This document provides an overview of acute liver failure (ALF), including definitions, causes, prognosis, management, and treatment considerations. Some key points: - ALF is defined as coagulation abnormality with any degree of encephalopathy and illness duration under 26 weeks without preexisting cirrhosis. Prior to transplantation, survival was under 15%; it is now over 65% including those who receive transplants. - Prognostic factors for outcomes include stage of encephalopathy, laboratory markers, etiology, INR, bilirubin, encephalopathy, and multiorgan failure. Scoring systems like MELD and King's College criteria are used but do not perfectly predict survival. - Liver

1. Acute Liver Failure
A Management Update
From Comatose Confusion to Clarity
Palepu B Gopal
1

2. Potentially and Increasingly Reversible Condition
+
Survival Rates by Era for ALF at King’s College Hospital
with grade 3 or 4 encephalopathy, regardless of management
2

3. Acute Liver Failure
AASLD Definition and Prognosis
Definition Evidence of coagulation abnormality (INR 1.5),
any degree of encephalopathy without
preexisting cirrhosis and with an illness of <26
weeks’ duration
Prognosis Prior to transplantation < 15% survival
Currently overall short-term survival (one year)
including those undergoing transplantation is
greater than 65%
3

4. Etiology of Acute Liver Failure
Non-Paracetamol drug
Induced ALF requiring
Emergency LTx
USA 1987–2006
Bernal W et al Lancet 2010
Mindikoglu AL et al Liver Transpl 2009
Khuroo MS et al. J Viral Hepat 2003
Acharya SK et al. J Gastroent Hepatol 2002
4

5. ALF– A Multi-Organ Failure Syndrome
Acute Liver
Failure
5

6. Classification of Acute Liver Failure
O’Grady et al, 1993; Ellis et al, 1995
Types Jaundice-encephalo
pathy
Cerebral
edema
Prognosis Leading
causes
Hyperacute <7days Common Moderate Virus A,B,E
acetaminop
hen
Acute 8-28days Common Poor Non A,B,C
and drugs
Sub-acute 29 days -
12weeeks
Infrequent Poor Non A,B,C
drugs
Late onset 8weeks-
24weeks
Infrequent poor Non A,B,C
drugs
6

7. Predicting Outcomes in Acute Lifer Failure
• Important predictive factor
Stage of encephalopathy
• Suggested laboratory markers:
Factor V
AFP
Serum Phosphate
VII/V ratio > 30
Gc globulin
• Four factors Etiology of ALF
INR, bilirubin
Encephalopathy and brain edema
Multiorgan failure
7

8. Variables Used for Prognostic Models of ALF
King’s Clichy MELD Indian
John O’Grady. Clin Liver Dis 11 (2007) 291–303
Acharya SK et al . Hepatology 23: 1996
8

9. 9

10. Clichy- Villejuif Criteria from France
Criteria from India Acharya SK et al . Hepatology 23: 1996
Presence of > 3 factors – 90% Mortality
Model for End-stage Liver Disease (MELD) Score
10

11. United Network for Organ Sharing (UNOS)
Status 1 - most urgent level
• Rapid development of grade 3 - 4 encephalopathy
• Prothrombin time > 25 sec
• On vasopressors or ventilatory support
• Are expected to live less than 7 days without a transplant
• Inborn error of metabolism with metabolites that are toxic
to the CNS
11

12. Clichy Criteria Vs KCH Criteria
• 81 non-paracetamol & nontransplanted patients from
French ICU - mortality was 81%
• When Clichy and KC criteria were applied at admission
data, predictive Mortality by
– Clichy was 60% and
– KC was 80 %
• Nonspecific liver function tests lactate & phosphate
sensitivity specificity
King’s College Criteria 92% 69%
APACHE II 92% 81%
12

13. 45. Currently available prognostic scoring systems
do not adequately predict outcome and determine
candidacy for liver transplantation. Reliance entirely
upon these guidelines is thus not recommended.(III)
2. Contact with a transplant center and plans to
transfer appropriate patients with ALF should be
initiated early in the evaluation process (III).
46. Urgent hepatic transplantation is indicated in
acute liver failure where prognostic indicators suggest
a high likelihood of death (II-3)
47. Living donor or auxiliary liver transplantation
may be considered in the setting of limited organ supply,
but its use remains controversial (II-3)
13

