Stephen Warrillow from the Austin Hospital in Melbourne Australia talks on Acute Liver Failure in the Victorian Intensive Care (VIN) Meeting 2013.

1. Critical Care Hepatology:
Acute Liver Failure
Stephen Warrillow FRACP FCICM Grad Cert Emerg Health (Aeromedicine & Retrieval)
Deputy Director
Department of Intensive Care
Austin Health, Melbourne, Australia
Senior Lecturer and Research Fellow, The University of Melbourne

2. What’s to be done?
• Intensivist on for the weekend in a rural hospital
• 22 year old woman admitted Friday afternoon
– Past mental health problems
– Recently back from trip to Bali
– Relationship issues over last few weeks
– Presented to ED with apparent intoxication and concerns
regarding risk of self-harm
• Morning bloods available- call from med reg;
– ‘Very abnormal results to discuss’

3. Path Results……
LFTs
– ALT 3565
– Bili 58
– ALP 89
– GGT 106
Clotting
– INR 7.8
– APTT 56
– Plat 89
U&Es
– Na 136
– K 4.8
– Bic 14
– Ur 7
– Cr 188
Lactate
– 6.2
BSL
– 3.3

4. See the Patient…..
Hx- Vague
• Tired
• RUQ discomfort
• N & V
Risk Factors
• IVDU, travel, medications,
ETOH, mushrooms, former
health, pregnancy, FHx
Ex
• Full clinical assessment, but
particular focus on
– Conscious state- GCS 13
– Evidence of CLD?
» No Ascites
» No spider naevi
» No prominent abdo veins
» No sarcopaenia
– No evidence of IVDU
– Circulation- tachycardia with
warm peripheries, BP 90/45
mmHg

5. Further Ix
• Paracetamol levels
• Pregnancy test
• Ammonia (send on ice)
• Viral serology
– Don’t forget HSV, CMV,
EBV (HIV?)
• Autoimmune screen
• Copper studies
• Full septic work up
– Pan-culture
• Liver US (with doppler)
• ABG
• Consider
– TTE
– Drug screen

6. Next Move?
• Contact a transplant
centre
• Start NAC infusion
• Give Vit K
• Prepare for likely need to
intubate
• Start 10% dextrose infusion
• Admit to ICU pending
arrival of retrieval team
• Arterial line and CVC
• Consider broad spectrum iv
ABx

7. ICU APPROACH TO FHF

8. Acute Liver Failure
• Rare, but life threatening
– often in previously fit young adults
• No pre-existing liver disease
– first symptom to encephalopathy < 8 weeks
• Presence of Hepatic Encephalopathy
+/- Haemodynamic instability
+/- Renal failure
+/- Coagulopathy
+/- Severe metabolic disturbances
+/- Susceptibility to infection

9. Fulminant Liver Failure
• Hyper-acute:
Jaundice - Encephalopathy < 8 days
• Acute:
Jaundice - Encephalopathy 8-28 days
• Sub-acute:
Jaundice - Encephalopathy > 28 days
O’Grady JG, Schalm S, Williams R: Acute Liver Failure: Redefining the syndromes. Lancet 342:373-375

10. Aetiology
• ALF - Developed world
– Paracetamol (50-70%) (‘staggered’ ingestion is more dangerous)
– Cryptogenic (Non A-E Hepatitis)
– Idiosyncratic drug reactions (10-15%)
» Traditional medicines a common cause in China
– Hepatitis B ( Most common in Asia / Sth Europe)
– Hepatitis A
– Wilson's, Budd-Chiari, Autoimmune and Pregnancy-related
conditions (e.g. fatty liver or HELLP syndrome)
– Reactivation of stable Hep B in setting of immunosuppression
• ALF - Developing world
– Viral hepatitis A, B, E

11. Hepatitis/Liver Failure in Setting of MOF
• Liver injury in severe sepsis, shock, cardiac arrest or
multiple organ failure is common
• Abnormalities of LFTs and clotting are frequent in the
critically ill ICU population
• Treatment is of the underlying condition rather than ‘liver
directed’ in most such cases
• Outcome is rarely dependant on what happens to the liver

