15163-7

Acute liver failure (ALF) is a relatively uncommon disorder affecting onlyabout 2500 patients in the United States each year

The majority of cases of ALF are young (median age 38 years) and female(73)

Current Opinion in Critical Care 2009 15163ndash 167

GENERAL MANAGEMENT OF ACUTE LIVER FAILURE

Once recognized clinical care should occur in a critical care setting makingearly contact with a liver specialist centre

Determining cause is a priority because disease-specific therapies mayreverse or ameliorate liver injury

Management aims to rapidly identify cause and provide multisystem supportto facilitate hepatic regeneration preventing infection and othercomplications LT wait-listing can be performed expediently

Neuberger J et al Gut 2008 57252ndash257

PS

Pa

lma

no

va

HBsAg positivo

Ac Anti HBc totali positivo

Anti HBc IgM positivo

HBeAg positivo

Anti HBe negativo

12 set 13 set 14 set 15 set

Infezione acuta da

HBV

Acetaminophen39

Indeterminant17

Idiosyncratic drug reaction

13

Viral hepatitis11

Ischaemic hepatitis6

Autoimmune hepatitis4

Wilson disease3

Other7

Common causes of acute liver failure

Curr Op Crit Care 2009 15163-7

di cuiHBV 7

12 set 13 set 14 set 15 set

Peggioramento del quadro neurologico (stato confusionale e in seguito soporoso)

TC CAPO

NEG GCS 8 IOT

Centralizzata a Udine

bull lt 7 daysHyperacute

bull 7-28 daysAcute

bull 28 days ndash 26 weeksSubacute

Crit Care Med 2006 34 Ndeg 9 Suppl

Bernal W Wendon J Acute liver failure N Engl J Med 2013 3692525ndash 2534

PS

Ud

ine2225

AP 9050 mmHg HR 100 bpm FiO2 04 SpO2 99 GCS 8

TC torace-addome addensamenti polmonari probabili atelettasie a

livello addominale probabile colecistite e ispessimento della C duodenale

Posizionamento di SNG con fuoriuscita di materiale caffeano (600 mL)

12 set 13 set 14 set 15 set

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Acute liver failure (ALF) is a relatively uncommon disorder affecting onlyabout 2500 patients in the United States each year

The majority of cases of ALF are young (median age 38 years) and female(73)

Current Opinion in Critical Care 2009 15163ndash 167

GENERAL MANAGEMENT OF ACUTE LIVER FAILURE

Once recognized clinical care should occur in a critical care setting makingearly contact with a liver specialist centre

Determining cause is a priority because disease-specific therapies mayreverse or ameliorate liver injury

Management aims to rapidly identify cause and provide multisystem supportto facilitate hepatic regeneration preventing infection and othercomplications LT wait-listing can be performed expediently

Neuberger J et al Gut 2008 57252ndash257

PS

Pa

lma

no

va

HBsAg positivo

Ac Anti HBc totali positivo

Anti HBc IgM positivo

HBeAg positivo

Anti HBe negativo

12 set 13 set 14 set 15 set

Infezione acuta da

HBV

Acetaminophen39

Indeterminant17

Idiosyncratic drug reaction

13

Viral hepatitis11

Ischaemic hepatitis6

Autoimmune hepatitis4

Wilson disease3

Other7

Common causes of acute liver failure

Curr Op Crit Care 2009 15163-7

di cuiHBV 7

12 set 13 set 14 set 15 set

Peggioramento del quadro neurologico (stato confusionale e in seguito soporoso)

TC CAPO

NEG GCS 8 IOT

Centralizzata a Udine

bull lt 7 daysHyperacute

bull 7-28 daysAcute

bull 28 days ndash 26 weeksSubacute

Crit Care Med 2006 34 Ndeg 9 Suppl

Bernal W Wendon J Acute liver failure N Engl J Med 2013 3692525ndash 2534

PS

Ud

ine2225

AP 9050 mmHg HR 100 bpm FiO2 04 SpO2 99 GCS 8

TC torace-addome addensamenti polmonari probabili atelettasie a

livello addominale probabile colecistite e ispessimento della C duodenale

Posizionamento di SNG con fuoriuscita di materiale caffeano (600 mL)

12 set 13 set 14 set 15 set

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

GENERAL MANAGEMENT OF ACUTE LIVER FAILURE

Once recognized clinical care should occur in a critical care setting makingearly contact with a liver specialist centre

