The document discusses critical care hepatology and management of acute and chronic liver conditions in the intensive care unit. It covers topics such as acute liver failure, decompensated chronic liver disease, abnormal liver function tests, and liver injury in multi-organ failure syndromes. Management of specific conditions is discussed, including cerebral edema in acute liver failure, variceal hemorrhage, spontaneous bacterial peritonitis, and hepatic encephalopathy. The "4H therapy" approach to preventing neurological deaths in acute liver failure using hyperventilation, hypernatremia, hemodiafiltration, and mild hypothermia is also summarized.

1. Critical Care Hepatology
Is life worth living? It all depends on the liver.
- William James
Stephen Warrillow FRACP FCICM Grad Cert Emerg Health (Aeromedicine & Retrieval)
Director, Department of Intensive Care
Austin Health, Melbourne, Australia
Senior Lecturer and Research Fellow, The University of Melbourne

2. Austin Health
• University Teaching Hospital
founded as a ‘hospital for
incurables’ in 1882
• Serves North-Eastern suburbs
of Melbourne
• Affiliated with The University of
Melbourne
• All major medical & surgical
specialties
• State Liver Transplant Centre

3. Scope
The Liver in ICU:
A sprint through critical care
hepatology with tips and tricks
• Acute Liver Failure
• Decompensated Chronic Liver
Disease
• Weirdly abnormal LFTs in ICU
• Liver injury in MOFS
• Ischaemic hepatitis
• Liver Transplantation
• Hepatic Disorders of Pregnancy
• Malignant hepatic infiltration
A truly miraculous and transformative intervention that
helps maintain one’s essential ‘incurable optimism’

4. ICU APPROACH TO ALF

5. Acute Liver Failure
• Also known as Fulminant Hepatic Failure (FHF)
• No pre-existing liver disease
– first symptom to encephalopathy < 8 weeks
• Presence of Hepatic Encephalopathy
+ Derangements of measured clotting parameters
+/- Haemodynamic instability
+/- Renal failure
+/- Severe metabolic disturbance
+/- Susceptibility to infection

6. Fulminant Hepatic Failure
• Hyper-acute:
Jaundice - Encephalopathy < 8 days
• Acute:
Jaundice - Encephalopathy 8-28 days
• Sub-acute:
Jaundice - Encephalopathy > 28 days
Acute Liver Failure

7. Aetiology (in ANZ)
• Paracetamol, paracetamol, paracetamol…….
• Viral Hepatitis: HAV, HBV, CMV, HSV, VSV, HEV
• Idiopathic (actually viral?)
• Idiosyncratic drug reactions, herbal medicines
• Miscellaneous:
– Amanita mushrooms, Wilson's, Budd-Chiari,
Autoimmune, Pregnancy-related
• Ischaemic
• Malignancy

8. • 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 and
cytotoxic processes
» Ammonia seems to be an important player
– Can progress suddenly
• Cerebral oedema and elevated intra-cranial pressure
(ICP)
– Cerebral oedema occurs in the majority of patients with grade
three or four encephalopathy and was once major cause of
death
– Oedema formation is secondary to marked hyperaemia and
cytotoxic processes
» Ammonia seems to be an important player
– Can progress suddenly
• 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
Key Management Problems

9. Key Management Problems
• Complex coagulopathy/pro-
thrombotic state
• Renal failure
• Vasodilatory shock
• Fluid and electrolyte
management

10. Haematological Issues in Liver Failure
• ↑PT, ↑INR, ↓platelets, ↓fibrinogen (differentiating from DIC may
be hard)
• INR on its own is a poor guide to bleeding risk in liver failure
• ↑APTT and ↓↓platelets probably does predict risk of bleeding
• If not bleeding and no invasive procedures are planned, avoid
clotting factor administration if INR <5(?)
• Vitamin K is OK for all patients with liver failure
• If giving clotting factors, use FFP, rather than prothrombin
concentrates e.g. prothrombinX
• Be alert to potential thrombotic complications
– PV thrombosis, DVT, PE, stroke