12. Mortality
• Dependent upon classification, aetiology and availability of
liver transplantation
• Medical management only:
Mortality
Hyper-acute 64%
Acute/Subacute 86%

13. Mortality by Aetiology
• Hep A alone has mortality 2%
• Hep A superimposed on Chronic Hep C has mortality of
86%
• Wilson's and Autoimmune Hepatitis have near 100%
mortality in the absence of liver transplantation
• High mortality with idiosyncratic drug induced
• High mortality if no cause identified

14. Characteristics of FHF
• Patients with hyper-acute liver failure inevitably have
rapidly progressive serious derangement of function in
multiple organ systems
• Frequent clinical evaluation and vigilant assessment of
various biochemical and haematological parameters forms
the cornerstone of clinical care

15. ALF or decompensated Chronic Liver Disease?
• History crucial
• Clinical examination
– Classic stigmata of advanced chronic liver disease are not
present
– No evidence of portal HT
• No cirrhosis appearance on imaging

16. Key Management Problems
• Cerebral oedema and elevated intra-cranial pressure
(ICP)
– Cerebral oedema occurs in the majority of patients with grade
three or four encephalopathy and is a major cause of death
– Oedema formation is secondary to marked hyperaemia
» Ammonia seems to be an important player
– Can progress suddenly and even occur in the period
immediately post transplantation
– Cerebral oedema is uncommon in patients with chronic liver
disease

17. Key Management Problems
• Sepsis (particularly G- and fungal).
– Infection is a major cause of death in patients with FHF
– High risk of overwhelming gram negative and fungal sepsis

18. Key Management Problems
• Coagulopathy/bleeding
– Coagulopathy is one of the defining features of hepatic
decompensation.
– Hepatic synthesis of clotting factors fails and most patients
also develop significant thrombocytopaenia.
– Bleeding may complicate the insertion of invasive devices, or
occur spontaneously. While spontaneous intracranial
haemorrhage is rare, the consequences can be devastating.

19. Key Management Problems
• Renal failure
– Whether as a result of the primary pathology that also affects
the liver (e.g. paracetamol overdose), shock or as a
consequence of systemic inflammatory response, renal
failure is a common problem in patients with FHF
– Consequences of renal failure include:
» Electrolyte derangement
» Fluid balance problems
» Uraemia
» Acidosis

20. Key Management Problems
• Vasodilatory shock
– A vasodilated, hyperdynamic circulation is a characteristic
feature in most patients with FHF
– Many patients will be shocked and require vasopressor
therapy
– Occasional patients may also exhibit a low cardiac output
state (perhaps due to pre-existing cardiac pathology or
critical illness) and require inotropic support

21. Key Management Problems
• Fluid and electrolyte management.
– Tendency to accumulate a positive fluid balance,
predisposing to cerebral oedema
– Electrolyte abnormalities can contribute to cerebral oedema
and encephalopathy
– Careful control and therapeutic manipulation of serum
sodium in particular can attenuate some of these problems

22. ALF and Transplantation
• Outcome studies suggest 1 year survival of 50-75% in
OLTx for FHF
– Much higher in Australia
• Need for objective criteria to select out those most severely
affected and hence most likely not to survive with medical
therapy alone

23. Paracetamol and OLTx
• Liver transplantation is a potentially life saving
procedure for a small group patients with FHF
secondary to paracetamol OD
• However:
– Most patients survive with supportive care
– Difficult to decide who requires transplantation
»Not sick enough vs. Too sick for transplant
• King’s College criteria for consideration of
OLTx are most widely accepted

24. King’s College Criteria
• High risk of death without OLTx for patients with FHF
post-paracetamol OD
– pH<7.30 (regardless of degree of encephalopathy)
OR
– PT>100sec (INR>6.0) and
– Cr>0.300 and
– Grade III or IV encephalopathy

25. King’s College Criteria
• King’s College Criteria
– Sensitivity 72%
– Specificity 98%
– PPV 89%
For identifying patients with poor prognosis who need transplantation
Mortality rate of 90% without OLTx
Validated and evaluated in multiple subsequent studies
O’Grady et al Gastroenterology 1989;97(2) 439-45
Anand et al J Hepatol 1997;26(1):62-68
Bernal et al Hepatology 1998;27(4):1050-55
Benoit et al Crit Care Med 2003;31(1):299-305