Determining cause is a priority because disease-specific therapies mayreverse or ameliorate liver injury

Management aims to rapidly identify cause and provide multisystem supportto facilitate hepatic regeneration preventing infection and othercomplications LT wait-listing can be performed expediently

Neuberger J et al Gut 2008 57252ndash257

PS

Pa

lma

no

va

HBsAg positivo

Ac Anti HBc totali positivo

Anti HBc IgM positivo

HBeAg positivo

Anti HBe negativo

12 set 13 set 14 set 15 set

Infezione acuta da

HBV

Acetaminophen39

Indeterminant17

Idiosyncratic drug reaction

13

Viral hepatitis11

Ischaemic hepatitis6

Autoimmune hepatitis4

Wilson disease3

Other7

Common causes of acute liver failure

Curr Op Crit Care 2009 15163-7

di cuiHBV 7

12 set 13 set 14 set 15 set

Peggioramento del quadro neurologico (stato confusionale e in seguito soporoso)

TC CAPO

NEG GCS 8 IOT

Centralizzata a Udine

bull lt 7 daysHyperacute

bull 7-28 daysAcute

bull 28 days ndash 26 weeksSubacute

Crit Care Med 2006 34 Ndeg 9 Suppl

Bernal W Wendon J Acute liver failure N Engl J Med 2013 3692525ndash 2534

PS

Ud

ine2225

AP 9050 mmHg HR 100 bpm FiO2 04 SpO2 99 GCS 8

TC torace-addome addensamenti polmonari probabili atelettasie a

livello addominale probabile colecistite e ispessimento della C duodenale

Posizionamento di SNG con fuoriuscita di materiale caffeano (600 mL)

12 set 13 set 14 set 15 set

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

PS

Pa

lma

no

va

HBsAg positivo

Ac Anti HBc totali positivo

Anti HBc IgM positivo

HBeAg positivo

Anti HBe negativo

12 set 13 set 14 set 15 set

Infezione acuta da

HBV

Acetaminophen39

Indeterminant17

Idiosyncratic drug reaction

13

Viral hepatitis11

Ischaemic hepatitis6

Autoimmune hepatitis4

Wilson disease3

Other7

Common causes of acute liver failure

Curr Op Crit Care 2009 15163-7

di cuiHBV 7

12 set 13 set 14 set 15 set

Peggioramento del quadro neurologico (stato confusionale e in seguito soporoso)

TC CAPO

NEG GCS 8 IOT

Centralizzata a Udine

bull lt 7 daysHyperacute

bull 7-28 daysAcute

bull 28 days ndash 26 weeksSubacute

Crit Care Med 2006 34 Ndeg 9 Suppl

Bernal W Wendon J Acute liver failure N Engl J Med 2013 3692525ndash 2534

PS

Ud

ine2225

AP 9050 mmHg HR 100 bpm FiO2 04 SpO2 99 GCS 8

TC torace-addome addensamenti polmonari probabili atelettasie a

livello addominale probabile colecistite e ispessimento della C duodenale

Posizionamento di SNG con fuoriuscita di materiale caffeano (600 mL)

12 set 13 set 14 set 15 set

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Acetaminophen39

Indeterminant17

Idiosyncratic drug reaction

13

Viral hepatitis11

Ischaemic hepatitis6

Autoimmune hepatitis4

Wilson disease3

Other7

Common causes of acute liver failure

Curr Op Crit Care 2009 15163-7

di cuiHBV 7

12 set 13 set 14 set 15 set

Peggioramento del quadro neurologico (stato confusionale e in seguito soporoso)

TC CAPO

NEG GCS 8 IOT

Centralizzata a Udine

bull lt 7 daysHyperacute

bull 7-28 daysAcute

bull 28 days ndash 26 weeksSubacute

Crit Care Med 2006 34 Ndeg 9 Suppl

Bernal W Wendon J Acute liver failure N Engl J Med 2013 3692525ndash 2534

PS

Ud

ine2225

AP 9050 mmHg HR 100 bpm FiO2 04 SpO2 99 GCS 8

TC torace-addome addensamenti polmonari probabili atelettasie a

livello addominale probabile colecistite e ispessimento della C duodenale

Posizionamento di SNG con fuoriuscita di materiale caffeano (600 mL)

