Liver Transplantation ICU Management

Quick Answer Card

Liver transplantation ICU management in 60 seconds:

• Three surgical phases: Dissection (pre-anhepatic), anhepatic (no hepatic blood flow), and neo-hepatic/reperfusion phases - each with distinct physiological challenges
• Post-reperfusion syndrome (PRS): >30% MAP drop for >1 minute within 5 minutes of reperfusion; occurs in 25-40% of cases; treat with calcium, vasopressors (epinephrine/norepinephrine), bicarbonate (PMID: 3550233)
• Primary non-function: Graft failure requiring urgent re-transplantation; incidence 2-7%; defined by severe coagulopathy, encephalopathy, hypoglycaemia, and persistent acidosis within 72 hours
• Early allograft dysfunction (Olthoff criteria): Bilirubin ≥10 mg/dL on day 7, INR ≥1.6 on day 7, or AST/ALT >2000 IU/L in first 7 days; occurs in 25-35% of transplants (PMID: 20583094)
• Key vascular complications: Hepatic artery thrombosis (2-9%), portal vein thrombosis (1-3%), hepatic vein/IVC complications (<1%)
• Immunosuppression: Tacrolimus-based regimen standard; target trough 8-12 ng/mL early, 6-10 ng/mL by month 3; monitor nephrotoxicity closely
• Australian outcomes: ~200 transplants/year; 1-year survival 85-90%; 5-year survival 75-80% (ANZLTR data)

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CICM Exam Focus

Why This Topic is Examined

Liver transplantation is a high-frequency CICM Hot Case and SAQ topic because it integrates:

• Complex perioperative physiology
• Multi-organ system management
• Immunosuppression pharmacology
• Surgical complication recognition
• Ethical considerations (organ allocation, re-transplantation)

Common Exam Presentations

Examiner Expectations

1. Understand the surgical phases and their physiological implications
2. Recognize early graft dysfunction using Olthoff criteria
3. Know the vascular complications and their presentations/management
4. Demonstrate immunosuppression knowledge including drug levels and toxicities
5. Articulate a systematic approach to post-operative ICU care
6. Discuss ethical frameworks for re-transplantation decisions

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Key Points

Key Points: 1. Post-reperfusion syndrome occurs in 25-40% of liver transplants, defined as >30% MAP drop for >1 minute within 5 minutes of reperfusion (PMID: 3550233)

2. Primary non-function (PNF) occurs in 2-7% of cases; characterised by severe coagulopathy, encephalopathy, hypoglycaemia, and acidosis within 72 hours; requires urgent re-transplantation

3. Early allograft dysfunction (EAD) is defined by Olthoff criteria: bilirubin ≥10 mg/dL on day 7, INR ≥1.6 on day 7, or AST/ALT >2000 IU/L in first 7 days (PMID: 20583094)

4. Hepatic artery thrombosis (HAT) is a surgical emergency; occurs in 2-9% of cases; biliary tree is solely hepatic artery-dependent; diagnosis via Doppler USS then CT angiography (PMID: 19820510)

5. Tacrolimus is the cornerstone immunosuppressant; target trough 8-12 ng/mL weeks 1-4, 6-10 ng/mL months 1-6, 4-7 ng/mL long-term; major toxicities include nephrotoxicity and neurotoxicity (PMID: 28318288)

6. Daily Doppler ultrasound is standard for first 3-7 days post-transplant to monitor hepatic artery and portal vein patency

7. MELD score (Model for End-Stage Liver Disease) determines transplant allocation priority; calculated from bilirubin, INR, and creatinine; higher scores indicate higher mortality without transplant

8. Coagulopathy post-transplant is complex; may have both bleeding and thrombotic tendencies; viscoelastic testing (ROTEM/TEG) preferred over conventional coagulation tests

9. CMV prophylaxis with valganciclovir is standard for high-risk (D+/R-) recipients for 3-6 months post-transplant (PMID: 30814545)

10. Biliary complications are the "Achilles heel" of liver transplantation; include anastomotic leaks (5-10%) and strictures (10-15%); ischaemic cholangiopathy associated with HAT and prolonged ischaemia

11. Living donor liver transplantation and split-liver transplantation carry higher complication rates (biliary leaks, small-for-size syndrome) but expand the donor pool

12. Acute cellular rejection occurs in 15-25% of recipients, typically day 5-30; diagnosed by liver biopsy; treated with methylprednisolone 500-1000 mg daily for 3 days

13. Renal protection is critical; pre-operative hepatorenal syndrome may persist; tacrolimus nephrotoxicity is dose-dependent; consider delayed tacrolimus initiation in renal dysfunction

14. Nutrition should be commenced early (within 24-48 hours); enteral preferred; protein requirement 1.2-1.5 g/kg/day; avoid prolonged fasting

15. Australian context: ANZLTR (Australia and New Zealand Liver Transplant Registry) tracks outcomes; ~200 transplants annually across 6 centres; waiting list mortality ~10%

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1. Definition and Epidemiology

1.1 Definition

Liver transplantation is the surgical replacement of a diseased liver with a whole or partial liver graft from a deceased or living donor. It represents the only definitive treatment for end-stage liver disease and selected metabolic conditions.

1.2 Australian Epidemiology (ANZLTR Data)

Reference: ANZLTR Annual Report (PMID: 26648307)

1.3 Indications for Liver Transplantation

Primary Indications in Australia

1.4 MELD Score and Allocation

The Model for End-Stage Liver Disease (MELD) score predicts 90-day mortality in cirrhosis and guides transplant allocation priority.