26. Lactate
• In FHF with multi-organ failure, rises in blood
lactate reflect:
– Reduction in lactate clearance due to extensive
hepatic necrosis
– Systemic haemodynamic dysfunction
– Impaired oxygen utilisation
• Good correlation between elevated early blood
lactate concentrations and mortality

27. Lactate
• Lactate >3.5 mmol/L at 4 hours post admission correlated
with high risk of mortality
– Sensitivity 67%
– Specificity 95%
Mortality rate of 78%
Bernal et al Lancet 2002;16(359):558-63

28. Lactate
• Lactate >3.0 mmol/L after fluid resuscitation at 12 hours
post admission also correlated with high risk of mortality
– Sensitivity 76%
– Specificity 97%
Mortality rate of 89%
Bernal et al Lancet 2002;16(359):558-63

29. Cerebral Oedema in FHF
• Occurs in the majority of FHF patients
with high grade encephalopathy
– 60-80% of Gd III and IV patients
– Probably all patients with FHF intubated
in ICU(?)
• Leading cause of death
– Responsible for 60-80% of mortality
CT on admission

30. Cerebral Oedema in FHF
• Difficult to monitor
– Especially once sedated and intubated
in the ICU
• May progress rapidly
• Difficult management problem with no
single effective therapy
• May occasionally develop and progress
even after commencement of liver
recovery CT day 4

31. Pathophysiology of Cerebral Oedema in FHF
A mix of two processes
• Cytotoxic cerebral oedema
– Metabolic/Toxic injury to astrocytes results in swelling
• Vasogenic cerebral oedema
– Disruption of the BBB such that plasma constituents seep
into the brain parenchyma

32. Ammonia & Glutamine Cytotoxic Hypotheses
• Hepatic processing of
ammonia extremely
effective
• Minimal extra-hepatic
metabolism
– Skeletal muscle
– Brain
• Hyperammonaemia a
hallmark of severe liver
failure

33. Ammonia & Glutamine Cytotoxic Hypotheses
• Ammonia is a neuro-cytotoxin:
– induces membrane
depolarisation
– increases calcium influx
– interferes with
neurotransmitter release
– causes glutamate release
(which contributes to osmotic
drag)
– activates lipases & proteases
– increases production of free
radicals
– induces neuronal protein
nitration
– causes mitochondrial damage

34. Vasogenic Oedema
• Cerebral blood flow usually under tight auto-regulation
across a wide range of physiological states (e.g. MAP 50-
160 mmHg in healthy patients)
– Approx. 50 ml/100g brain tissue/min
– About 15% of Cardiac Output
– Note that cerebral oxygen extraction fraction is higher than
most other tissues and has little scope for increase
• Autoregulation of cerebral blood flow is lost in FHF,
resulting in cerebral hyperaemia and oedema, with loss of
BBB integrity and fluid leak into cerebral extracellular space

35. Mechanism of Vasogenic Oedema
Metabolic changes in astrocytes and neurones interfere with
autoregulation of normal regional blood flow
Hyperammonaemia
NDMA receptor
activation iNos activity
Vasodilatation &
Vessel
permeability
Cerebral
oedemaProstaglandin
&
Eiconasoids

36. The Cerebral Perfusion Pressure
MAP – ICP = CPP
Might make sense in neurointensive care
Driving MAP to achieve desired
CPP may be a bad idea in FHF

37. Why no Cerebral Oedema in CLD?
• Why doesn’t cerebral oedema occur in
cirrhotic patients with hyperammonaemia?
– Astrocytes have sufficient time to adapt to
higher levels of ammonia and the
cytotoxicity is attenuated markedly
– Systemic inflammation is less
– Cerebral hyperaemia does not occur

38. Intracranial Hypertension in FHF
Venous
Volume
Art.
Vol. Brain CSF
Brain CSFArt.
Vol.
Ven.
Vol.
Vblood + Vbrain + VCSF = Constant
Monro-Kellie Doctrine