12 set 13 set 14 set 15 set

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

12 set 13 set 14 set 15 set

Peggioramento del quadro neurologico (stato confusionale e in seguito soporoso)

TC CAPO

NEG GCS 8 IOT

Centralizzata a Udine

bull lt 7 daysHyperacute

bull 7-28 daysAcute

bull 28 days ndash 26 weeksSubacute

Crit Care Med 2006 34 Ndeg 9 Suppl

Bernal W Wendon J Acute liver failure N Engl J Med 2013 3692525ndash 2534

PS

Ud

ine2225

AP 9050 mmHg HR 100 bpm FiO2 04 SpO2 99 GCS 8

TC torace-addome addensamenti polmonari probabili atelettasie a

livello addominale probabile colecistite e ispessimento della C duodenale

Posizionamento di SNG con fuoriuscita di materiale caffeano (600 mL)

12 set 13 set 14 set 15 set

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

bull lt 7 daysHyperacute

bull 7-28 daysAcute

bull 28 days ndash 26 weeksSubacute

Crit Care Med 2006 34 Ndeg 9 Suppl

Bernal W Wendon J Acute liver failure N Engl J Med 2013 3692525ndash 2534

PS

Ud

ine2225

AP 9050 mmHg HR 100 bpm FiO2 04 SpO2 99 GCS 8

TC torace-addome addensamenti polmonari probabili atelettasie a

livello addominale probabile colecistite e ispessimento della C duodenale

Posizionamento di SNG con fuoriuscita di materiale caffeano (600 mL)

12 set 13 set 14 set 15 set

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Bernal W Wendon J Acute liver failure N Engl J Med 2013 3692525ndash 2534

PS

Ud

ine2225

AP 9050 mmHg HR 100 bpm FiO2 04 SpO2 99 GCS 8

TC torace-addome addensamenti polmonari probabili atelettasie a

livello addominale probabile colecistite e ispessimento della C duodenale

Posizionamento di SNG con fuoriuscita di materiale caffeano (600 mL)

12 set 13 set 14 set 15 set

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

PS

Ud

ine2225

AP 9050 mmHg HR 100 bpm FiO2 04 SpO2 99 GCS 8

TC torace-addome addensamenti polmonari probabili atelettasie a

livello addominale probabile colecistite e ispessimento della C duodenale

Posizionamento di SNG con fuoriuscita di materiale caffeano (600 mL)

12 set 13 set 14 set 15 set

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

TI

2245

In analgosedazione con remifentanil 002 mcgkgmin Soporosa ma risvegliabile

esegue ordini semplici Intubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 100 AP

9060 mmHg HR 110 bpm senza supporto In corso 1 PFC Addome globoso peristalsi presente diuresi 1 mLkgh non stimolata

Apiretica

12 set 13 set 14 set 15 set

2300

pH 734

PaCO2 223 mmHg

PaO2 102 mmHg

FiO2 04

PF 256

HCO3- 149 mmolL

BE -128 mmolL

SaO2ScvO2 974799

Lac 23 mmolL

Allertato CNT per OLTx urgente

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Ore 600bullIn analgosedazione con remifentanil 005 mcgkgmin

Risvegliabile orientata Pupille isocoriche isocicliche fotoreagentibullIntubata e ventilata in BiPAP (5+10) FiO2 04 SpO2 99bullEmodinamica stabile senza supporto AP 11870 mmHg HR 100 bpmbullAddome dolente alla palpazione peristalsi presentebullDiuresi 08 mLkgh senza stimolo farmacologico

12 set 13 set 14 set 15 set

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Ore 1300Finestra neurologica paziente risvegliabile apparente lieve deficit arto superiore dxDiuresi 05 mLkgh Si avviano furosemide e fenoldopam

12 set 13 set 14 set 15 set

PDR 24-R15 698

Ore 1500Emodinamica tendente allrsquoipotensione con necessitagrave di supporto aminico Noradrenalina fino a 018 mcgkgmin CI 56 EVLWI 96 ITBVI 764 (EV1000)Anurica rarr CVVH

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1209

12 set 13 set 14 set 15 set

13091309

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

611 2149

PLT 136000m

cL

120000mcL

PT 279 802

INR 260 693

aPTTr 090 124

AT 43 28

D-dimero 18081

FEUngmL

57200

FEUngmL

Fibrinogeno 177 mgdL 132mgdL

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 564 247 94 320 10 23K 00 377 -133 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