11. 4H THERAPY
Practical Strategies for Preventing Neurological Deaths in ALF

12. A Key Management Problem in Severe ALF
• Cerebral oedema and elevated
intra-cranial pressure (ICP)
– Cerebral oedema occurs frequently
with high grade encephalopathy
and remains a major cause of
death if not managed well
– Can progress suddenly and occur
even during or immediately after
OLTx
– No single effective therapy and
management approaches are often
institution specific1
– Many of the usual clinical guides
are hard to assess in the critically ill
CT on admissionCT day 4
1. Stravitz RT, Kramer AH, Davern T, et al.
Intensive care of patients with acute liver
failure: Recommendations of the U.S.
Acute Liver Failure Study Group. Critical
Care Medicine 2007;35:2498-508

13. Pathophysiology of Cerebral Oedema in ALF
A mix of two processes
• Cytotoxic cerebral oedema1
– Metabolic/Toxic injury to astrocytes results in swelling
• Vasogenic cerebral oedema2
– Loss of normal autoregulation of cerebral blood flow
– Hyperaemia and disruption of the BBB such that plasma
constituents seep into the brain parenchyma
1. Tofteng F, Hauerberg J, Hansen BA, Pedersen CB, Jorgensen L, Larsen FS. Persistent arterial
hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates
with intracranial pressure in patients with fulminant hepatic failure. J Cereb Blood Flow Metab
2006;26:21-7
2. Durham S, Yonas H, Aggarwal S, Darby J, Kramer D. Regional cerebral blood flow and CO2
reactivity in fulminant hepatic failure. J Cereb Blood Flow Metab 1995;15:329-35

14. Development of Hyperammonaemia in ALF
• Hepatic processing of
ammonia extremely
efficient (≈85%)
• Minimal extra-hepatic
metabolism (≈15%)
– Skeletal muscle
– Brain
• Hyperammonaemia is a
hallmark of severe liver
failure
• Renal failure further
reduces ammonia
excretion
Warrillow SJ, Bellomo R. Preventing cerebral oedema in acute liver failure; the case for
quadruple-H therapy. Anaesth Intensive Care 2014:42:78-88

15. Ammonia & Glutamine Cytotoxic Hypotheses
Ammonia is neuro-cytotoxic:
– induces membrane
depolarisation
– increases calcium influx
– interferes with
neurotransmitter release
– causes glutamate release
(contributes to osmotic drag)
– activates lipases & proteases
– increases production of free
radicals
– induces neuronal protein
nitration
– causes mitochondrial
damage
Warrillow SJ, Bellomo R. Preventing cerebral oedema in acute liver failure; the case for
quadruple-H therapy. Anaesth Intensive Care 2014:42:78-88

16. 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

17. Management of Cerebral Oedema in ALF
• Accumulating evidence that
cerebral oedema in severe ALF
can be effectively managed
• No evidence of benefit from ICP
monitoring1,2
Now no reason to
place ICP monitors?
1. Vaquero J, Fontana RJ, Larson AM, et al. Complications and use of intracranial pressure
monitoring in patients with acute liver failure and severe encephalopathy. Liver
transplantation : official publication of the American Association for the Study of Liver
Diseases and the International Liver Transplantation Society 2005;11:1581-9.
2. Keays RT, Alexander GJ, Williams R. The safety and value of extradural intracranial
pressure monitors in fulminant hepatic failure. Journal of hepatology 1993;18:205-9.

18. 4H Components
1. Hyperventilation (Mild)
2. Hypernatraemia
3. Haemo(dia)filtration
4. Hypothermia (Mild)

19. (Mild) Hyperventilation
• Ensure mechanical ventilation
provides a minute volume sufficient
to achieve a low normal PaCO2
(PaCO2 32-35 mmHg)1 or similar
level to that achieved by the patient
prior to intubation
• Monitor with frequent ABG and
EtCO2 monitoring
• Reserve extreme hyperventilation
for use as a recue therapy2 whilst
awaiting imminent transplantation
1. Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver failure:
Recommendations of the U.S. Acute Liver Failure Study Group. Critical Care Medicine
2007;35:2498-508
2. Lee WM, Stravitz RT, Larson AM. Introduction to the revised American Association for the Study
of Liver Diseases Position Paper on acute liver failure 2011. Hepatology 2012;55:965-7.