39. Volume and Pressure
Compensation
Herniation
Volume of brain
ICP
(mm Hg)
5-
10-
15-
20-
25-
30-
35-
40-
45-
50-
55-
60-

40. Monitoring of Intracranial Pressure/Perfusion
• Direct
– Fluid filled catheters
– Electromechanical devices
– Fiber-optic catheters
• Indirect
– Sonography(?)
• Surrogates of ICP / cerebral blood flow
– JVB Oxygen Saturation
– Near infrared cerebral spectroscopy (NIRS)

41. Subdural Pressure Monitoring
• Solid state ‘skinny’ line
• No drainage of CSF
• Lower risk of infection/bleeding
• Difficult placement
• Cannot be ‘zeroed’
• Accuracy?
– drifts over a week or so

42. What to do About an Elevated ICP?
• Normal
• Mild elevation
• Moderate elevation
• Severe elevation
Best to avoid significant sustained elevations of ICP,
otherwise risk of positive feedback cycle……

43. Managing
Intracranial
Hypertension

44. Cerebral Oedema and Intracranial Hypertension
Reduced
cerebral
blood flow
Cerebral
ischaemia
Cerebral
injury
Cerebral
oedema
Elevated
ICP

45. Problems with ICP Monitoring
• (Usually) requires a neurosurgeon for
monitor insertion
– May be difficult to convince it is a good
idea!
• Is the measured ICP telling the full story?
– Regional variation across cerebrum
– Pressure gradients across relatively
fixed structures
• Risks of bleeding, infection
• Another number for the intensivists to
worry about/play with?
– Is targeting CPP a good idea anyway?!

46. Maybe not!
CCM 2014 May;42(5):1157-67.
Outcomes and complications of intracranial pressure monitoring in acute liver
failure: a retrospective cohort study.
Karvellas et al
‘In intracranial pressure monitored patients with acute liver failure, intracranial hypertension is
commonly observed. The use of intracranial pressure monitor in acetaminophen acute liver
failure did not confer a significant 21-day mortality benefit, whereas in non-acetaminophen
acute liver failure, it may be associated with worse outcomes. Hemorrhagic complications
from intracranial pressure monitor placement were uncommon and cannot account for
mortality trends.’

47. Other Means of Evaluating Intracranial
Events: JVB Venous Oxygen Saturation
• Analogous to using mixed venous
oxygenation as a measure of cardiac
output/total body blood flow
• Easily inserted
– Intermittent sampling and analysis on
ABG machine is simple
– Continuous devices disappointing
• Low saturations imply diminished
cerebral blood flow (due to ↑ICP)
• Many issues with interpretation
– Dependant on state of systemic
circulation/oxygenation, Hb, etc

48. JVB Catheter
Placement

49. Using SjO2 to
guide
neurological
management

50. NIRS
• Near Infrared Spectroscopy may be used to estimate
cerebral blood flow
• Non-invasive
• Continuous
• Difficulties with reliability
– Artifact
– Regional versus Global perfusion
• Use in hyperaemic states?
• Not in routine clinical use

51. An Important Disclaimer……
The Austin Health Department of Intensive Care has not
placed an ICP monitor in a patient with FHF for…….
NEARLY
9 YEARS

52. Management of Cerebral Oedema in FHF
• Accumulating evidence that cerebral oedema in severe
FHF can be effectively managed and subsequent serious
elevations of ICP can be prevented
• Multimodal approach using a comprehensive guideline
developed and refined over seven years
No ‘neurological’ deaths in FHF patients at Austin Health
for nineyears…….
=
Now no reason to place ICP monitors

53. ‘Quad-H’ Therapy for FHF
A new approach……

54. Background Concepts
• Quad-H for FHF is a multi-modal approach bringing
together a range of biologically plausible and potentially
effective interventions to attenuate processes leading to
cerebral oedema and prevent serious elevations of ICP
– Reasonable and emerging evidence for each component
when used in isolation
– Additional leverage when used in combination
• Administered to all intubated FHF patients in the ICU
• Applied in the context of a coordinated management
strategy which guides clinical care across all systems

