ACUTE LIVER FAILURE

Dr Neerav GoyalSenior Consultant and HeadApollo Liver Transplant, Hepatobiliary and Pancreatic Surgery UnitIndraprastha Apollo Hospital, New Delhi

• Introduction• Criteria• Pre transplant issues • Critical care management• When to offer &When to say No • Transplant outcome• Overall survival• Evidence

ACUTE LIVER FAILURE• ALF is a life-threatening, rare medical

emergency that arises from massive acute hepatic necrosis

• Defined: 1. Presence of hepatocellular dysfunction

(coagulopathy, jaundice)2. Encephalopathy 3. No prior history of liver disease

Definitions of ALF

Which Definition to be followed?

Definitions of ALF

Onset Defining event

Illness duration

Trey and Davidson, 1970

First symptoms Encephalopathy 8 weeks

Bernuau et al, 1986

Jaundice Encephalopathy 2 weeks-Fulminant2-12 weeks- Subfulminant

O’Grady et al,1993

Jaundice Encephalopathy 1 week- Hyperacute1-4 weeks-Acute5-12 weeks-Subacute

• Interval between onset of acute hepatic injury (jaundice) and onset of liver failure (encephalopathy with or without coagulopathy (Icterus-encephalopathy interval; IEI)

• Between 4 weeks (Indian definition)2–4 to 24 weeks (AASLD–ALF study group)

What is the significance of the jaundice to encephalopathy interval?

What is the significance of the grade of hepatic encephalopathy?

Hepatic encephalopathy and spontaneous recovery

Trey C, CMAJ 1972

Survival Grade 2 HE Grade 3 HE Grade 4 HE

65-70% 40-50% <20%

What are common etiological factors for ALF?

What are the main prognostic determinants in ALF?

Prognostic Criteria• Four key determinants: 1. Aetiology2. Rate Of Progression Of The Disease3. Age Of The Patient4. Laboratory Markers Of Disease Severity

Kings College Hospital Criteria

• Overall specificity of 82% for non-paracetamol aetiologies and 92–95% for paracetamol-related ALF

• Nonparacetamol aetiologies, involving 1105 patients in 18 studies

• Specificity increased to 93% in patients with more advanced encephalopathy

• 88% when the criteria were applied dynamically• Second meta-analysis of paracetamol-induced

ALF involved 8 studied and reported a specificity of 92% , sensitivity of 69%

Reason for criteria

The probability of spontaneous recovery must be compared with the risks of surgery and immunosuppression

• King’s college hospital poor prognostic criteria• Clichy (Paris)criteria• Acute liver failure study group of Japan criteria• MELD score• ALF in-hospital mortality score (ALFIHMS)

King’s vs MELD

380 patients with ALF

ALF early dynamic (ALFED) model was constructed

Whether the levels of predictive variables remained persistently high or increased over 3 days above the discriminatory cut-off values

Demonstrated excellent discrimination with an area under the receiver operator characteristic curve of 0.91 & 0.92

• ALFED score of > 4 had a high positive predictive value (85%) and negative predictive value (87%)

• Accurately predicted outcome in patients with ALF, which may be useful in clinical decision-making

CASE 1

• Mr. X• 27/male• Jammu• Admitted with - History of jaundice for past 24 days- History of hepatic encephalopathy for past 3

days

• No h/o any fever/prodromal symptoms/upper GI bleed / abdominal distension

• Patient was started on ATT following surgery for intestinal perforation (3 m back - Intensive Phase)

• H/o jaundice after 5 weeks• Stopped ATT however Jaundice continued to

increase• Developed Encephalopathy ~ 4 weeks following

jaundice

Examination• PR- 130/min • BP-100/70 mm Hg • Temp: febrile (101 F) Icterus present • RS- NAD CVS-S1,S2 normal • CNS- Pupil dilated reacting to light• P/A: Soft, Non Distended, Non Tender,

Scar mark of previous surgery present, no e/o free fluid

• ATT induced ALF- Which drugs are most reponsible?

• How often do you see DILI as a cause of ALF and which drugs in clinical practice?