20. 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?
– Therapeutic hypernatraemia seems safe1
– Theoretically safer than mannitol? (does not accumulate in brain tissue)
– At least as effective as mannitol?
1. Murphy N, Auzinger G, Bernel W, Wendon J. The effect of hypertonic sodium
chloride on intracranial pressure in patients with acute liver failure. Hepatology
2004;39:464-70

21. 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
– Beware fluctuations during initiation of RRT

22. Haemo(dia)filtration
• Continuous Renal Replacement Therapy provides a range of
potential benefits in setting of FHF
– Effective reduction in ammonia concentrations
– Intervention for Acute Renal Failure (almost universal in
severe ALF)
» Manages fluid balance
» Manages electrolyte disturbance
» Corrects Acid-Base derangement
» (Uraemia)

23. RRT and Ammonia Clearance
CRRT is remarkably
effective at ammonia
clearance1
• similar kinetics to urea
clearance
Ammonia level
0
200
400
600
800
1000
0 5 10 15 20 25 30 48
Time (hours)
Plasmaammonia(mcg/l)
dialysis started
CVVH started
dialysis started
1. Licari E, Calzavacca P, Warrillow SJ, Bellomo R. Life-threatening
sodium valproate overdose: a comparison of two approaches to
treatment. Critical care medicine 2009;37:3161-4.

24. Managing CRRT in Severe ALF
• Start early and keep to an even daily fluid balance
• Aim for near normal blood ammonia levels (<60 μmol/L)
• Mode probably doesn’t matter a lot:
– Haemofiltration vs Diafiltration → probably not a big deal
– Diffusive clearance might provide better ammonia clearance
• Anticoagulation often unnecessary if good flows and 50% of replacement
fluid given as pre-dilution (for CVVH), or consider prostacyclin + low dose
heparin
• Turn heater off and use circuit for temperature management
• Run fairly high blood flows (>250 ml/min)
• Try to achieve exchanges of plasma water of 40-50 ml/kg/hr

25. Pitfalls of Managing CRRT in ALF
• 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, phosphate and magnesium
• Anticoagulant management issues

26. (Mild) Hypothermia
• Multiple animal and small clinical studies studies demonstrating
benefit
• Suggested mechanisms1
– Reduced CBF/hyperaemia
– Reduced cerebral ammonia uptake
– Neuro-inhibitory
– Lowers glutamate production
– Anti-inflammatory effects within the CNS
• Target Temperature- 35°C
– Most of benefit achieved with mild reductions in temperature?2
– Problems with lowering core temperature further
↓Vasogenic oedema
↓Cytotoxic oedema
1. Warrillow SJ, Bellomo R. Preventing cerebral oedema in acute liver failure; the case for
quadruple-H therapy. Anaesth Intensive Care 2014:42:78-88
2. Jalan R. Intracranial hypertension in acute liver failure: pathophysiological basis of rational
management. Semin Liver Dis 2003:23:271-82

27. DECOMPENSATED CLD

28. Decompensated CLD
• Regardless of the cause,
advanced chronic liver
disease/cirrhosis results in
fragile patients with complex
multisystem problems
• Decompensation is common
and frequently results in
critical illness that may
necessitate ICU admission

29. Consequences of Advanced Cirrhosis
• Encephalopathy
• Coagulopathy
• Cachexia
– Sarcopenia
– Nutritional deficits
• Immunosuppression
• Portal HT
– Varices
– PHT
gastropathy
– Hypersplenism
– Ascites

30. Complications of Advanced Cirrhosis
• Variceal
Haemorrhage
• Encephalopathy
• Renal Failure
– HRS I and HRS II
– Other causes
• Sepsis/Septic Shock
– Especially from SBP
• Hepatopulmonary
syndrome
• Portopulmonary
hypertension

31. Variceal Haemorrhage
• Often dramatic and often
fatal
• Amount of bleeding quite
variable, but generally brisk
• Prognosis closely
associated with severity of
liver disease and
associated organ failure

32. Variceal Haemorrhage- Resuscitation
• Wide-bore IV access
• Blood and clotting factors
– Prepare for massive transfusion
• Give iv ABx e.g. ampicillin & ceftriaxone
• Endoscopic banding is the optimal
approach
• Balloon tamponade can buy time until
endoscopist arrives

