Acute Liver Failure Basic Pathophysiology and Management

Critical Care of Acute Liver Failure

1. Dr. Eduardo Martinez

3. Foie gras(pronounced/fwɑːˈɡrɑː/in
English;Frenchfor "fat liver") is afood
productmade of theliverof
aduckorgoosethat has been specially
fattened.

4. Metabolic
◦Carb metabolism
◦Protein and lipoprotein metabolism
◦Fatty acid metabolism
◦Biotransformation of drugs
Storage
◦Glycogen
◦Vitamins A, D, E, and K
◦Iron and copper

5. Immunological function s
◦Synthesis of immunoglobulins
◦Phagocytosis by Kupffer cells
◦Filtration of bacteria
◦Degradation of endotoxins
Excretion of bilirubin and urea formation
Haematological functions
◦Blood reservoir
◦Haematopoiesis in the foetus

6. •Syndrome that leads to MOF and death
oPreviously normal liver may fail within days
•High grade encephalopathy, survival is
<20%
•Early death:
ocerebral oedema, CVS collapse
•Late death:
oSepsis , MOF

7. •ALF: Sd. defined by
oEncephalopathy
oCoagulopathy
oJaundice
oIndividual with previously normal liver

8. •Fulminant Hepatic Failure
oPotentially reversible condition
oConsequence of severe liver injury
oEncephalopathy appears within 8 wks. of
initial Sx.
oAbsence of pre-existing liver ds.

9. •King’s classification:
oHyperacute: encephalopathy within <7 days
Paracetamol, ischaemic, viral, toxins
oAcute: 8-28 days
oSubacute: 5-26 weeks
Seronegative, idiopathic, drug-related
Different etiology
Poorer prognosis

10. Cause Agent Responsible
Viral Hepatitis Hep. A, B, D, E, CMV, HSV, seronegative hepatitis
(14-25% in UK)
Drug-related Dose-related, e.g.paracetamol; idiosyncratic
reactions, e.g. anti-TB, statins, recreational drugs,
anticonvulsants, NSAIDs, many others
Toxins Carbon tetrachloride, amanita phalloides
Vascular events Iscahemic hepatitis, veno-occlusive disease,
Budd-Chiari, heatstroke
Other Pregnancy-related liver disease, Wilson’s disease,
lymphoma, carcinoma, trauma

11. •Most common causes:
oWorldwide:
Hepatotrophic viruses A-E
oUK
Paracetamol overdose
Seronegative or non-A-E hepatitis
Idiosynchratic drug rxs. or Wilson’s ds.

12. •Identify the etiology
oHx., examination, viral and autoimmune
profiles
•Bloods
oFBC, EUC, CMP, coags, LFTs, drug levels
•Abdo USG and CT
oVascular pattern, ascitis, splenomegaly

13. •Liver Bx.
oDone by transjugular route
oMays suggest specific Dx.
oWatch for sample from healthy liver
o>50% necrosis assoc. with poor prognosis
oNeed to reverse coagulopathy before doing
it

14. •Hepatic encephalopathy
oalteration in mental status and cognitive function
occurring in the presence of liver failure
•Liver failure leads to:
oportal HTN
osplachnic vasodilation
oHypoalbuminaemia
oReduced plasma oncotic pressure
oLeads to ascitis and organ oedema

15. •Decreased intravascular volume
oKidneys try to “compensate” and retain Na+
and water making oedema worse
•Also,
•Gut-derived toxins reach the liver
oAmmonia levels are often high
oCorrelation between ammonia and
symptoms is poor

16. •Depend on the severity, which depends
on:
oEtiology
oSpeed of onset of symptoms
•Non-specific
oN&V, abdo pain
•Neurological
oConfusion, agitation, coma

17. Grade Level of Consciousness Personality and Intellect Neurologic Signs Electroencephalogram
(EEG)Abnormalities
0 Normal Normal None None
Subclini
cal
Normal Normal Abnormalities only on psychometric testingNone
1 Day/night sleep reversal,
restlessness
Forgetfulness, mild confusion, agitation,
irritability
Tremor, apraxia, incoordination, impaired
handwriting
Triphasic waves (5 Hz)
2 Lethargy, slowed responsesDisorientation to time, loss of inhibition,
inappropriate behavior
Asterixis, dysarthria, ataxia, hypoactive
reflexes
Triphasic waves (5 Hz)
3 Somnolence, confusion Disorientation to place, aggressive behaviorAsterixis, muscular rigidity, Babinski signs,
hyperactive reflexes
Triphasic waves (5 Hz)
4 Coma None Decerebration Delta/slow wave activity