CASE 2

• Mr. D• 30/M• R/O Delhi• H/O Fever with prodromal symptoms for 10

days• Evaluated locally and found to be

jaundiced• Developed Encephalopathy 2 weeks after

initial symptoms

• No history s/o CLD

• No comorbidity

• No h/o any substance abuse

• No h/o any previous surgery

Examination• Comatose (Gr IV Encephalopathy)• Icterus +++• Pupil: B/L reacting• P: 107/min BP: 106/80 mm Hg RR:

20/min• RS/CVS:NAD• CNS: No e/o any focal neurological deficit• P/A: non distended/No organomegaly/No

e/o free fluid/ Liver Span ~10 cm

• Gr IV Encephalopathy with INR 9.1 (Absolute Criteria)

• CT Brain: Normal• On etiological work up : Anti HEV I g M

(Positive)• Diagnosis : Fulminant Hepatic Failure (HEV

Related)

Case 3• Master J• 7 Yr./M• R/o Nagpur• H/o vomiting and fever for 1 month• History of dark urine• Evaluated in a multispecialty hospital in

Nagpur and found to have deranged LFT along with coagulopathy (Referred)

• Drowsy, Icterus +• Blood pressure – 160/80, Pulse – 72, RR –

24/min• RS/CVS:NAD• CNS: No e/o any focal neurological deficit• P/A: non distended/No organomegaly/No e/o

free fluid

• Patient was admitted and evaluated• Hepatic encephalopathy(Gr 3) and INR was 7.5• S. Ceruloplasmin : 16.67• 24 urinary copper : High• KF rings +• CT liver Angio : essentially normal liver, patent PV

and minimal ascites• Diagnosed as acute Wilson’s disease • Family was counseled, prognosis explained &

advised regarding need of emergency liver transplant

• His encephalopathy worsened over night

• Wilsons disease: Acute Liver Failure

What are the goals of Management?

Goals in ALF Managment

Intensive medical management1.

Identify patients not achieving sufficient liver regeneration

Emergency liver transplantation

2.

• Major complications usually associated with death

1. Cerebral edema2. Seizures3. Infections4. Bleeding due to coagulopathy 5. Renal failure6. Electrolyte and acid base imbalance7. Hypoglycaemia

Cerebral edema

• Cerebral edema Most common cause of mortality• ALF 58% have CE at admission• Mortality rate 82% with CE

44% without CE• Recent data suggest that cerebral edema is less

frequent- Acharya SK et al. Hepatology 2006

- O Grady et al.Lancet 2003

Intracranial pressure

• Normal ICP: • 7–15 mmHg (supine), −10 mmHg (vertical position).

• CPP= MAP-ICP• Goals:

★ICP < 20–25 mm Hg.★CPP at 60–70 mm Hg

Cerebral auto-regulation

ALF-loss of auto-regulation

Should we measure ICP?

Should we measure ICP?

• Survival of patients with grade III-IV HE not improved by ICP monitoring

• Vaquero J, Liver Transpl 2005• Keays RT, J Hepatol 1993

• Schmidt L, Crit Care Med 2006

• No information on long term neurological sequel

• Intracranial bleed in 10.3%

Should we measure ICP?

Vaquero J, Liver Transpl 2005

• Frequent bedside clinical evaluation diagnose <25% episodes of ICH detected by ICP monitoring.

• Keays RT. J Hepatol 1993

ICP monitoring- Is there a middle path?

• Ammonia levels• Jugular bulb oxygen saturation• Cerebral A-V difference of O2 saturation• Trans-cranial Doppler examination• Optic Nerve Sheath Diameter

Any specifics for nursing care?

Nursing care

• Head position- Neutral and 300 elevation

• Avoid stimulation• Treat fever aggressively

What measure would you take to decrease ICP?

Hyperosmolar therapy• Mannitol

• Hypertonic saline

• Surrogate goals in absence of ICP monitoring:

- Serum Osm 310-320 mOsm/Kg. - Serum sodium:145-150 mmol/L.

Mannitol

• Response 15 to 60 min after bolus• In 20% paradoxical rise in ICP• Best in mild to moderate ICH• Better survival with mannitol (47.1% vs. 5.9%)

Canalese J. Gut

1982

How to use mannitol in ALF?

• Use if preserved renal function.• Boluses iv. 0.25–0.5 g/kg when ICP >25

mmHg for >10 minutes.• Repeat if ICP remains > 25 mmHg and

serum osmolality < 310 mOsm/L.

Hypertonic saline• Target level: 145-155 mmol/L• Monitor sodium every 6 hours• Correction <12 mmol/L in 24 hours or 16

mmol/L in 48 hours• Small RCT- incidence and severity of ICH

reduced in patients with induced hypernatremia

Murphy N, Wendon J. Hepatology 2004

How to use hypertonic saline in ALF?

• 3% NS 250 cc bolus over 10-15 minutes (~4 cc/kg).

• Keep Na<160 and Osm<330 (?? upto 360).