14. Liver Transplant for ALF
• OLT is the definitive treatment for those who
meet the criteria
• 1 yr. and 5 yr . survival of patients undergoing
OLT for ALF is about 20% lower than cirrhotics
• Post ALF OLT Survival rates
USA 63%
Europe 61%
Individual centers 59% to 79%
• Better prognosis: Paracitomol, HAV, ischemia,
AFLP
• Worse prognosis: HBV, AIH, Wilson’s, Bud-Chiari
John O’Grady. Clin Liver Dis 11:2007
Toru Ikegami et al.
J Am Coll Surg 2008
14

15. Liver Transplant for FHF – 17 Yrs and 200 Patients
Douglas G. Farmer et al
ANNALS OF SURGERY
Vol. 237 : 2003
15

16. Variations of Liver Replacement Therapy
Transplantation : Orthotopic LT
DDLT or LDLT
Auxiliary liver transplant
Split Liver TransplantT
Two-stage procedures : Hepatetctomy followed
later by OLT
Non-Transplanta Therapies
Xenotransplantation
Hepatocyte Transplantation
Hepatic Assist Devices
16

17. Contraindications to LTx in FHF
• Un-controlled sepsis with MOF
• Extra hepatic malignancy
• Irreversible brain damage
- neurologic exam
- imaging studies
- sustained ICP >50 or
- CPP <40 for > 1-2hrs
• Respiratory - ALI/ARDS PEEP >12 and FiO2 >60%
- Pulmonary arterial hypotension(MPAP
>40mmHg)
- Intrapulmonary shunt (HPS) paO2/FiO2 <100
• Functional status - Bedbound >10 days 17

18. Liver Support / Assist Devices
Bio-Arteficial Arteficial Hybrid
18

19. Use of MARS in Liver Failure
19

20. Improves Bilirubin levels
Improves Encephalopathy & CBF
Variable effects on ICP
Decreased serum Cu+ in Wilson’s
Improves pruritus
Improves renal function
Improves hemodynamics
may worsen coagulopathy and bleeding
may cause hypoglycemia
alter PK of antibiotics and antifungals
Molecular Adsorbent Recycling System
MARS
Artificial and bioartificial support systems for liver failure
Liu JP, Gluud LL, Als-Nielsen B, Gluud C
Acute-on-chronic liver failure may benefit from treatment
with the more recently developed artificial support systems.
The evidence for ALF seemed less conclusive.
20

21. Bioartificial liver support- Hepatocytes ± Filters ± Oxygenator
Detoxification, biosynthesis and regulation
Artificial - Filters ± Adsorbers
Only detoxification
CVVHD
Hemadsorption
Plasmapheresis
‘Is there life in MARS?’
Meta-analysis of 4 RCTs - No survival benefit with MARS
AASLD 48 Not recommended
Future (II-1)
LADs only in Clinical research setting
On AoCLF rather than ALF
Bridge to transplantation
Liver support devices
J Phuaa and KH Lee.
Curr Opin Crit Care 14:208–21
215

22. A non-statistically significant reduction
of mortality was shown in patients with ALF
treated with MARS (OR = 0,75 [CI= 95%,
0,42 – 1,35]; p= 0,3427)
acute on chronic liver failure MARS therapy,
clinical trial results showed a not statistically
significant reduction in mortality
(odds ratio [OR] =0,78; [CI] =95%:
0,58 – 1,03; p= 0,1059,
22

23. Encephalopathy
In the presence of cerebral edema,
Maintain the head in neutral position and elevated to 30 degrees.
Ventilate patient maintaining PCO2 between 30 and 40 mm Hg
Fluids and vasopressors may be used to achieve CPP goal
Lactulose (PR or NG) to keep serum ammonia <50 mcg/dL
If serum ammonia is >50 mcg/dL despite adequate stool output
with lactulose,
Rifaximin
CVVHD with serum ammonia goal >200 mcg/dL
Neomycin not recommended by ALFSG because of nephrotoxicity
CT Head Stage 3-4 HE or focal deficits
23

24. Seizure Prophylaxis and Surveillance
• Nonconvulsive seizure activity is common
o Prophylactic antiepileptics not recommended
o EEG when:
 Grade II/IV encephalopathy
 Sudden neuro deterioration
 Myoclonus
 To titrate use of barbiturates
• Treatment
o Phenytoin
o Propofol
o barbiturates
o Fosphenytoin
o low-dose benzodiazepine
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25. Management of Cerebral Edema / Raised ICP
• Manitol: first line therapy 0.5g/kg
– Only if serum osmolality < 320 mosmol/l
• Thiopentone infusion -Barbiturate coma
– Anti-oxidant, decreases CMRO2, anticonvulsant
• Strong sodium (1)
– Even if serum osmolality is high
– Target Na level 145 -150
• Acetylcysteine
– Decreases incidence of cerebral edema but increases CMRO2
• Specific management
o Induced hypothermia (32-33ºC)
o Indomethacin: 25mg IV over 1min.
• Hyperventilation
• Corticosteroids – No Role (1)
25

