Acute Liver Failure Update

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Acute Liver FailureA Management Update

From Comatose Confusion to Clarity

Palepu B Gopal

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Survival Rates by Era for ALF at King’s College Hospitalwith grade 3 or 4 encephalopathy, regardless of management

Potentially and Increasingly Reversible Condition

TRANSPLA

NTATIO

N

CRITICAL CARE+

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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% survivalCurrently overall short-term survival (one year) including those undergoing transplantation is greater than 65%

Acute Liver Failure AASLD Definition and Prognosis

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Bernal W et al Lancet 2010Mindikoglu AL et al Liver Transpl 2009Khuroo MS et al. J Viral Hepat 2003Acharya SK et al. J Gastroent Hepatol 2002

Etiology of Acute Liver Failure

Non-Paracetamol drug Induced ALF requiring

Emergency LTx USA 1987–2006

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ALF– A Multi-Organ Failure SyndromeAcute Liver

Failure

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O’Grady et al, 1993; Ellis et al, 1995

Types Jaundice-encephalopathy

Cerebral edema

Prognosis Leading causes

Hyperacute <7days Common Moderate Virus A,B,Eacetaminophen

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,Cdrugs

Classification of Acute Liver Failure

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Predicting Outcomes in Acute Lifer Failure

• Important predictive factorStage of encephalopathy

• Suggested laboratory markers: Factor VAFPSerum Phosphate VII/V ratio > 30Gc globulin

• Four factors Etiology of ALF INR, bilirubin Encephalopathy and brain edema Multiorgan failure

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John O’Grady. Clin Liver Dis 11 (2007) 291–303

Acharya SK et al . Hepatology 23: 1996

Variables Used for Prognostic Models of ALF

King’s IndianMELDClichy

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Model for End-stage Liver Disease (MELD) Score

Presence of > 3 factors – 90% Mortality

Clichy- Villejuif Criteria from France

Criteria from India Acharya SK et al . Hepatology 23: 1996

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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

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sensitivity specificity

King’s College Criteria 92% 69%

APACHE II 92% 81%

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

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45. Currently available prognostic scoring systemsdo not adequately predict outcome and determinecandidacy for liver transplantation. Reliance entirelyupon these guidelines is thus not recommended.(III)

2. Contact with a transplant center and plans totransfer appropriate patients with ALF should beinitiated early in the evaluation process (III).46. Urgent hepatic transplantation is indicated inacute liver failure where prognostic indicators suggesta high likelihood of death (II-3)

47. Living donor or auxiliary liver transplantationmay be considered in the setting of limited organ supply,but its use remains controversial (II-3)

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• 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

Liver Transplant for ALF

John O’Grady. Clin Liver Dis 11:2007Toru Ikegami et al. J Am Coll Surg 2008

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Douglas G. Farmer et alANNALS OF SURGERYVol. 237 : 2003

Liver Transplant for FHF – 17 Yrs and 200 Patients

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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

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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

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Liver Support / Assist DevicesBio-Arteficial HybridArteficial

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Use of MARS in Liver Failure

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may worsen coagulopathy and bleeding

may cause hypoglycemia

alter PK of antibiotics and antifungals

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.

Improves Bilirubin levels

Improves Encephalopathy & CBF

Variable effects on ICP

Decreased serum Cu+ in Wilson’s

Improves pruritus

Improves renal function

Improves hemodynamics

Molecular Adsorbent Recycling SystemMARS

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Bioartificial liver support- Hepatocytes ± Filters ± Oxygenator

Detoxification, biosynthesis and regulation

Artificial - Filters ± Adsorbers

Only detoxification

CVVHD

Hemadsorption

Plasmapheresis

Meta-analysis of 4 RCTs - No survival benefit with MARSAASLD 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 14:208–215

‘Is there life in MARS?’

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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,

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)

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EncephalopathyIn 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 goalLactulose (PR or NG) to keep serum ammonia <50 mcg/dL If serum ammonia is >50 mcg/dL despite adequate stool output with lactulose,

RifaximinCVVHD with serum ammonia goal >200 mcg/dL

Neomycin not recommended by ALFSG because of nephrotoxicityCT Head Stage 3-4 HE or focal deficits

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Seizure Prophylaxis and Surveillance• Nonconvulsive seizure activity is common

o Prophylactic antiepileptics not recommendedo EEG when:

Grade II/IV encephalopathy Sudden neuro deterioration Myoclonus To titrate use of barbiturates

• Treatmento Phenytoino Propofol o barbiturateso Fosphenytoin o low-dose benzodiazepine

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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 managemento Induced hypothermia (32-33ºC)o Indomethacin: 25mg IV over 1min.

• Hyperventilation • Corticosteroids – No Role (1)

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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

Role of Hypertonic Saline in Management of HE

27Vaquero J et al. ALF Study Group: Liver Transpl 2005

Intracranial Pressure Monitored VsNon- Monitored GroupHigher medication Utilization in Monitored Group

Brain Edema in Liver Failure Andres T Blei. Critical Care Clinics 2008

ICP MonitoringICP bolts May be useful to optimize CPP

Extra-dural system preferredLowest complication with Epidural

Risk : benefit ICP/CPP measurement vs. Sepsis and bleeding

Have not been shown to improve survivalALF 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 thosewith poor prognosis and signs of systemic inflammation, by experienced

Wendon JA et al. Hepatology 2006 28

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Algorithm For ICP Monitoring

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Coagulopathy of ALF & Correction

Pts. with ALF are by definition coagulopathicSpontaneous bleeding is rareVery 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 transfusionIf clinically significant bleeding or < 10 - 20,000/mm3ALFSG 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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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

Hemodynamic Failure

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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).

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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 withstress (I).

●

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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

n-Acetyle Cystine

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NAC Administration

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

NAC -140 mg/kg orally followed by 70mg/kg every 4 hrs for 72 hrs

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Anti-Viral Treatment Improves the Prognosis of Fulminant Hepatitis B

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

withoutInt 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).

AASLD Recommendations

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Standard ATT isoniazid , rifampicin, ethambutol, and pyrazinamideINH and PZA Hepatotoxic and may lead to ALFDilemmas? ATT when to stop?

When to restart What to do in case OLT and immunosuppression ?

After LT Standard ATT can no longer be usedAvoid RIF Hepatotoxic

interferes with immunosuppressantleads to acute rejection

Avoid PZA due to it’s hepatotoxicity

After improvement of hepatic function, second-line ATT can be usedalternative nonhepatotoxic ATT drugs: Ofloxacin , ciprofloxacin ,

Moxifloxacin , and amikacin Possible anti-TB regimen INH + ETH + FQ (MOX) ± Amikacin

Ichai Et Al .Liver Transplantation, 2010

Anti-Tuberculous Therapy – ALF & Transplantation

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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 isolateso Advanced stage (III/IV) encephalopathy (III)o Refractory hypotensiono SIRS

Prophylactic fluconazole - with multiple-site colonization with yeast

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Other Issues

SteroidsNo19. 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 beconsidered for LTx even while corticosteroids are being administered (III)

AASLD Recommendations

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ConclusionsTransplantation is a definitive treatment for ALFGood quality critical care and aggressive transplant

programmes have improved survival of ALF Early etiological diagnosis and aggressive managementOptimal referral to Transplant unit to

Improve Survival, and Economize on organ pool

LAD devices are not of proven benefitConservative Blood product usageFurther prognostication tools are neededWatch the space for guidance from AASLD and ALFG

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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