• Problems- Hyperchloremic acidosis- Volume expansion.- Demyelination- Small brain hemorrhages- Aggravation of coagulopathy

Barbiturates

• Thiopentone loading dose 3-5mg/kg (maximum 500mg) over 15 minutes, followed by a continuous infusion at 0.5-2.0mg/h

• Must be used with continuous ICP and arterial

BP monitoring

• ICP normalized in 8/12 with unresponsive ICT

Forbes et al. Hepatology 1989

When not to use barbiturates in ALF?

• Problems:- Hypotension.- Anergy and poikilothermia- Hypokalemia

Hypothermia

• Normalization of cerebral blood flow• ↓ Brain ammonia delivery/uptake• ↓ Anaerobic glycolysis & oxidative stress in astrocytes

• ↓ Brain ECF glutamate• External cooling blankets suffice

32o -35o C

Hypothermia

- Cardiovascular instability- Shivering (paralysis needed)- Worsening coagulation- Reduced platelets- Increased infection risk- ? impairment of hepatic regeneration

Ammonia and ICT

Kaplan-Meier plot of ICH in 165 ALF patients according to arterial ammonia on admission.

Bernal W. Hepatology 2007Clemmesen JO. Hepatology 1999

Arterial ammonia in 30 patients who did not develop CH and 14 patients who died from CH

Role of Ammonia

Arterial ammonia levels >124 mmol/l 78.6% sensitive and 76.3% specific for predicting mortality

Bhatia V. Gut 2006

Anti-ammonia measures• Lactulose• L-Ornithine L-Aspartate• Sodium Benzoate

L-Ornithine L-Aspartate

Blinded RCT of LOLA vs. Placebo in ALF patients. 92 patients received LOLA, 93 received placebo

Acharya SK et al. Gastroenterology. 2009

Hyperventilation

• Prophylactic hyperventilation no reduction in ICH

• pCO2 reduction to 25-30mm Hg decrease ICP once cerebral edema begins to develop

• Ede et al. J Hepatol 1986

• JVO2 monitoring mandatory.Normal JVO2: 60%-80%.

What should be goals of cardiovascular management?

Management of circulation- Goals

• Ensure adequate vascular filling (CVP: 8-12 cm water)

• Avoid over hydration and hypotonic fluids – increase in ICP

• Vasopressor agents (NorAdr) if MAP < 60 mmHg despite adequate fluids

• Hypotension in spite of above - a sign of bacterial or fungal sepsis

Goal: MAP > 60mmHg

Choice of vasopressor

• Norepinephrine > Dopamine

• ? Terlipressin

• Avoid epinephrine

Steiner LA. Crit Care Med. 2004

What role does NAC play?

Gastroenterology. 2009 September ; 137(3): 856–864

NAC dosing in non-acetaminophen ALF

• Initial loading dose of 150 mg/kg/hr over one hour

• Followed by 12.5 mg/kg/hour for 4 hours

• Then continuous infusions of 6.25 mg/kg for the remaining 67 hours (Total 72 hours)

Prophylactic drugs usage?

Prophylactic anti-seizure drugs

• Subclinical seizure activity- exacerbation of cerebral edema

• All patients with deep HE should be treated with prophylactic phenytoin

Ellis et al, Hepatology 2000

• RCT 42 ALF patients – no benefit Bhatia V, et

al. J Hepatol 2004

Glucose homeostasis

100-200mg/dL<100mg/dL >200mg/dL

√X X

Hypoglycemia Infection risk

Increased cerebral lactate

Correction of bleeding diathesis

• Clinically significant bleeding uncommon (<10%)

• Prophylactic FFP not recommended

• Maybe...• Profound coagulopathy (INR >7 with abnormal TEG) , FFP and cryoprecipitate transfusion to maintain INR between 5-7

Infections in ALF-Consequences

1.Neurological deterioration

2.Aggravation of liver damage

3.Increased mortality

Infection and neurological deterioration

DeterioratedImproved

100%

84.8%

15.2%

Infection during grade I-II HE predicts worsening HE

Infection and mortality

n=268

p <0.001RR for mortality: 2.11 (1.54-2.90)Infection is an independent predictor of mortality

Sites of infections in ALF

Recommendations for managing renal failure?

Renal failure• 40%–80% of patients • Associated with a poor prognosis• More frequently in acetaminophen induced

ALF (70%) and less frequently in ALF due to other causes (30%)

• Renal failure is reported in 10% of patients from India

- - Acharya SK et al. Hepatology 2006

- O Grady et al.Lancet 2003

Role of CRRT and Bio-arteficial Liver Assist Devices ?