1 FRANCO CARLA -- 132435464 Citrated native

Campione 13092015 1147PM-0225AM

12 set 13 set 14 set 15 set

2 PFC

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Ore 700Finestra neurologica non contattabile pupille isocoriche isocicliche fotoreagenti smorfie allo stimolo doloroso

Emodinamica tendente allrsquoipertensione AP 13070 mmHg HR 101 bpmCI 55 ITBVI 900 EVLWI 115

Oligo-anurica rarr CVVH + furosemide 8 mgh + fenoldopam

12 set 13 set 14 set 15 set

PDR 23 R15 708

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Eco addome hellipil fegato appare di dimensioni nei limiti di norma a margini un porsquo arrotondati a ecostruttura omogenea senza sicura riconoscibilitagrave della cisti segnalata al VII segmento Non alterazioni focali ove esplorabile Colecisti attualmente contratta a pareti diffusamente ispessite senza calcoli endoluminali Non dilatazioni delle vie biliari Vena porta pervia di calibro regolare con flusso ortodirettonon turbolento con velocitagrave di ca 20 cms Arteria epatica pervia con picco sistolico regolare e scarsa componente diastolica in quadro che rende difficile misurare lrsquoIR ed egrave compatibile con aumento delle resistenze intraparenchimali Vene sovraepatiche pervie con flusso trifasico

12 set 13 set 14 set 15 set

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

0

2000

4000

6000

8000

10000

12000

14000

800 1744 611 2149 555 1607

AST

ALT

LDH

0

1

2

3

4

5

6

7

8

9

800 1744 611 2149 555 1607

BR tot

BR dir

1209 1309 1409 140913091209

12 set 13 set 14 set 15 set

Ammonio 2266 mcmolL

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

555 1607

PLT 116000mcL 10000mcL

PT 290 539

INR 269 479

aPTTr 144 112

AT 35 24

D-dimero 76222FEUngmL

79807FEUngml

Fibrinogeno 137 mgdL 98 mgdL

12 set 13 set 14 set 15 set

10 millimetri

R K Angle MA PMA G EPL A CI LY30min min deg mm dsc mm 83 170 179 229 10 15K 00 320 -34 00

9 mdash 27 2 mdash 9 22 mdash 58 44 mdash 64 36K mdash 85K 0 mdash 15 -3 mdash 3 0 mdash 8

2 FRANCO CARLA -- 132435464 Citrated native

Campione 14092015 1236AM-0205AM

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

12 set 13 set 14 set 15 set

600 1200 1600

pH 744 742 751

PaCO2 39 mmHg 373 mmHg 27 mmHg

PaO2 102 mmHg 61 mmHg 71 mmHg

FiO2 04 04 06

PF 254 152 116

HCO3- 268 mmolL 247 mmolL 247 mmolL

BE 27 mmolL 04 mmolL -04 mmolL

SaO2ScvO2 981803 927 95

Lac 58 mmolL 53 mmolL 76 mmolL

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Ore 1700Finestra neurologica non risvegliabile pupille midriatiche isocoriche fotoreagenti Sguardo deviato verso dx

12 set 13 set 14 set 15 set

TC capo urgente non significative alterazioni densitometriche parenchimali Diffuso spianamento dei solchi corticali da verosimile edema Cavitagrave ventricolari in sede di dimensioni lievemente ridotte rispetto alla norma in sede sovratentoriale

Mannitolo 18

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Ore 2200Paziente non in analgosedazioneNon responsiva a stimoli verbali e dolorosi Pupille anisocoriche reagenti alla luce (dxgtsn)

Emodinamica stabile senza supporto Intubata e ventilata in BIPAP (PEEP 10 + ASB 18) FiO2 06 SpO2 95 RR 37 attimin

Diuresi 06 mLkgh stimolato da furosemide 8 mgh in corso fenoldopam e CVVH TC 376 degC

12 set 13 set 14 set 15 set

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Ore 600Alla finestra neurologica pazientenon responsiva a stimoli verbali odolorosi Pupille anisocoriche nonfotoreagentiIntubata e ventilata in BiPAP connecessitagrave di supporti sempremaggiori (12+18) FiO2 09 SpO2 89Diuresi 08 mLkgh stimolato dafurosemide 8 mgh Apiretica