33. Variceal Haemorrhage- Drug Therapy
• Always in combination with other measures
– Intention is to reduce portal pressures and blood flow
• Vasopressin (0.2-0.4 Units/min)
• Terlipressin a good alternative
– Both may also improve systemic arterial pressure
• Somatostatin or analogue e.g. octreotide

34. Balloon Tamponade
• SSB (three lumen) or Minnesota Tube is a
means of achieving temporary control when
other measures have failed
• Correct insertion technique important
• Only gastric balloon usually needs to be
inflated
• Traction very important- usually 0.5 kg
• High risk of complications
– especially after 24 hours

35. TIPS
• Transjugular intrahepatic portosystemic
shunt
– Requires and experienced interventional
radiologist who can achieve >90% success
rate
• Portal pressures reliably reduced and
effectively controls variceal bleeding
• Does not prevent subsequent OLTx
• Reserved for instances where other
measures have failed

36. Traps in Variceal Bleeding
• Sepsis a common complication
• Encephalopathy almost always
ensues
• Many patients are beta-blocked
• Risks of over-transfusion
causing rebound in portal
pressures
• Delayed re-bleeding

37. Spontaneous Bacterial Peritonitis
• Important to consider especially when site of infection not
obvious
• Need to have a high index of suspicion
• Undertake diagnostic taps as part of septic work-up
– Look at Gram stain and WCC >250 x 106 /l
• Always start broad spectrum gram negative cover
– Beta-lactams preferred
• Usually gram negatives, especially E. coli and
enterococcus spp. (n.b. CLD patients often harbour VRE)

38. Hepatic Encephalopathy
• Pathophysiology complex
and incompletely
understood
• Failure to achieve hepatic
clearance of various
substances
– Ammonia
– Mercaptans
– False neurotransmitters

39. Hepatic Encephalopathy
Grading system (West-Haven)
0 Normal
1 Confusion- flap often present
2 Drowsiness- foetor sometimes present
3 Somnolent
4 Coma
• GCS might be a better system for ICU because we’re
more familiar with it
• Correlation between ammonia levels and degree of
encephalopathy is not great, but still useful

40. Precipitants
• Stopping medications
• Sedatives
• Protein loads in gut (especially blood)
• Electrolyte and pH abnormalities
(especially from loop diuretics)
• Infection (e.g. UTI, SPB, pneumonia etc)
• Constipation
• Alcohol
• New shunt (e.g. post-TIPS, but may be
spontaneous)

41. Hepatic Encephalopathy
• Correction of precipitants
• Avoid sedation
• Treat infection
• Protect airway
• Lactulose
– fairly safe and probably effective
– reduces ammonia production and absorption
• Non-absorbable antibiotics (e.g. rifamixin)
• BCAA?- probably no additional benefit if on other treatments
• CRRT?- maybe, but usually only if also in significant renal failure

42. Renal Failure in Cirrhosis
• When is it HRS?
• When is it not HRS?
• Does it really change the
management?
A key consideration is whether
the patient is a transplant
candidate….. What are the
goals of care?

43. HRS I
• Rapid onset
– Doubling of Cr to greater
than 221 µmol/l in two
weeks
• Absence of
– Hypovolaemia
– Infection
– Nephrotoxins
– Other explanations for
renal failure (e.g. GN)
• No improvement after stopping
diuretic and giving fluid
• Not nephrotic or nephritic
• Very low urinary sodium
<10mmol/l
HRS II
• Slowly progressive
• Strongly associated with
presence of significant ascites

44. HRS Management
• Treat reversible precipitants
• Albumin
• Vasopressors
– Terlipressin (used for suitably trained ward staff or home-
based care)
– Noradrenaline (restricted to the ICU)
• Treat for likely sepsis (although definition excludes this)
• Tap ascites
– avoid massive fluid shifts that produce intravascular volume
depletion

45. Thank you
Mt Feathertop and the
Razorback, Victorian Alps

46. HEPATIC DISEASE IN
PREGNANCY

47. Liver Disease and Pregnancy
• Acute Fatty Liver of Pregnancy
• HELLP
• Viral Hepatitis
• Intrahepatic Cholestasis of Pregnancy
• Liver Rupture
• Cirrhosis

48. AFLP
• 1 per 10 000 pregnancies
• 2nd or, (more commonly) 3rd trimester
• More common in older primips and assoc with pre-
eclampsia
• Assoc with 3-hydroxyacyl-coenzyme A dehydrogenase
(LCHAD) deficiency
• A microvesicular steatohepatisis
– Histology looks like valproate and Reye’s syndrome

49. AFLP
• Symptoms of liver failure occur over
days to weeks
• ARF in 50%
• Encephalopathy in 60%
• Clinical syndrome c/w pre-eclampsia
in 50%
• Liver biopsy reveals microvesicular
steatosis, fat droplets surrounding a
centrally placed nucleus (rarely done!)