Renal replacement therapy

• CRRT >IRRT (especially if cerebral edema)• Heparin avoided• Bicarbonate buffer preferred over citrate

and lactate• Biocompatible dialysis membranes like

polysulphone or polyacrylnitrate• Route Femoral• Avoid hyponatremia and other electrolyte

changes

Artificial liver supportExcretory function

Synthetic and Biotransformatory

process

Dialysis √ (Ammonia) ×

Exchange transfusionPlasmapheresis

√ (Protein bound molecules) ×

Bioartificial extracorporeal devices √ √

Charcoal hemoperfusion

√ (Mercaptans, GABA, AAA,

and FA)×

Albumin dialysis √ ×

Case 1: ATT induced ALF

King´s college Criteria

Age 28 N

Jaundice 27 mg/dl Y

INR 4.4 Y

Non A/Non B ATT Induced Y

Jaundice to encephalopathy

20 days Y

HOSPITAL COURSE• Admitted in ICU as a referred case of acute

liver failure• At time of admission was fulfilling king`s

college criteria (4/5)• Features of severe sepsis

(fever/tachycardia/hypotension)• At time of admission was in grade 4

encephalopathy

• Electively intubated and kept on ventilatory support

• For hypotension required inotropic support• Management started as per ALF protocol• Relatives appraised regarding patient

condition and need for optimization followed by liver transplant

• No potential donor in family

• Patient condition continued to be critical• Persistent Hyper- bilirubinemia (Up to

57mg/dl) associated with coagulopathy(Up to 5.1)

• In view of no potential donor with detoriating liver and renal profile Plasmapheresis and CRRT started

• Required 3 sessions of plasmapheresis

• Patient condition stabilized with improvement in liver and renal profile

• Inotropes were stopped• Extubated on day 9 when regained

sensorium• Shifted to ward after 2 weeks• Discharged after 25 days of admission with

serum bilirubin of 7 mg/dl• Doing well in follow up with completely

recovered liver profile

When not to transplant?

Contraindication for LT in ALF• Pt’s outside different prognostic criteria

• Active and resistant alcohol dependence/ substance abuse

• Documented previous history of noncompliance with medical or psychiatric therapy

• Medically unfit to survive LT• Brainstem Herniation• Active Sepsis

• Under Went LRLT(Right lobe without MHV) with anterior sector reconstruction, Single duct (Duct to duct)

• Underwent uneventful surgery and was shifted to ICU

• POD 2 developed Intra abdominal bleed• Laparotomy done, Bleed from drain site• Extubated on POD 5

Case 2: Hep E

• Immunosuppression started from POD 5• Shifted to ward on POD 9• Discharged on POD 19• Doing well on follow up

Case-3: Fulminant Wilson’s• Under Went LRLT(Right lobe without MHV)

with anterior sector reconstruction, Single duct (Duct to duct)

• Uneventful surgery• Extubated POD1• In view of persistent drowsiness and fall in

saturation, he was re-intubated • Extubated on POD 4

• Immunosuppression started from POD 2• Shifted to ward on POD 10• Uneventful Recovery• Discharged on POD 18• Doing well on regular follow up

Outcome

• Results of liver transplantation for ALF are acceptable in the context of the severity of the illness and limited therapeutic alternative

• Survival rates at 1 year are 7% to 15% below those obtained for elective transplants in patients with chronic liver disease

• Compare favourably when compared with the 64.4% survival rate seen in patients in intensive care immediately prior to transplantation

• Relative risk of death was 1.6 3 months after liver transplantation - Mcphil M et al. Int Care Med 2009

• Beyond the first year, the survival curve flattens out, so that in Europe at 10 years, the gap in survival between these 2 groups has fallen from 15% to 5%

• 1-year survival for deceased donor liver transplantation was 78.6%, and for living donor liver transplantation, it was 87%

- Merlon m et al.AJT 2008

LDLT in ALF• Safe and effective alternative • Survival comparable to DDLT• Less infectious complication in recipient• Less waiting time• Good graft quality from healthy donor

P=0.21 NS

P=0.001

LDLT vs DDLT

Outcome of 14 patients with acute liver failure evaluated for LDLT. Abbreviations: DDLT, deceased donor liver transplantation; LD, living donor; LDLT, living donor liver transplantation; txp, transplant

• Results of living donor liver transplantation for ALF in a Japanese experience of 42 patients were very comparable to overall outcomes

• 80% 1-year survival and 68% 10- year survival• Study indicated that the results were

influenced by the ratio of the graft to standard liver volume

• 1-year survival rate of 87.1% in those with a ratio 50% versus 80.7% in those with volumes in the 40% to 50% range

- Kayishama H JACS 2008- Lee SG et al . Journ Hepat 2007