26. Role of Hypertonic Saline in Management of HE
7 -30 % NaCl : Maintain S. Na 145 – 155:Monitor S. Osmolality
High ICP Surges Hypertonic saline & Mannitol infusion
Most important Tts of cerebral edema
Increases colloid osmotic pressure in the cerebral capillaries
Reduces Interstitial water content.
Reduces ICP
Improves cerebral perfusion
CMRO 2 and lactate
Murphy et al. Hepatology. 2004
26

27. Brain Edema in Liver Failure
Andres T Blei. Critical Care Clinics 2008
Intracranial Pressure Monitored Vs
Non- Monitored Group
Higher medication Utilization in Monitored Group
27
Vaquero J et al. ALF Study Group: Liver Transpl 2005

28. ICP Monitoring
ICP bolts May be useful to optimize CPP
Extra-dural system preferred
Lowest complication with Epidural
Risk : benefit
ICP/CPP measurement vs. Sepsis and bleeding
Have not been shown to improve survival
ALF G: 10% Incidence of bleeding 10%
No Randomized control Trials
Surrogate markers of CBF Transcranial Doppler
Near infrared spectroscopy
IJV oxygen saturation
Cerebral microdialysis
ICP monitoring is only used in hyperammonemia above 200 mmol/l and those
with poor prognosis and signs of systemic inflammation, by experienced
Wendon JA et al. Hepatology 2006 28

29. Algorithm For ICP Monitoring
29

30. Coagulopathy of ALF & Correction
Pts. with ALF are by definition coagulopathic
Spontaneous bleeding is rare
Very difficult to obtain complete correction
Vitamin K No Role, At least one dose (AASLD)
Fresh Frozen Plasma Best prognostic indicator
Prophylactic FFP not recommended
Does not reduce risk of significant bleeding
volume overload
ALFSG recommends aiming for: INR 1.5
Platelets Limited role for prophylactic transfusion
If clinically significant bleeding or < 10 - 20,000/mm3
ALFSG recommends aiming for Plts. 50,000
Cryoprecipitate When fibrinogen <100 mg/dL.
Recombinant VII When FFP fails to correct PT/INR
Risk of hrombotic complication
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31. Hemodynamic Failure
Decreased SVR and High Cardiac output
Restoration of hemodynamics
Correct hypovolaemia with Crystalloids initially
Once euvolemic, studies show albumin is better
Pressors Noradrenaline is the agent of choice
Vasopressin not recommended as it increases ICP
Low-dose terlipressin
Inotropes Low CO syndromes carry poor prognosis
dopamine or dobutamine, Adrenaline
Adrenaline may compromise HBF
No proven benefit of NAC, prostaglandins and steroids
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32. Renal Issues of ALF
• AKI and Renal Dysfunction common
Hypovolaemia
Hepato-Renal Syndrome
Acute tubular necrosis
• Protect and maintain renal functions by m
• Optimize volume
• Optimize hemodynamics
• Avoid nephrotoxic agents
• Infection and Sepsis Management
• Renal Replacement Therapy
• Renal failure
• Fluid overload
• Severe hyperammonemia
• Severe Lactic Acidosis
•CRRT preferred over IRRT
• Anticoagulation
Usually not needed
Use citrate over heparin
Monitor ionized calcium
• Bicarb buffer over lactate or citrate buffer
• Avoid hyponatraemia
AASLD 40. If dialysis support is
needed for acute renal failure, it is
recommended that a continuous mode
rather than an intermittent mode be
used (I). 32

33. General Supportive
Measures
● Monitor blood glucose 2-hourly and maintain between 140 to 180mg%.
● Monitor serum electrolytes and correct
● Nutrition— Early NG feed with gradual increase in protein
• AASLD No38: H2 blocking agents or proton pump inhibitors (or sucralfate as a
second-line agent) for acid-related gastrointestinal bleeding associated with
stress (I).
●
33