50. AFLP
• Delivery is the definitive treatment
– Usually caesarean (75% are pre-term with assoc issues)
• All infants of mothers with AFLP are tested for defects in
fatty acid oxidation because prompt recognition and
treatment can decrease mortality and morbidity
• Mortality previously reported as high as 70%, but now less
than 15%
• Full recovery is expected, but may occasionally take
months

51. Haemolysis, elevated liver enzymes, and low platelets (HELLP)
• Usually as a complication of pre-eclampsia
• Affects 1-6 per 1,000 pregnancies and 4-12% of patients
with severe preeclampsia
• 70% present before delivery
• 30% develop in the postpartum period

52. HELLP
• Caused by several mechanisms combining to cause,
– Haemolysis
– Liver necrosis
– Thrombocytopenia
• Initial source of the insult is unknown
• Evidence of endothelial injury with fibrin deposit that causes
a microangiopathic hemolytic anemia and platelet activation
and consumption
• Fibrin deposits cause obstruction in the hepatic sinusoids,
which leads to areas of haemorrhage

53. HELLP
• Clinical presentation
– Right upper quadrant or epigastric pain
– Nausea and vomiting, malaise
– Nonspecific viral-like symptoms
– Headache (30-60%)
– Visual disturbance
– Hypertension and proteinuria are common, as most of the
patients have preeclampsia
• Ix show elevated ALT, elevated LDH, low haptaglobin
thrombocytopenia and an abnormal blood film

54. HELLP
• Definitive management if foetal delivery
• Management as per pre-eclampsia care
– Magnesium sulphate infusion
• Maternal mortality around 1%
• Complications:
– pulmonary oedema
– ARF
– DIC
– abruptio placenta
– liver heamorrhage, failure or rupture
– acute respiratory distress syndrome
– stroke

55. Intrahepatic Cholestasis of Pregnancy
• Approx 1 per 1000 pregnancies
• Almost always in third trimester
• Geographic/Racial variation
• Risk factors include:
– advanced maternal age
– Multiparity
– personal or family history of the disease
– history of cholestasis while taking OCP

56. Intrahepatic Cholestasis of Pregnancy
• ICP is due to abnormal biliary transport resulting in saturation of
the hepatic transport system
• Recurrent familial ICP likely to be a heritable defect in the
multidrug resistance 3 (MDR3) gene, which encodes for a
canalicular phospholipid translocator involved in bile duct
secretion of phospholipids
– 15% of cases??
• Female sex hormones important
– Almost all cases are seen in the third trimester, when oestrogen
levels are rising
– oestrogens are known to be cholestatic, and administration to
nonpregnant women with a history of ICP has been shown to
induce signs of cholestasis

57. Intrahepatic Cholestasis of Pregnancy
• Clinical presentation
– generalized pruritus that begins in the periphery, often worse on the palms
and soles, and moves centrally to the trunk and face
– Pruritus persists and worsens as pregnancy continues and resolves within
48 hours of delivery
– Often worse at night - may cause sleep disturbance, irritability, and
psychiatric disturbances
– 10-25% of patients develop jaundice, usually 1-4 weeks after the onset of
pruritus
– Rarely, constitutional symptoms
» chills, abdominal pain, diarrhoea
» steatorrhoea
• Markedly cholestatic LFTs

58. Intrahepatic Cholestasis of Pregnancy
• Treatment is ursodeoxycholic acid (UDCA)
– doses of 1 gram per day
– may allow progress through to term
• LFTs may take weeks to normalise
• Maternal prognosis extremely good
• Infants usually premature and may have associated morbidity

59. Viral Hepatitis
• Hepatitis A, B, C, D and E
• CMV, EBV, HSV
• Similar management issues to non-pregnant state