55. Quad-H Components
1.Hyperventilation (Mild)
2.Haemo(dia)filtration
3.Hypernatraemia
4.Hypothermia (Mild)

56. Hyperventilation (Mild)
• Patients with coma from Hepatic Encephalopathy
hyperventilate
• Logical to target same PaCO2 as that achieved by the
patient prior to intubation
• Maintain PaCO2 at lower end of normal range
• Aggressive hyperventilation only as a rescue therapy whilst
awaiting more definitive intervention
– Duration of benefit is brief

57. Haemo(dia)filtration
• Continuous Renal Replacement Therapy provides a range of
benefits in setting of FHF
– Intervention for Acute Renal Failure (almost universal in FHF)
» Manages fluid balance
» Controls Electrolyte disturbance
» Uraemia (although actually rare in severe liver failure)
» Remedies Acid-Base derangement
– Thermoregulation much easier
– Effective reduction in ammonia concentrations
– (Modulation of inflammatory response?)

58. Why Continuous RRT?
• Less haemodynamic impact
• Not associated with worsening of intracranial hypertension
• Greater overall effective treatment dose of therapy over 24
hour period
• Can be more readily titrated
• Temperature management a major goal of therapy
• Managed by trained ICU bedside nurse
• (Attenuates inflammatory response?)

59. How to Run the CRRT in Severe FHF
• Start early and keep to a daily even fluid balance
• Aim for near normal blood ammonia levels (<60 μmol/L)
• Mode probably doesn’t matter a lot:
– Haemofiltration vs Diafiltration → not a big deal
– Dialytic (diffusive) clearance might improve ammonia clearance
– Filtration (convective) clearance might have (unproven) benefits relating to
modulation of the inflammatory response
• Anticoagulation often unnecessary if good flows and some replacement fluid
given as pre-dilution (for CVVH)
• Turn heater off
• Run high blood flows
• Try to achieve exchanges of plasma water of 40-50 ml/kg/hr if possible-
avoid disruptions to therapy

60. CVVHD
Blood
Pump
Dialysate
Dialysate + Ultrafiltrate
Heater
AV
Filter
Qb= 200 - 300 ml/min
Qd= 35-45 ml/min
(Qdf= approx 40-50 ml/min)

61. Pitfalls of CRRT
• Starting too late
– Do not wait for usual indications associated with ARF
• Not lowering the ammonia sufficiently
• Not providing truly continuous RRT
• Not achieving satisfactory blood flow
– Circuit clotting/failure
• Not managing electrolyte status
– Especially sodium, potassium and phosphate
• Anticoagulant management issues

62. Hypernatraemia
• An ‘osmotherapy’, largely reliant on an intact BBB
to be effective
• Creates an osmotic gradient which favours egress
of water from brain tissue to the circulation
• Also expands circulating volume with minimal total
volume of fluid administration
• Better than other osmotherapies?
– May be safer than mannitol (does not accumulate
in brain tissue)
– At least as effective as mannitol (probably better)

63. Hypernatraemia
• How?
– Continuous infusion using syringe driver of 20% NaCl via
dedicated CVC lumen
– Target serum sodium of 150 mmol/L (148-155 mmol/L)
– Monitor serum sodium on regular blood gas analysis
» Preferably every hour
– Avoid hypotonic fluids
– Beware fluctuations during initiation of RRT

64. Sodium Pitfalls
• Avoid:
– Rapid/Major fluctations in serum sodium
» Risk of CPML- irreversible and often fatal neurological injury
» Especially important if patient presents hyponatraemic- change
serum sodium target to lower level and do not allow more than 1-2
mmol/L increase every four hours
– Recurrent positive fluid balance
– Running concentrated saline via CRRT
» Risk of discontinuation if filter clots
– Hypotonic fluids
» If patient patient needs dextrose (common), use concentrated
infusions (e.g. 25% dextrose), NEVER 5% Dextrose

65. (Mild) Hypothermia
• Multiple animal and small clinical studies studies
demonstrating benefit
• Mechanisms
– Reduced CBF/hyperaemia
– Reduced cerebral ammonia uptake
– Neuro-inhibitory
– Lowers glutamate production
– Anti-inflammatory effects within the CNS
• Target Temperature 33-35°C
– Problems with lowering core temperature further
↓Vasogenic oedema
↓Cytotoxic oedema