600

pH 731

PaCO2 341 mmHg

PaO2 668 mmHg

FiO2 09

PF 743

HCO3- 179 mmolL

BE -81 mmolL

SaO2 90

Lac 132 mmolL

12 set 13 set 14 set 15 set

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Ore 1100 Contattata eacutequipe trapiantologica rarr Visto il quadro TC e la clinica in rapido peggioramento si decide per la non trapiantabilitagrave

12 set 13 set 14 set 15 set

Ore 1120peggioramento delle condizioni FiO2 1 SpO2 72 AP 8540 mmHg HR 130 bpm

Ore 1130progressiva ipotensione cui segue bradicardia e ACC Exitus

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

Doan Y Dao1 Emmanuel Seremba2 Veeral Ajmera1 Corron Sanders1 Linda S Hynan3 William M Lee1 and the Acute Liver Failure Study Group

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remainscontroversial

Patents who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analoguespresumably because of rapid disease evolution and short treatment duration Despite the lack of benefit NAs should still be given to transplantation candidates since viral suppression prevents recurrenceafter grafting

Dig Dis Sci 2012 May 57(5) 1349-57

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Trattamento

bull IFN nessun beneficio dimostrato potenziale attivazione immunitaria con peggioramento dellrsquoepatite

bull Analoghi nucleosidici

bull OLTx

Tillman HL et al Management of severe acute to fulminant hepatitis B Liver International 2012

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Liver Transplantation for Hepatitis B in the United StatesC Camci A Gurakar J Rose S Rizvi H Wright T Bader R Monlux RR Schade BM

Nour and A Sebastian

Transplantation Proceedings 37 4350ndash4353 (2005)

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

(33 mmolL)

(33 mmolL)

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Crit Care Med 2006 Vol 34 No 9 (Suppl)

Hepatic encephalopathy

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Sistema nervoso centrale

Edema cerebrale e ipertensione intracranica (ICH) rarr rischio di erniazioneuncale (fatale)

Edema cerebrale rarr danno ischemico e ipossico con deficit neurologici a lungo termine

Eziologia non completamente chiara disturbi osmotici elevato flussoematico cerebrale da perdita di autoregolazione cerebrovascolare infiammazione eo infezioni

Lee WM et al AASLD Position Paper 2011

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Management dellrsquoencefalopatia

Journal of Critical Care (2013) 28 783ndash791

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Management of intracranial hypertension

Invasive intracranial pressure monitoring is controversial

Curr Opin Crit Care 2015 21134-41

It allows measurement of cerebral perfusionpressure and detection of ICH that otherwiseclinically silent This may facilitate timely and rational use of ICP-lowering therapies and allow optimization of ICP before and duringliver transplantation

Insertion of ICP monitors risks intracranialhaemorrhageand no mortality benefit hasbeen demonstrated

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Curr Opin Crit Care 2015 21134-41

Prophylactic reversal of assumed coagulopathy with bloodproducts such as fresh frozen plasma might

bull heighten portal venous pressuresbull promote bleedingbull raise ICPbull obscure true INR readings

Management della diatesi emorragica

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Fresh frozen plasma should only be given for active bleeding

Vitamin K deficiency should be corrected with parenteraladministration

Platelet transfusion is recommended if counts are less than50000mcL although a higher target might be more appropriate if bleeding continues

Management della diatesi emorragica

Curr Opin Crit Care 2015 21134-41

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Profilassi infettiva

Crit Care Med 2007 35 N 11

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Supporti epatici biologici e non

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Bridge to OLTx

bull MARS molecular adsorbent and recirculation systembull SPAD single-pass albumin dyalisisbull CAPS continuous albumin purification systembull SEPET selective plasma filtration therapybull FPSA fractional plasma separation and adsorption

Maiwall R et al Liver dialysis in acute-on-chronic liver failure current and future perspectives Hepatol Int 2014 8(2)S505-13

SPAD

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

11Bridging therapies and liver transplantation in ALF

MARS device is coupled with a conventional haemo-dialysis or haemofiltration unit removing water- soluble toxins The beneficial effects of the MARS treatment are thought to arise from the removal of neurotoxic and vasoactive substances (eg copper bilirubin bile acids aromatic amino acids tryp-tophan endogenous benzodiazepine-like substances urea creatinine ammonia and nitric oxide) (1)