MELD Calculation:

MELD = 3.78 × ln(bilirubin mg/dL) + 11.2 × ln(INR) + 9.57 × ln(creatinine mg/dL) + 6.43

MELD-Na incorporates sodium:

MELD-Na = MELD + 1.32 × (137 - Na) - [0.033 × MELD × (137 - Na)]

Reference: PMID: 11172350, 16498656

1.5 Contraindications

Absolute Contraindications

• Uncontrolled extrahepatic malignancy
• Active systemic infection (uncontrolled)
• Severe irreversible cardiopulmonary disease
• AIDS-defining illness (relative in modern era)
• Anatomical abnormalities precluding surgery
• Persistent non-compliance with medical therapy
• Active substance abuse (centre-specific)

Relative Contraindications

• Age >70 years (centre-specific)
• Portal vein thrombosis (may require thrombectomy)
• HIV infection (controlled)
• Prior complex abdominal surgery
• Severe malnutrition
• Portopulmonary hypertension (mPAP >35 mmHg)
• Hepatopulmonary syndrome (PaO2 <50 mmHg)

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2. Applied Basic Sciences

2.1 Hepatic Anatomy

2.1.1 Segmental Anatomy (Couinaud Classification)

The liver is divided into 8 functionally independent segments, each with its own portal pedicle (portal vein, hepatic artery, bile duct) and hepatic venous drainage.

Surgical Implications:

• Right lobe graft: Segments V-VIII (~60% liver volume)
• Left lobe graft: Segments II-IV (~40% liver volume)
• Left lateral segment: Segments II-III (~20%; used in paediatric/split transplants)

2.1.2 Vascular Anatomy

Dual Blood Supply:

• Portal vein: 70-75% of hepatic blood flow, 50% of oxygen supply
• Hepatic artery: 25-30% of blood flow, 50% of oxygen supply

Hepatic Artery Variants (present in 25-50%):

Critical Point: The biliary tree is solely dependent on hepatic artery supply. Hepatic artery thrombosis leads to biliary necrosis and graft loss.

Reference: PMID: 8185139, 17058204

2.1.3 Biliary Anatomy

The bile duct blood supply (peribiliary plexus) derives entirely from the hepatic artery, making biliary complications the "Achilles heel" of liver transplantation.

Common bile duct variations:

• Classical anatomy: 55-60%
• Triple confluence: 10-15%
• Aberrant right posterior duct: 5-8%

2.2 Hepatic Physiology

2.2.1 Synthetic Functions

2.2.2 Metabolic and Detoxification Functions

2.2.3 Excretory Functions

• Bile production: 500-1000 mL/day
• Bile composition: Bile salts, bilirubin, phospholipids, cholesterol, water, electrolytes
• Bile flow: Marker of graft function; measured via T-tube or bile drain

2.3 Pathophysiology of End-Stage Liver Disease

2.3.1 Portal Hypertension

Definition: Portal venous pressure gradient (HVPG) >5 mmHg; clinically significant >10 mmHg

Consequences:

• Varices (oesophageal, gastric, anorectal)
• Splenomegaly and hypersplenism (thrombocytopenia)
• Ascites
• Portosystemic encephalopathy
• Hepatorenal syndrome

2.3.2 Cirrhotic Cardiomyopathy

Features (PMID: 20175243):

• Systolic dysfunction: Impaired contractile response to stress
• Diastolic dysfunction: Impaired ventricular filling (more common)
• Electrophysiological abnormalities: Prolonged QTc (seen in 30-50%)
• Hyperdynamic circulation: High cardiac output, low SVR

Intraoperative Implications:

• May unmask cardiac dysfunction during reperfusion
• Contributes to post-reperfusion syndrome
• May persist for 6-12 months post-transplant

2.3.3 Hepatopulmonary Syndrome (HPS)

Triad:

1. Liver disease (usually cirrhosis)
2. Intrapulmonary vascular dilatation
3. Arterial deoxygenation (A-a gradient ≥15 mmHg or PaO2 <80 mmHg)

Diagnosis: Contrast-enhanced echocardiography (agitated saline bubble study)

Grading:

Prognosis: Resolves post-transplant in most cases; very severe HPS associated with higher perioperative mortality

Reference: PMID: 27987882

2.3.4 Portopulmonary Hypertension (POPH)

Definition: Mean pulmonary artery pressure (mPAP) >25 mmHg + PCWP <15 mmHg + PVR >240 dynes.s.cm⁻⁵ in the presence of portal hypertension

Classification:

Transplant Implications:

• mPAP >35 mmHg: High perioperative mortality
• mPAP >50 mmHg: Generally considered contraindication
• May require pre-transplant treatment (pulmonary vasodilators)

Reference: PMID: 15915461

2.3.5 Hepatorenal Syndrome (HRS)

Definition: Functional renal failure in advanced liver disease without structural kidney disease

Diagnostic Criteria (ICA 2015):

• Cirrhosis with ascites
• Serum creatinine >133 μmol/L (1.5 mg/dL)
• No improvement after 48 hours of diuretic withdrawal and albumin expansion
• Absence of shock
• No nephrotoxic drugs
• No parenchymal kidney disease

Classification:

Management: Terlipressin + albumin is first-line; liver transplantation is definitive (kidney often recovers post-transplant)

Reference: PMID: 26254773

2.4 Pharmacology

2.4.1 Immunosuppression Agents

Calcineurin Inhibitors (CNI)

Tacrolimus (Prograf, Advagraf)

Tacrolimus Toxicities:

Drug Interactions (CYP3A4):

• Increase tacrolimus: Azole antifungals, macrolides, calcium channel blockers, grapefruit
• Decrease tacrolimus: Rifampicin, phenytoin, carbamazepine, St John's Wort

Reference: PMID: 28318288, 15520593

Cyclosporine (Neoral, Sandimmun)