34. n-Acetyle Cystine
AASLD 2011 Recommendation 12 :
NAC may be beneficial for ALF due to drug-induced liver injury (I)
NAC is infused in a 3 stage iv infusion
Total dose of 300 mg/kg of over 20 hours
First Infusion 150mg/kg in 200mL of 5% D over 15 to 60 mins
Caution : anaphylactoid reactions.
Second Infusion 50mg/kg in 500mL of 5% D over the next 4 Hrs
Third Infusion 100mg/kg in 1 Lof 5% gluc over next 16 Hrs
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35. NAC Administration
NAC -140 mg/kg orally followed by 70mg/kg every 4 hrs for 72 hrs
Mix 30gm of NAC in 1Lt of 5%Dextrose
Patient treated
<8hrs after acute
ingestion
Patient treated >8hrs
after acute ingestion
Loading dose 150mg/kg in 1hr Loading dose 150mg/kg in 1hr
Run infusion at 15mg/kg/hr
for 4 hrs
Run infusion at 15mg/kg/hr for
44 hrs
Cont. infusion at 7.5mg/kg/hr for 16hrs
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36. Anti-Viral Treatment Improves the Prognosis of
Fulminant Hepatitis B
AASLD Recommendations
No 14. Nucleos(t)ide analogues
should be considered for Hep B-associated
ALF and for prevention
of post-LT recurrence.(III)
Cumulative Survival for Patients
treated with Lamivudine and
without
Int Med 47: 2008
No 15. Patients with known or
suspected Herpes Virus or varicella
zoster as cause of ALF should be
treated with acyclovir and may be
considered for Transplantation (III).
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37. Anti-Tuberculous Therapy – ALF & Transplantation
Standard ATT isoniazid , rifampicin, ethambutol, and pyrazinamide
INH and PZA Hepatotoxic and may lead to ALF
Dilemmas? ATT when to stop?
When to restart
What to do in case OLT and immunosuppression ?
After LT Standard ATT can no longer be used
Avoid RIF Hepatotoxic
interferes with immunosuppressant
leads to acute rejection
Avoid PZA due to it’s hepatotoxicity
After improvement of hepatic function, second-line ATT can be used
alternative nonhepatotoxic ATT drugs: Ofloxacin , ciprofloxacin ,
Moxifloxacin , and amikacin
Possible anti-TB regimen INH + ETH + FQ (MOX) ±
Amikacin
37
Ichai Et Al .Liver Transplantation, 2010

38. Infections
Bacterial (90%): Gram Neg. organisms & Staphylococci
Fungal (30%)
Prophylactic antibiotics? Decrease rate of infections
But no improvement in outcomes (III)
Empirical ATBs are recommended by ALFSG & AASLD when:
o Surveillance cultures reveal significant isolates
o Advanced stage (III/IV) encephalopathy (III)
o Refractory hypotension
o SIRS
Prophylactic fluconazole - with multiple-site colonization with yeast
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39. Other Issues
AASLD Recommendations
Steroids
No19. Patients with coagulopathy and mild HE due to
autoimmune hepatitis may be considered for corticosteroid
treatment (prednisone 40-60 mg/day) (III)
No 20. Patients with autoimmune hepatitis should be
considered for LTx even while corticosteroids are being
administered (III)
39

40. Conclusions
Transplantation is a definitive treatment for ALF
Good quality critical care and aggressive transplant
programmes have improved survival of ALF
Early etiological diagnosis and aggressive management
Optimal referral to Transplant unit to
Improve Survival, and
Economize on organ pool
LAD devices are not of proven benefit
Conservative Blood product usage
Further prognostication tools are needed
Watch the space for guidance from AASLD and ALFG
40

41. Suggested Reading
1. Acute liver failure. Bernal W, Auzinger G, Dhawan A, Wendon J.. Lancet 2010;
376:190–201.
2. Acute liver failure. Fin Stolze Larsen and Peter Nissen Bjerring.
Current Opinion in Critical Care 2011, 17:160–164
3. AASLD Position Paper : Introduction to the Revised American Association for
the Study of Liver Diseases Position Paper on Acute Liver Failure 2011
William M. Lee, R. Todd Stravitz, and Anne M. Larson
4. Modern Management of Acute Liver Failure.
John O’Grady. Clin Liver Dis 11: 2007
5. Intensive care of patients with acute liver failure: recommendations of the U.S.
Acute Liver Failure Study Group.
Stravitz RT, Kramer AH, Davern T, Shaikh AO, Caldwell SH et al.
Critical Care Medicine 2007; 35: 2498-508
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