MARS treatment has been investigated in different liver failure aetiologies although in RCTs most pa-tients have had acute-on-chronic liver failure Due to the low incidence of and high mortality in ALF RCTs are not easy to accomplish in ALF patients Currently all but one published MARS studies on ALF patients are case series (10 40ndash45) Overall survival in MARS treated ALF patients (transplanted and non-trans-planted) is approximately 60ndash80 (42ndash45) although some studies report much lower rates (20ndash30) (40 41) In a recently completed RCT on MARS treatment in ALF patient randomisation was done after listing for emergency LT and 75 of listed patients received a graft within 24h Even with a very short period of MARS treatment the results suggest a trend of higher overall survival in transplanted MARS treated pa-tients compared with the controls receiving standard medical therapy alone (10)

In clinical setting MARS treatment contributes to the improved neurological status in addition to at-tenuation of hyperdynamic circulation and improved renal function in ALF patients Significant improve-ment in encephalopathy has been reported in several studies (46ndash48) Even a complete resolution of grade 4 HE has been documented during MARS treatment (43 49)

The most common side-effects reported with MARS include thrombocytopenia moderate bleeding from mucous membranes or puncture sites and catheter infections (1)

THE FINNISH LIVER TRANSPLANTATION AND MARS EXPERIENCE

In Finland MARS treatment was started in 2001 and over 150 ALF patients have been treated so far In Finland 5ndash10 ALF patients are transplanted annually and approximately 20ndash30 patients receive MARS

treatment for ALF All LTs and intensive care are per-formed in a single centre in Helsinki The current initiation criteria for MARS treatment in Finland are presented in Table 1 With a lethal dose of hepato-toxin without an antidote MARS treatment is started immediately before the signs of ALF develop Haemo-dialysis is always combined with MARS

Of the transplanted ALF patients 62 had un-known and 21 toxic aetiology The aetiological pro-file is changing towards toxic liver injury (43) with a high rate of spontaneous recovery However para-cetamol-induced ALF is rare in Finland compared to other Western countries (4) Only three patients have been transplanted due to pure paracetamol intoxica-tion in Finland by 2009 with over 800 transplants

The implementation of MARS treatment has likely contributed to improved 6-month survival in both non-transplanted (40 before vs 66 after MARS P = 003) and transplanted (77 vs 94 ns) ALF patients (Fig 1) (43) The 92 1-year survival of ALF patients bridged to emergency LT with MARS (50) compares favourably to previous data from LT regis-ters and studies (2 11) Compared to a historical co-hort of ALF patients from our unit MARS reduced the need for LT (29 vs 57 P = 0001) (43)

Regarding the outcome in ALF the most important factor predicting 6-month survival in MARS treated patients was the aetiology of liver failure (43) The grade of HE was an important predictor of survival in ALF with toxic aetiology but not in ALF with un-known aetiology (51)

In our ALF series MARS treatment significantly decreased serum ammonium and bilirubin levels and induced a favourable blood amino acid profile by decreasing neuroactive amino acids (52) Impor-tantly the grade of HE improved during MARS treat-ment and the percentage of patients dying from brain herniation has decreased since the implementation of MARS treatment (43)

In the only published study on the cost-utility of MARS in ALF MARS treatment in our centre pro-vided a less expensive and more cost-efficient treat-ment when compared to standard medical therapy (53) This was attributable to the fewer LTs in MARS treated patients All medical expenses directly related to the liver disease from 6 months before to 3 years after ICU treatment were determined The incremen-

Etiology MARS treatment initiation criteria Treatment protocol Contraindications for MARS-treatment

Acute liver failure Rapid deterioration in clinical condition and hepatic synthetic function despite standard medical therapy and patient fulfills the criteria for a high urgent Ltx

OR

Ingestion of a lethal dose of known hepatotoxin without specific antidote (Amanita mushrooms etc)

22 hour sessions daily until1) Native liver recovers2) Liver transplantation3) Irreversible multi-organ

damage

Acute bleeding

TABLE 1

The current initiation criteria for Molecular Adsorbent Recirculating System (MARS)