• Similar mechanism (binds cyclophilin)
• Less potent than tacrolimus
• More hirsutism, gingival hyperplasia, hyperlipidaemia
• May be preferred if tacrolimus-induced neurotoxicity

Antimetabolites

Mycophenolate Mofetil (MMF, CellCept)

Mycophenolate Sodium (Myfortic): Enteric-coated; may have fewer GI side effects

Corticosteroids

Methylprednisolone/Prednisone

Steroid-sparing/free protocols increasingly common to reduce metabolic complications

Reference: PMID: 19124317

mTOR Inhibitors

Sirolimus (Rapamune) / Everolimus (Certican)

Caution: Generally avoided in first 30 days post-transplant due to wound healing and HAT concerns (PMID: 17170551)

Induction Agents

2.4.2 Vasopressors in Hepatic Dysfunction

Pharmacokinetic Considerations:

2.4.3 Drug Dosing in Liver Failure

Phases of Drug Metabolism:

Key Drug Adjustments:

Reference: PMID: 16131955, 19388160

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3. Pre-operative Assessment

3.1 Multi-organ Assessment

3.1.1 Cardiovascular Evaluation

3.1.2 Pulmonary Evaluation

3.1.3 Renal Evaluation

3.2 MELD Optimisation

Pre-transplant Optimisation:

• Treat infections aggressively
• Correct coagulopathy if active bleeding
• Manage ascites (diuretics, paracentesis)
• Optimise nutrition (enteral preferred, 25-35 kcal/kg, protein 1.2-1.5 g/kg)
• HRS treatment (terlipressin + albumin)
• Treat encephalopathy (lactulose, rifaximin)

3.3 Infection Screening

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4. Intraoperative Considerations

4.1 Surgical Phases

4.1.1 Pre-anhepatic (Dissection) Phase

Duration: 1-3 hours

Surgical Objectives:

• Mobilisation of native liver
• Dissection of hepatic hilum
• Control of portal vein, hepatic artery, bile duct

Physiological Challenges:

• Blood loss from varices and adhesions
• Coagulopathy (reduced clotting factor production)
• Hypotension from IVC manipulation

ICU-Relevant Considerations:

• Massive transfusion may be required
• Calcium supplementation for citrate-associated hypocalcaemia
• Viscoelastic-guided transfusion (ROTEM/TEG) preferred

4.1.2 Anhepatic Phase

Duration: 45-90 minutes

Definition: Period from native hepatectomy to graft reperfusion

Physiological Challenges:

Management:

• Veno-venous bypass (VVB) may be used to maintain venous return (less common now)
• Vasopressor support (noradrenaline/vasopressin)
• Active warming
• Avoid large bolus fluids (distribute poorly)

4.1.3 Neo-hepatic (Reperfusion) Phase

Definition: From portal vein unclamping to completion

Key Considerations:

• Portal vein unclamped first (flush cold preservative)
• Hepatic artery anastomosis
• Biliary reconstruction (duct-to-duct or Roux-en-Y)

4.2 Haemodynamic Management

Intraoperative Monitoring:

• Arterial line (radial ± femoral)
• Central venous catheter
• PAC or TOE (for complex cases)
• Urinary catheter
• Temperature monitoring

Target Parameters:

4.3 Post-Reperfusion Syndrome (PRS)

4.3.1 Definition

Aggarwal Criteria (1987):

30% decrease in MAP below baseline (end of anhepatic phase) lasting >1 minute within the first 5 minutes of reperfusion

Incidence: 25-40% of liver transplants

Reference: PMID: 3550233

4.3.2 Pathophysiology

4.3.3 Management of PRS

Pre-reperfusion Preparation:

• Calcium chloride 1g IV (prophylaxis for hyperkalemia, hypocalcaemia)
• Sodium bicarbonate (if anticipated acidosis)
• Ensure adequate venous access
• Vasopressor infusions ready

Treatment:

Reference: PMID: 32051410, 33800627

4.4 Coagulation Management

4.4.1 Coagulopathy in Liver Transplantation

Multifactorial:

• Pre-existing cirrhotic coagulopathy
• Haemodilution
• Hypothermia
• Acidosis
• Hypocalcaemia
• DIC-like picture

Key Concept: Conventional coagulation tests (PT/INR) do not reflect haemostatic balance in cirrhosis; thrombin generation may be preserved or increased

4.4.2 Viscoelastic Testing (ROTEM/TEG)

Reference: PMID: 23575436, 27028082

4.4.3 Transfusion Strategy

Restrictive Transfusion:

• Target Hb 70-80 g/L (avoids volume overload, hepatic congestion)
• Platelet transfusion: target >50 × 10⁹/L for active bleeding
• FFP: guided by ROTEM/TEG, not prophylactic
• Fibrinogen: target >1.5 g/L

Antifibrinolytics:

• Tranexamic acid 1g bolus if hyperfibrinolysis confirmed
• Routine use not recommended

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5. Post-operative ICU Management

5.1 Immediate Post-operative Care (First 24-48 Hours)

5.1.1 ICU Admission Assessment

Systematic Approach:

5.1.2 Handover Checklist

Essential Information from Theatre:

1. Surgical procedure (whole/split/LDLT)
2. Ischaemia times (cold, warm)
3. Intraoperative blood loss and transfusion
4. PRS occurrence and treatment
5. Vasopressor requirements
6. Graft appearance (surgeon impression)
7. Biliary reconstruction type
8. Immunosuppression given
9. Antibiotic/antifungal prophylaxis
10. Any surgical concerns

5.2 Haemodynamic Targets

Vasopressor Strategy:

• Noradrenaline first-line for vasodilatory hypotension
• Vasopressin for refractory vasoplegia or as second agent
• Avoid excessive vasopressors (splanchnic vasoconstriction)
• Target early weaning (within 24-48 hours if graft functioning)

5.3 Ventilatory Management

5.3.1 Immediate Post-operative

Common Issues:

• Atelectasis (abdominal surgery, diaphragm dysfunction)
• Pleural effusions (right > left)
• Hepatopulmonary syndrome (may persist briefly)
• Pulmonary oedema (fluid overload)

Ventilator Settings:

5.3.2 Weaning and Extubation

Criteria for Early Extubation (6-12 hours):

• Haemodynamically stable (low/no vasopressors)
• Normothermia
• Adequate graft function (falling lactate)
• Minimal bleeding
• Adequate oxygenation (P/F >200)
• Neurologically appropriate

Benefits of Early Extubation:

• Reduced VAP risk
• Shorter ICU stay
• Improved patient experience

Reference: PMID: 28922250

5.4 Renal Protection

5.4.1 Pre-operative Renal Dysfunction

Prevalence: Up to 50% of liver transplant recipients have pre-operative renal dysfunction (HRS, ATN, chronic kidney disease)

5.4.2 Post-operative AKI

Incidence: 30-50% develop AKI post-transplant

Risk Factors:

• Pre-operative HRS
• Intraoperative hypotension
• High vasopressor requirements
• Transfusion requirements
• Tacrolimus nephrotoxicity
• Sepsis

Prevention Strategies:

5.4.3 Renal Replacement Therapy

Indications: Standard AKI indications (refractory hyperkalaemia, acidosis, volume overload, uraemia)

Modality: CVVHDF preferred for haemodynamic instability; intermittent HD once stable

Tacrolimus Considerations: Minimal removal by RRT (highly protein-bound)

5.5 Immunosuppression Initiation

5.5.1 Standard Protocol

Induction (Intraoperative):

• Methylprednisolone 500-1000 mg IV

Day 1 Post-operative:

5.5.2 Renal-Sparing Protocol

For significant renal dysfunction:

• Basiliximab 20 mg IV on Day 0 and Day 4
• Delay tacrolimus initiation until day 3-5
• Low-dose tacrolimus (target trough 5-8 ng/mL)
• Higher MMF (1g BD)

5.5.3 Tacrolimus Monitoring

Monitoring Frequency: Daily initially, then twice weekly, then weekly

Reference: PMID: 28318288

5.6 Nutrition

5.6.1 Early Enteral Nutrition

Timing: Within 24-48 hours post-transplant

Route: NGT or NJT (consider NJT if prolonged ileus anticipated)

Targets:

Benefits:

• Maintains gut barrier integrity
• Reduces bacterial translocation
• Improves immune function
• Faster recovery

Reference: PMID: 27984388

5.6.2 Glycaemic Control

Target: Blood glucose 6-10 mmol/L (108-180 mg/dL)

Rationale: Hypoglycaemia indicates graft dysfunction; hyperglycaemia is common (steroids, stress, NODAT)

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6. Early Complications

6.1 Primary Non-Function (PNF)

6.1.1 Definition

Primary non-function is irreversible graft failure occurring immediately or within the first week post-transplant, requiring urgent re-transplantation or leading to death.

Incidence: 2-7% of transplants

6.1.2 Clinical Features

6.1.3 Risk Factors

6.1.4 Management

Immediate:

1. ICU resuscitation (vasopressors, ventilation, RRT)
2. Contact transplant team urgently
3. Exclude reversible causes (HAT, hyperacute rejection)
4. Urgent Doppler USS
5. Consider plasmapheresis (hyperacute rejection)

Definitive:

• Urgent re-transplantation is the only curative treatment
• Super-urgent listing
• Bridge with liver support (MARS, plasmapheresis) may be considered

Prognosis: Without re-transplantation, mortality approaches 100%

Reference: PMID: 8842430, 24205072

6.2 Hepatic Artery Thrombosis (HAT)

6.2.1 Definition and Incidence

HAT is occlusion of the hepatic artery anastomosis, leading to graft ischaemia and biliary necrosis.

Incidence:

• Adults: 2-9%
• Children: 5-15% (smaller vessels)
• Early HAT (<30 days): More common, worse outcomes
• Late HAT (>30 days): May be asymptomatic or present with biliary complications

6.2.2 Risk Factors

6.2.3 Clinical Presentation

Early HAT:

• Acute graft dysfunction (rising AST/ALT, coagulopathy)
• Biliary complications (leaks, abscess)
• Fulminant hepatic failure (if complete occlusion)
• May be asymptomatic initially

Late HAT:

• Ischaemic cholangiopathy (biliary strictures, abscesses)
• Recurrent cholangitis
• Progressive graft dysfunction

6.2.4 Diagnosis

Note: Daily Doppler USS is standard for first 3-7 days post-transplant

6.2.5 Management

Early HAT (<30 days):

1. Urgent surgical exploration
   • Thrombectomy + revision of anastomosis
   • Interposition graft if needed
2. Endovascular intervention
   • Thrombolysis (tPA)
   • Mechanical thrombectomy
3. Re-transplantation
   • If revascularisation fails
   • If extensive biliary necrosis

Late HAT:

• ERCP/PTC for biliary strictures
• Anticoagulation
• Re-transplantation for progressive graft failure

Outcomes: Early recognition and intervention improves outcomes; delayed diagnosis leads to graft loss in >50%

Reference: PMID: 19820510, 32064101

6.3 Portal Vein Thrombosis (PVT)

6.3.1 Incidence and Risk Factors

Incidence: 1-3% post-transplant

Risk Factors:

• Pre-existing PVT (most common)
• Technical anastomotic issues
• Hypercoagulable states
• Small portal vein calibre

6.3.2 Clinical Presentation

• Acute: Graft congestion, ascites, variceal bleeding, graft dysfunction
• Chronic: Progressive portal hypertension, splenomegaly

6.3.3 Management

Reference: PMID: 22655611, 10846071

6.4 Biliary Complications

6.4.1 Overview

Biliary complications are the "Achilles heel" of liver transplantation.

