Critical Care Hepatology:Acute Liver Failure

Stephen Warrillow FRACP FCICM Grad Cert Emerg Health (Aeromedicine & Retrieval)Deputy DirectorDepartment of Intensive CareAustin Health, Melbourne, AustraliaSenior Lecturer and Research Fellow, The University of Melbourne

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’

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

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

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

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

ICU APPROACH TO FHF

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

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

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

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

Mortality

• Dependent upon classification, aetiology and availability of liver transplantation

• Medical management only:

Mortality

Hyper-acute 64%

Acute/Subacute 86%

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

Ammonia & Glutamine Cytotoxic Hypotheses

• Hepatic processing of ammonia extremely effective

• Minimal extra-hepatic metabolism

– Skeletal muscle– Brain

• Hyperammonaemia a hallmark of severe liver failure

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

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

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 oedema

Prostaglandin &

Eiconasoids

The Cerebral Perfusion Pressure

MAP – ICP = CPPMight make sense in neurointensive care

Driving MAP to achieve desired CPP may be a bad idea in FHF

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

Intracranial Hypertension in FHF

VenousVolume

Art.Vol. Brain CSF

Brain CSFArt.Vol.

Ven.Vol.

Vblood + Vbrain + VCSF = Constant

Monro-Kellie Doctrine

Volume and Pressure

Compensation

Herniation

Volume of brain

ICP(mm Hg)

5-10-15-20-25-30-35-40-45-50-55-60-

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)

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

What to do About an Elevated ICP?

• Normal 7 - 15 mmHg

• Mild elevation 20 – 25 mmHg

• Moderate elevation 25 – 40 mmHg

• Severe elevation >40 mmHg

Best to avoid significant sustained elevations of ICP, otherwise risk of positive feedback cycle……

Managing Intracranial

Hypertension

Cerebral Oedema and Intracranial Hypertension

Reduced cerebral

blood flow

Cerebral ischaemia

Cerebral injury

Cerebral oedema

Elevated ICP

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?!

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.’

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

JVB Catheter Placement

Using SjO2 to

guide neurological management

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

An Important Disclaimer……

The Austin Health Department of Intensive Care has not placed an ICP monitor in a patient with FHF for…….

NEARLY9 YEARS

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

‘Quad-H’ Therapy for FHFA new approach……

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

Quad-H Components

1.Hyperventilation (Mild)

2.Haemo(dia)filtration

3.Hypernatraemia

4.Hypothermia (Mild)

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

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?)

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?)

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

CVVHD

BloodPump

Dialysate

Dialysate + Ultrafiltrate

Heater

AV

Filter

Qb= 200 - 300 ml/min

Qd= 35-45 ml/min

(Qdf= approx 40-50 ml/min)

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

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)

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

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

(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

(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 variationsFever must a

lways be prevented

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

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

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?

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

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

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

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??

Extracorporeal Blood Purification Therapies

MARS (Molecular adsorption and Recirculation System)

MARS

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

Extracorporeal Blood Purification Therapies

CPFA (Coupled Plasma Filtration and Adsorption)

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

Role of OLTX in FHF with Severe Cerebral Oedema

?

Questions?

Mt Feathertop and the Razorback