18. •Mortality is higher for Grade III/IV
oMostly due to cerebral oedema
oOccurs in 80% of pts. w/ALF
Due to lack of equilibration of osmotic gradient
30% of those have cerebellar tonsil and/or
temporal lobe herniation causing death
oWe’re now better at treating cerebral
oedema

19. •Elevated ICP
oHTN, bradycardia, blown pupils: occur late
oCTB won’t tell you
oICP monitor is best way of knowing
•CVS changes
oSimilar to sepsis
oMight be due to infection

20. •Renal failure
oOliguric
oPoor prognosis
Except with paracetamol overdose where it has
a good prognosis
•Impaired immunity
oDecreased complement synthesis, Kupffer
cell dysfunction, poor neutrophil adhesion
and superoxide production

21. •Increased susceptibility to infection
o80% of pts. have bacteriologically proven
infections
oMajor sepsis is contributor to death in 20%
of cases
Staph. aureus 70% of gram (+)
E. Coli most common gram (-)
C. albicans in 30% of pts.

22. •Pts. need HDU/ICU
•Need CVC and continuous IBP
monitoring and IDC
•Baseline ABG and lactate
oLactate >3mmo/L after adequate resus has
same sensi. and speci. for death as The
King’s College Hospital criteria

23. •Early indicators of prognosis in fulminant
hepatic failure.
O'Grady JG,Alexander GJ,Hayllar KM,Williams R.
Gastroenterology.1989 Aug;97(2):439-45.
•King’s Collage Hospital Criteria
oOriginally devised as prognostic criteria to predict
patient survival without liver transplant
oNow used as selection criteria for potential liver
transplant recipients

25. •Patients with paracetamol
toxicity
opH <7.3 (7.25 if given NAC)
Or
all three of the following:
oProthrombin time>100s
oSerum creatininelevel >300
μmol/l
oGrade III or
IVencephalopathy
•Other patients
oProthrombin time >100
seconds or
Three of the following
variables:
oAge <10 yr or >40 yr
oJaundice >7 days before
encephalopathy
oPT > 50s
oBilirubin > 300mmol/L

26. Positive predictive value for ICU death without
transplantation of 0.98
Negative predictive value of 0.82

27. •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 Medicine2007;35:2498-508

28. •Adult U.S. Acute Liver Failure Study
Group
oData from
23 liver transplant centers
>1,110 pts.
oIn 2005 convened to
review literature on management
Care of pts. w/high ICPs
Compare practices of different centers

29. •Admit to hospital and HDU/ICU
oWhen evidence of ALF
E.g.: INR>1.5
oD/W:
Physician
Intensivist
Nearest transplant center
Regarding best time to refer

30. •Etiology-specific treatment
oStudies only for paracetamol overdose
oNAC regardless of time of overdose
IV if Grade I encephalopathy
Hypotension
Any other reason PO NAC is not tolerated
oHELLP or acute fatty liver of pregnancy
Tx. Is immediate delivery

31. •NAC
o150mg/kg IV in 200ml NS over 15-60mins
o50mg/kg IV over 4hrs
o100mg/kg IV over 16hrs
Total dose: 300mg/kg over 20hrs
oInfusion recommended until there is
evidence of improved hepatic function
rather than time or paracetamol levels

32. •Hepatic encephalopathy and
hyperammonaemia
•Infections
•Sedation and analgesia
•Bleeding diathesis
•Nutrition
•Seizures
•Circulatory dysfunction

33. •Standard treatment:
oLactulose
Watch for:
Abdo distension
Oesophageal variceswill need a scope
Avoid intravascular depletion
oNon-absorbable ATBs
Neomycin not recommended by ALFSG
because of nephrotoxicity

34. •Infection is one of main causes of death in
ALF
•Most common sites:
oLung
oUrinary tract
oBlood
•Most common M.O.
oGram (+) cocci: Staph aureus
oGram (-) rods: E. coli
oFungi: candida