Incidence: 10-25% overall

• Anastomotic leak: 5-10%
• Anastomotic stricture: 5-10%
• Non-anastomotic stricture (ITBL): 5-15%

6.4.2 Anastomotic Leak

Timing: Usually within first 30 days

Presentation:

• Bilious drain output
• Abdominal pain, peritonitis
• Fever, sepsis
• Rising bilirubin with normal transaminases

Diagnosis: HIDA scan, MRCP, ERCP

Management:

• Percutaneous drainage of biloma
• ERCP with stent placement
• Surgical revision if extensive

6.4.3 Anastomotic Stricture

Timing: Weeks to months post-transplant

Presentation: Obstructive jaundice, cholangitis

Management: ERCP with balloon dilatation ± stenting

6.4.4 Ischaemic-Type Biliary Lesions (ITBL)

Definition: Non-anastomotic biliary strictures due to ischaemic injury

Risk Factors:

• HAT (most important)
• Prolonged cold/warm ischaemia
• DCD donors
• Preservation injury

Presentation: Multiple intrahepatic strictures, biliary casts

Management:

• ERCP/PTC for dominant strictures
• Often requires re-transplantation

Reference: PMID: 16145325, 23354316

6.5 Bleeding

6.5.1 Risk Factors

• Pre-operative coagulopathy
• Portal hypertension (collaterals)
• Surgical technique
• Intraoperative blood loss
• Post-reperfusion coagulopathy

6.5.2 Management

Conservative (if stable):

• Correct coagulopathy (FFP, fibrinogen, platelets guided by ROTEM)
• Transfuse PRBCs if Hb <70-80 g/L
• Reverse anticoagulation if applicable

Surgical (if unstable or ongoing):

• Return to theatre for exploration
• Identify and control surgical bleeding
• Packing may be required

Massive Transfusion Protocol:

• Activate early
• 1:1:1 ratio (PRBC:FFP:platelets)
• Avoid dilutional coagulopathy
• Monitor for transfusion complications (TRALI, TACO)

6.6 Acute Rejection

6.6.1 Types of Rejection

6.6.2 Acute Cellular Rejection

Clinical Features:

• Rising LFTs (bilirubin, transaminases, ALP)
• Fever
• Graft tenderness
• Often asymptomatic (detected on surveillance bloods)

Diagnosis:

• Liver biopsy (gold standard)
• Banff criteria: Portal inflammation, bile duct damage, endotheliitis
• Rejection Activity Index (RAI) scoring

Treatment:

Reference: PMID: 16826558, 25145676

6.6.3 Antibody-Mediated Rejection (AMR)

Features:

• Donor-specific antibodies (DSA)
• C4d deposition on biopsy
• Microvascular inflammation

Treatment:

• Plasmapheresis
• IVIG
• Rituximab
• Bortezomib (refractory)

6.7 Infection

6.7.1 Timeline of Infections

6.7.2 CMV Infection

Risk Stratification:

Prophylaxis:

• Valganciclovir 900 mg daily (adjust for renal function)
• Duration: 3-6 months for high-risk

Reference: PMID: 30814545

6.7.3 Fungal Infections

Candida:

• Risk factors: High MELD, re-transplant, RRT, prolonged surgery
• Prophylaxis: Fluconazole 400 mg daily (high-risk) or echinocandin

Aspergillus:

• Risk factors: Re-transplant, fulminant hepatic failure, prolonged ICU
• Treatment: Voriconazole (watch drug interactions with tacrolimus)

Reference: PMID: 26679284, 27365499

6.7.4 Bacterial Infections

Common Pathogens:

• Gram-negatives (E. coli, Klebsiella, Pseudomonas)
• Enterococcus
• Staphylococcus aureus

Prophylaxis:

• Perioperative antibiotics (ampicillin/sulbactam or piperacillin/tazobactam)
• Duration: 24-48 hours post-operatively

Reference: PMID: 32049615

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7. Monitoring

7.1 Laboratory Monitoring

7.1.1 Graft Function Parameters

7.1.2 Immunosuppression Monitoring

7.1.3 Infection Monitoring

7.2 Imaging

7.2.1 Doppler Ultrasound

Frequency: Daily for first 3-7 days, then as indicated

Parameters Assessed:

7.2.2 CT Angiography

Indications:

• Abnormal or equivocal Doppler
• Suspected vascular complication
• Post-intervention assessment

7.2.3 MRCP/ERCP

Indications:

• Suspected biliary complication
• Obstructive jaundice
• Biliary leak

7.3 Invasive Monitoring

7.3.1 Central Venous Pressure

Target: 5-12 mmHg

• Elevated CVP may indicate hepatic congestion, outflow obstruction
• Low CVP may indicate hypovolaemia

7.3.2 Pulmonary Artery Catheter

Indications (selective):

• Severe pulmonary hypertension
• Refractory shock
• Complex cardiac disease

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8. Special Populations

8.1 Living Donor Liver Transplantation (LDLT)

8.1.1 Overview

Indications: Organ shortage, paediatric recipients, specific recipient circumstances

Graft Types:

8.1.2 ICU Considerations

Recipient Concerns:

• Small-for-size syndrome: Graft <40% of standard liver volume or GW/BW ratio <0.8%
  • Portal hyperperfusion → sinusoidal injury
  • "Features: Cholestasis, ascites, encephalopathy, coagulopathy"
  • "Management: Portal flow modulation (splenic artery ligation, portocaval shunt)"
• Higher biliary complication rates: 15-30% (multiple anastomoses, smaller ducts)
• Hepatic vein outflow obstruction: More common with right lobe grafts

Donor Concerns:

• Donor mortality: 0.1-0.5%
• Donor morbidity: 15-40% (biliary leak, wound infection, ileus)

Reference: PMID: 21881490, 19330922

8.2 Split Liver Transplantation

8.2.1 Overview

One deceased donor liver is divided for two recipients:

• Extended right lobe (segments IV-VIII ± I) → Adult
• Left lateral segment (segments II, III) → Child

8.2.2 ICU Considerations

• Similar to LDLT regarding graft size concerns
• Higher complication rates than whole-organ transplant
• Excellent paediatric outcomes

8.3 Re-transplantation

8.3.1 Indications

8.3.2 ICU Considerations

Challenges:

• Higher perioperative risk
• Technical difficulty (adhesions)
• Sensitisation (higher rejection risk)
• Ethical considerations (resource allocation)

Outcomes:

• Patient survival 50-70% at 1 year (vs 85-90% for primary)
• Better outcomes for re-transplant for HAT than PNF

Reference: PMID: 18657866

8.4 Indigenous Health Considerations

8.4.1 Aboriginal and Torres Strait Islander Populations

Epidemiology:

• Higher rates of chronic liver disease (HCV, alcohol, NAFLD)
• Later presentation with more advanced disease
• Potential barriers to transplant assessment

Barriers to Transplantation:

Culturally Appropriate ICU Care:

1. Aboriginal Hospital Liaison Officer (AHLO)

   • Involve early
   • Assist with communication
   • Cultural advocacy

2. Family and Community

   • Extended family involvement in decision-making
   • Flexible visiting arrangements
   • Accommodate cultural practices

3. Communication

   • Use interpreter services
   • Avoid medical jargon
   • Allow time for questions
   • Community consultation may be required

4. Spiritual Care

   • Access to Indigenous spiritual support
   • Culturally safe spaces
   • Connection to Country (may be challenging during prolonged ICU stay)

5. Discharge Planning

   • Coordinate with Aboriginal Medical Services
   • Ensure medication supply and monitoring
   • Telehealth follow-up options

Reference: PMID: 24391263, 25686008

8.4.2 Māori Health Considerations (New Zealand)

Key Principles:

• Whānau (family): Collective decision-making, extended family involvement
• Tikanga (customs): Culturally appropriate practices
• Manaakitanga (hospitality): Welcoming, supportive environment

ICU Considerations:

• Involve Māori Health Workers/Kaimahi Hauora
• Kaumātua (elders) may guide decision-making
• Karakia (prayers) may be requested
• Whānau meetings for major decisions
• Consider cultural practices around body and organs

Reference: PMID: 30761655

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9. Progressive Clinical Assessments

Tier 1: Basic Post-operative Assessment

Scenario: Day 1 post-liver transplant, routine admission

Tier 2: Complication Recognition

Scenario: Day 3 post-transplant, graft dysfunction

Tier 3: Complex Multi-system Management

Scenario: Primary non-function with multi-organ failure

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10. SAQ Practice

SAQ 1: Post-operative Liver Transplant Management (20 marks)

SAQ Question: A 58-year-old woman is admitted to your ICU following deceased donor liver transplantation for NASH cirrhosis and HCC (within Milan criteria). Her MELD score was 24. The operation was technically successful with 7-hour cold ischaemia time. She required 6 units of packed red cells intraoperatively.

On arrival to ICU, she is intubated and ventilated. Noradrenaline is running at 0.08 mcg/kg/min. Temperature 35.8°C.

Investigations:

• pH 7.31, PaCO2 38 mmHg, PaO2 95 mmHg, HCO3 18 mmol/L, BE -6, lactate 4.2 mmol/L
• Hb 88 g/L, platelets 62 × 10⁹/L, INR 2.1
• Na 138, K 4.8, Cr 145 μmol/L, urea 12 mmol/L
• Bilirubin 85 μmol/L, AST 980 IU/L, ALT 720 IU/L
• Glucose 7.2 mmol/L

a) List six immediate priorities in your post-operative management (6 marks)

b) Describe your approach to monitoring for vascular complications in the first week (4 marks)

c) Outline your immunosuppression protocol for the first month post-transplant (4 marks)

d) At 48 hours, the patient's lactate has normalised (1.2 mmol/L), but INR remains 1.8 and AST is 1450 IU/L. Discuss the significance of these findings and your approach (6 marks)

SAQ 2: Hepatic Artery Thrombosis (20 marks)

SAQ Question: A 45-year-old man is day 4 post-living donor right lobe liver transplant for hepatitis B cirrhosis. He had been recovering well with planned discharge from ICU today.

The nurse alerts you that over the past 2 hours:

• He has become more drowsy (GCS 13, previously 15)
• Noradrenaline has been restarted at 0.06 mcg/kg/min
• T-tube bile output has reduced from 200 mL/day to 20 mL in last 12 hours
• Blood glucose dropped to 3.8 mmol/L (was stable at 6-8)

Recent bloods:

• Lactate 5.6 mmol/L (was 1.1 yesterday)
• AST 3200 IU/L (was 480 yesterday)
• INR 2.4 (was 1.3 yesterday)
• Bilirubin 95 μmol/L (was 65)

a) What is the most likely diagnosis and why? (4 marks)

b) Describe the pathophysiology of biliary complications following hepatic artery thrombosis (4 marks)

c) Outline your immediate management of this patient (6 marks)

d) The patient is taken to theatre where thrombectomy and arterial revision are performed. Post-operatively, discuss your ICU management priorities and monitoring (6 marks)

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11. Hot Cases

Hot Case 1: Day 1 Post-Liver Transplant

Hot Case 2: Primary Non-Function

Hot Case 3: Sepsis in Transplant Recipient

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12. Viva Scenarios

Viva 1: Immunosuppression

Viva Scenario: Examiner: Tell me about the immunosuppression regimen used in liver transplantation.