66. (Mild) Hypothermia
• How?
– Sedation (sometimes), muscle relaxants (usually at induction)
– Cutaneous vasodilatation makes external measures fairly effective
– External cooling blankets (servo-controlled via core temp monitoring)
– Wind tunnel
– Extracorporeal circuit (CRRT)
Must provide continuous monitoring of core temperature and avoid marked variations

67. Hypothermia Pitfalls
• Too cold
– Immunosupression effects seem to become marked at
temperatures of <33°C for sustained periods- leads to
progressive and often refractory septic shock resulting in
death
• Too long
– 3-5 days is usually sufficient- stop cooling based on overall
clinical assessment
• Too fast
– Re-warming needs to be controlled and in context of close
monitoring

68. Daily ICU Management Plan for FHF
• Sepsis / Antimicrobials
– Sepsis / Shock / MOF are now the major cause of death in
FHF
– Frequent cultures and knowledge of important likely
pathogens / local resistance patterns
– Broad spectrum antibiotics e.g.
» Extended spectrum beta-lactam
» Third generation cephalosporin
– Antifungals if septic after about 5 days
» Liposomal amphotericin 5 mg/kg/day

69. Daily ICU Management Plan for FHF
• Metabolic
– NAC infusion for all POD patients until liver clearly recovering
– Glycaemic control (insulin infusion or 25% dextrose infusion
as required)
– Low dose hydrocortisone if marked vasodilatory shock
» Absolute or relative adrenal insufficiency?
» End-organ cortisol resistance?

70. Daily ICU Management Plan for FHF
• Respiratory
– Ventilate to low normal PaCO2
– Avoid deliberate ventilation to very low PaCO2 unless
compelling evidence of intracranial hypertension
• Cardiovascular
– Rough aim of CVP 6-12 mmHg with even fluid balance over
each day
– Noradrenaline infusion for MAP of >70 mmHg and CPP of
50-60 mmHg
– Consider measuring cardiac output and/or TTE

71. Daily ICU Management Plan for FHF
• Haematological
– Check clotting every four hours
– If not bleeding:
» Target Hb >7.0 g/dL
» Target INR <5
» Target platelet count >20 x 109/L
– Vit K for all patients
– FFP, Cryoprecipitate & Platelets if required

72. Specific Treatments for ALF
• NAC
– For POD (and possible all other causes of ALF too!)
– Continue while critically ill and/or detectable paracetamol in blood
• Amanita mushroom
– Charcoal, penicillin and NAC
– Extract of milk thistle (Silibinin)
• HSV- acycolvir
• CMV- gancyclovir
• HBV- entecavir
• HELLP- deliver baby ASAP

73. Key Recommendations
• Death from cerebral oedema in FHF patients is probably
preventable
• Early admission to ICU of patients with high grade
encephalopathy for Quad-H therapy is likely to reduce FHF
associated neurological deaths
• Ongoing challenges include managing sepsis as circulation
failure
– Role for other blood purification therapies??

74. Extracorporeal Blood Purification Therapies
MARS (Molecular adsorption and Recirculation System)

75. MARS

76. CPFA
• Coupled Plasma Filtration and Adsorption is an
emerging option for severe inflammatory states
– Septic shock
– FHF
• Adsorption of inflammatory cytokines, endotoxin, toxic
metabolites onto a resin cartridge
• Initial clinical data suggests improvement in
haemodynamics, cellular respiration and microcirculatory
function

77. Extracorporeal Blood Purification Therapies
CPFA (Coupled Plasma Filtration and Adsorption)

78. Benefits of CPFA
• Technically easier than MARS
• Existing ICU CRRT machines may be readily
configured to provide CPFA
• Cost of circuit is substantially lower
• Can often be managed within existing ICU
senior nursing/educator expertise/skill set

79. Role of OLTX in FHF with Severe Cerebral
Oedema

80. Questions?
Mt Feathertop and the Razorback