35. •Empirical ATBs are recommended by ALFSG
when:
oSurveillance cultures reveal significant isolates
oAdvanced stage (III/IV) encephalopathy
oRefractory hypotension
oSIRS
•3rd gen. Cephalosporin or Timentin,
Vancomycin, Fluconazole

36. •Agitation contributes to raised ICP
•Propofol vs. Benzos
oBoth increase GABA neurotransmission, therefore
may exacerbate encephalopathy
oPropofol decreases ICP and wears off quickly
•Opioids
oShorter acting are preferable
oWhen there is concommitant ARF, avoid morphine
or pethidine due to metabolite accumulation

37. •Pts. with ALF are by definition coagulopathic
oLow plts. and fibrinogen, Vit. K deficient
oSpontaneous bleeding is rare
•Very difficult to obtain complete correction
•ALFSG recommends aiming for:
oINR 1.5
oPlts. 50,000

38. •Prophylactic FFP not recommended
oObscures the trend of PT as prognostic marker
•Cryo recommended when fibrinogen low
•When FFP fails to correct PT/INR, then
recombinant factor VIIa can be given
oShould be given before planned procedures
oAvoid in patients with risk of thrombotic
complication
MI, DVTs, etc.

39. •UGI bleeding
oreduced by H2 antagonists or PPIs
•TEDS and Scuds

40. •ALF is a catabolic state
oNegative nitrogen balance
oImmunodeficiency
•Enteral nutrition when possible
oHi-cal
oAvoid free water and hypo-osmolarity
•TPN when:
oSpecific contraindication for enteral feeds

41. •Nonconvulsive seizure activity is common
oProphylactic antiepileptics not recommended
oEEG when:
Grade II/IV encephalopathy
Sudden neuro deterioration
Myoclonus
To titrate use of barbiturates
•Tx.
oPhenytoin
oPropofol, midaz, barbiturates

42. •Correct hypovolaemia before starting
vasopressors
•Pressors needed for hypotension and low
CPP
oNorad is first line, can give high dose dopamine
oAdrenaline may compromise HBF
oVasopressin not recommended because directly
causes cerebral vasodilation and high ICPs
•Medium doses of steroid may improve
pressor response

43. •Raised ICP due to cerebral oedema is
one of major causes of M&M
•CTB for Grade III/IV
oTo rule out anything else, i.e. bleed
•ICP monitor
oGrade III/IV encephalopathy
oTo optimize CPP
oNot routine

44. •Aim for
oICP<25mmHg
oCPP 50-80
•General recommendations
oKeep it quiet , minimize chest physio and
ETT suctioning, head at 30o
oDon’t treat spontaneous hyperventilation,
keep PaCO2 35-40mmHg, treat fever
aggressively with physical measures

45. •Specific management
oManitol: first line therapy
oHypertonic Saline
oInduced hypothermia
oBarbiturate coma
oIndomethacin: 25mg IV over 1min.

46. •When to intubate:
oRespiratory failure
oAirway protection in advanced
encephalopathy
oAgitation
oImminent ICP monitor placement

47. •Pts. w/ALF often develop ALI/ARDS
oFollow ARDSNet protocol
oAvoid high PEEP
Use the minimum needed

48. •Indicated for:
oRenal failure
oFluid overload
oMetabolic derangements
oNeed to create space for IV colloids, i.e.
FFP
•CRRT preferred over IRRT
oHD instability common

49. •Use citrate over heparin
oMonitor ionized calcium
•Use bicarb buffer over lactate or citrate
buffer
oLiver won’t be able to convert them to
HCO3-
•Avoid hyponatraemia
oMay exacerbate cerebral oedema

50. Orthotopic liver transplant is the definitive
treatment for patients who meet the criteria
◦or·tho·top·ic(ôrth-tpk)adj.In the normal or usual
position
1 yr. and 5 yr . survival of patients
undergoing OLT for ALF is about 20% lower
than elective cases for cirrhotic patients
Auxiliary liver transplantation is and
alternative

51. Absolute contraindications
◦Overwhelming sepsis
◦Refractory hypotension
◦AIDS
◦Uncontrolled raised ICP with likely permanent
damange

53. MARS: molecular absorption and recirculation
system
◦Adaptation of haemodialysis
◦Blood is dialysed against 20% albumin
Shown to improve encephalopathy, renal function and
haemodynamic parameters
◦The efficacy of this technique has not yet been
studied