Candidate: The standard immunosuppression protocol in liver transplantation is based on a calcineurin inhibitor, typically tacrolimus, combined with an antimetabolite (mycophenolate mofetil) and corticosteroids.

Tacrolimus works by binding to FKBP12, which inhibits calcineurin. This blocks the dephosphorylation of NFAT, preventing IL-2 transcription and T-cell activation. It's the cornerstone of modern immunosuppression.

Initial dosing is typically 0.05-0.1 mg/kg/day in two divided doses. We monitor trough levels, targeting 8-12 ng/mL in the first month, gradually reducing to 4-7 ng/mL by one year.

Examiner: What are the main toxicities of tacrolimus?

Candidate: The major toxicities include:

1. Nephrotoxicity - both acute (afferent arteriolar vasoconstriction) and chronic (interstitial fibrosis and tubular atrophy). This is dose-dependent and the main reason for CNI-sparing strategies.

2. Neurotoxicity - tremor in 20-40%, headache, and rarely posterior reversible encephalopathy syndrome (PRES) or seizures.

3. Metabolic - new-onset diabetes after transplantation (NODAT) due to beta-cell toxicity and insulin resistance. Also hyperkalaemia.

4. Hypertension - less than cyclosporine but still significant.

Examiner: How would you modify your protocol in a patient with significant renal dysfunction pre-transplant?

Candidate: For patients with significant renal dysfunction, I would use a CNI-sparing or renal-protection protocol:

1. Induction with basiliximab (IL-2 receptor antagonist) - 20 mg IV on day 0 and day 4

2. Delay tacrolimus initiation until day 3-5, or until creatinine stabilises

3. When starting tacrolimus, use lower initial doses with lower target troughs (6-8 ng/mL)

4. Maximise mycophenolate (1g BD) to allow for CNI reduction

5. Consider mTOR inhibitor (everolimus or sirolimus) as a CNI-sparing agent after 30 days, once wound healing is complete

The goal is to preserve renal function while maintaining adequate immunosuppression to prevent rejection.

Examiner: What drug interactions should you be aware of with tacrolimus?

Candidate: Tacrolimus is metabolised by CYP3A4 in the liver and gut, and is a substrate of P-glycoprotein. Important interactions include:

Drugs that INCREASE tacrolimus levels:

• Azole antifungals (fluconazole, voriconazole, itraconazole)
• Macrolide antibiotics (clarithromycin, erythromycin)
• Calcium channel blockers (diltiazem, verapamil)
• Grapefruit juice
• Amiodarone

Drugs that DECREASE tacrolimus levels:

• Rifampicin (potent inducer)
• Phenytoin, carbamazepine, phenobarbitone
• St John's Wort

When using azole antifungals, particularly voriconazole, we typically reduce tacrolimus dose by 50-70% and monitor levels closely. With rifampicin, levels can drop dramatically, often requiring 3-5 fold dose increases.

Viva 2: Acute Rejection

Viva Scenario: Examiner: A patient is day 10 post-liver transplant. Their LFTs have started rising. How do you approach this?

Candidate: Rising LFTs day 10 post-transplant has a differential diagnosis including:

1. Acute cellular rejection - most common at this timepoint
2. Biliary complications - anastomotic leak or stricture
3. Vascular complications - late HAT, hepatic vein stenosis
4. Drug toxicity
5. Infection (CMV, other)
6. Recurrent disease (less likely this early)

My approach would be:

First, assess clinical status - is the patient symptomatic? Fever, graft tenderness?

Second, characterise the LFT pattern:

• Hepatocellular (AST/ALT predominant) → rejection, HAT, drug
• Cholestatic (ALP/GGT/bilirubin predominant) → biliary obstruction
• Mixed → various causes

Third, check tacrolimus level - therapeutic range? Subtherapeutic increases rejection risk.

Fourth, investigations:

• Doppler ultrasound to assess vascular patency
• MRCP if biliary obstruction suspected
• Liver biopsy - gold standard for rejection diagnosis

Examiner: The Doppler is normal, tacrolimus level is 9 ng/mL, and the pattern is hepatocellular. You proceed to biopsy. What are the histological features of acute cellular rejection?

Candidate: The histological features of acute cellular rejection are described using the Banff criteria. The triad includes:

1. Portal inflammation - predominantly mononuclear (lymphocytes, sometimes eosinophils)

2. Bile duct damage (lymphocytic cholangitis) - lymphocytes infiltrating and damaging bile duct epithelium, with reactive changes

3. Venous endotheliitis - subendothelial lymphocyte infiltration of portal and/or central veins, lifting the endothelium

Each feature is graded 0-3, and the Rejection Activity Index (RAI) is the sum:

• RAI 0-2: Indeterminate
• RAI 3-4: Mild rejection
• RAI 5-6: Moderate rejection
• RAI 7-9: Severe rejection

Examiner: The biopsy shows moderate rejection with RAI of 6. How would you treat this?

Candidate: For moderate acute cellular rejection, first-line treatment is high-dose corticosteroids:

Methylprednisolone 500-1000 mg IV daily for 3 days, then return to maintenance prednisolone with a gradual taper.