Scandinavian Journal of Surgery 100 8ndash13 2011

Bridge to OLTx

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

FULMAR study

Prospective randomized controlled multi-centre trial which comparedtwo groups (conventional treatment vs conventional treatment and MARS) showed no significant difference in 6-month overall and transplant-free survival A nonsignificant improvement in survival wasseen in the acetaminophen-induced ALF subgroup The brief periodbetween randomization and transplantation (162 h) in this studyprecluded adequate evaluation of MARS

Albumin dialysis with a noncell artificial liver support device in patientswith acute liver failure a randomized controlled trial

Saliba F Camus C Durand F Mathurin P Letierce A Delafosse B Barange K Perrigault PF Belnard M Ichaiuml P Samuel D

Ann Intern Med 2013 Oct 15159(8)522-31

Supporto epatico

Millis JM et al Technology insight liver support systems Nat Clin Pract Gastroenterol Hepatol 2005 2398-405

Controindicazioni

Burra P et al La gestione della lista drsquoattesa per trapianto di fegato Trapianti 2008 XII85-104

Trapianto da donatore vivente

bull Status 1 sopravvivenza dellrsquo86 dopo LDLT con lobi dx per FHF ma correlazione con il volume parenchimale trapiantato

bull Status 2A sopravvivenza a 1 anno 43-56 nei pazienti adulti sottoposti a LDLT in stato 2A (acute on chronic liver failure)

bull Status 2B e 3 il rischio laquodonatoreraquo non giustifica i benefici per il ricevente che puograve eventualmente essere considerato per LDLT se peggioramento a 2B massime chances di ottenere buoni risultati nel gruppo status 3

AISF Trapianto di fegato non urgente dellrsquoadulto 2004

Trapianto da donatore vivente

Legge n 483 del 16121999

2001 primi 20 casi

Revisione a maggio 2002

Attualmente in Italia non consentito

Autopsia

Epatite acuta necrotizzante massiva compatibile con epatite acuta fulminante NAS

Edema polmonare acuto con polmonite consensuale

Controindicazioni

Burra P et al La gestione della lista drsquoattesa per trapianto di fegato Trapianti 2008 XII85-104

Trapianto da donatore vivente

bull Status 1 sopravvivenza dellrsquo86 dopo LDLT con lobi dx per FHF ma correlazione con il volume parenchimale trapiantato

bull Status 2A sopravvivenza a 1 anno 43-56 nei pazienti adulti sottoposti a LDLT in stato 2A (acute on chronic liver failure)

bull Status 2B e 3 il rischio laquodonatoreraquo non giustifica i benefici per il ricevente che puograve eventualmente essere considerato per LDLT se peggioramento a 2B massime chances di ottenere buoni risultati nel gruppo status 3

AISF Trapianto di fegato non urgente dellrsquoadulto 2004

Trapianto da donatore vivente

Legge n 483 del 16121999

2001 primi 20 casi

Revisione a maggio 2002

Attualmente in Italia non consentito

Autopsia

Epatite acuta necrotizzante massiva compatibile con epatite acuta fulminante NAS

Edema polmonare acuto con polmonite consensuale

Trapianto da donatore vivente

bull Status 1 sopravvivenza dellrsquo86 dopo LDLT con lobi dx per FHF ma correlazione con il volume parenchimale trapiantato

bull Status 2A sopravvivenza a 1 anno 43-56 nei pazienti adulti sottoposti a LDLT in stato 2A (acute on chronic liver failure)

bull Status 2B e 3 il rischio laquodonatoreraquo non giustifica i benefici per il ricevente che puograve eventualmente essere considerato per LDLT se peggioramento a 2B massime chances di ottenere buoni risultati nel gruppo status 3

AISF Trapianto di fegato non urgente dellrsquoadulto 2004

Trapianto da donatore vivente

Legge n 483 del 16121999

2001 primi 20 casi

Revisione a maggio 2002

Attualmente in Italia non consentito

Autopsia

Epatite acuta necrotizzante massiva compatibile con epatite acuta fulminante NAS

Edema polmonare acuto con polmonite consensuale

Trapianto da donatore vivente

Legge n 483 del 16121999

2001 primi 20 casi

Revisione a maggio 2002

Attualmente in Italia non consentito

Autopsia

Epatite acuta necrotizzante massiva compatibile con epatite acuta fulminante NAS

Edema polmonare acuto con polmonite consensuale

Autopsia

Epatite acuta necrotizzante massiva compatibile con epatite acuta fulminante NAS

Edema polmonare acuto con polmonite consensuale