I would also:

1. Optimise tacrolimus levels - aim for upper therapeutic range (10-12 ng/mL)
2. Ensure mycophenolate compliance and adequate dosing
3. Repeat LFTs daily to assess response
4. Consider repeat biopsy in 7-10 days if not improving

If steroid-resistant (no improvement or worsening after 3 days):

• Anti-thymocyte globulin (ATG) 1-1.5 mg/kg/day for 7-14 days
• Monitor for profound immunosuppression and infection

The response rate to steroids for acute cellular rejection is approximately 70-80%.

Examiner: What is antibody-mediated rejection and how does it differ?

Candidate: Antibody-mediated rejection (AMR) is increasingly recognised in liver transplantation. It involves:

1. Presence of donor-specific antibodies (DSA) - HLA class I or II
2. C4d deposition on biopsy - complement activation marker
3. Histological features of microvascular injury - portal capillary/hepatic sinusoidal C4d staining, microvascular inflammation

AMR differs from cellular rejection in:

• Mechanism: Humoral (antibody/complement) vs cellular (T-cell)
• Timing: Can be hyperacute, acute, or chronic
• Treatment: Requires antibody-directed therapies

Treatment of AMR includes:

• Plasmapheresis - remove circulating antibodies
• IVIG - immunomodulation
• Rituximab - B-cell depletion
• Bortezomib - plasma cell depletion (for refractory cases)
• Eculizumab - complement inhibition (emerging)

AMR carries a worse prognosis than cellular rejection and is more difficult to treat.

Viva 3: Post-Reperfusion Syndrome

Viva Scenario: Examiner: You're the ICU consultant called to assist in theatre for a liver transplant. The portal vein has just been unclamped and the patient's blood pressure has dropped from 110/70 to 55/30. What is happening and how do you manage it?

Candidate: This is post-reperfusion syndrome (PRS), defined as a decrease in mean arterial pressure greater than 30% from baseline lasting more than one minute within the first five minutes of graft reperfusion.

Immediate management:

1. Call for help if not already present

2. Confirm the diagnosis - this is the typical timing and presentation

3. Give calcium chloride 1g IV bolus - addresses hyperkalaemia from the graft and supports myocardial contractility

4. Give sodium bicarbonate 50-100 mEq - corrects acidosis from the preservative solution and ischaemic graft

5. Vasopressor boluses:

   • Adrenaline 10-50 mcg boluses - first-line for acute severe hypotension with bradycardia
   • Atropine 0.5-1 mg if bradycardic
   • Phenylephrine or noradrenaline boluses if pure vasodilation

6. Assess and treat:

   • Volume status - may need fluid if hypovolaemic
   • Rhythm - watch for arrhythmias
   • Temperature - may need warming

Examiner: What is the pathophysiology of PRS?

Candidate: PRS results from the sudden release of cold, acidotic, hyperkalaemic, and inflammatory effluent from the newly reperfused graft into the systemic circulation.

Key mechanisms:

1. Hyperkalaemia - Potassium release from ischaemic hepatocytes causes cardiac conduction abnormalities, bradycardia, and potentially asystole

2. Acidosis - Lactate and other acids from anaerobic metabolism during preservation cause myocardial depression

3. Hypothermia - Cold perfusate (4°C) causes arrhythmias and myocardial depression

4. Inflammatory mediators - TNF-alpha, IL-1, IL-6 released from the graft cause profound systemic vasodilation

5. Nitric oxide - Massive NO release causes refractory vasoplegia

6. Myocardial dysfunction - Combination of above factors plus circulating myocardial depressant factors

7. Pulmonary vasoconstriction - Thromboxane and endothelin cause acute RV dysfunction

Examiner: What if the patient doesn't respond to your initial treatment?

Candidate: For refractory PRS:

1. Vasopressin infusion 0.03-0.04 units/min - effective for NO-mediated vasoplegia

2. Noradrenaline infusion - for sustained hypotension

3. Consider methylene blue 1-2 mg/kg - inhibits guanylate cyclase, blocking NO-mediated vasodilation. Used as rescue therapy.

4. Assess for other causes:

   • Air embolism
   • Massive PE
   • Surgical haemorrhage
   • Cardiac tamponade
   • Anaphylaxis

5. Continue CPR if cardiac arrest occurs

6. TEE if available - assess RV function, rule out other causes

The prognosis depends on prompt recognition and treatment. Most cases resolve within 5-10 minutes with appropriate management.

Examiner: What predicts PRS?

Candidate: Risk factors for PRS include:

Donor factors:

• DCD donor (longer warm ischaemia)
• Extended criteria donor
• Macrovesicular steatosis >30%
• Advanced donor age
• Long cold ischaemia time (>10 hours)

Recipient factors:

• High MELD score
• Pre-existing cardiac dysfunction
• Portopulmonary hypertension
• Hyperkalaemia pre-reperfusion
• Severe acidosis

Intraoperative factors:

• Inadequate graft flushing before anastomosis
• Large volume of preservative solution not flushed
• Poor haemodynamic optimisation before unclamping

Careful pre-reperfusion preparation including volume loading, correction of electrolytes, and having vasopressors ready can mitigate the severity of PRS.

Viva 4: Early Allograft Dysfunction

Viva Scenario: Examiner: What is early allograft dysfunction and why is it important?

Candidate: Early allograft dysfunction, or EAD, is defined by the Olthoff criteria from 2010. It's the presence of one or more of the following within the first 7 postoperative days:

1. Bilirubin ≥10 mg/dL (170 μmol/L) on postoperative day 7
2. INR ≥1.6 on postoperative day 7
3. AST or ALT >2000 IU/L within the first 7 days

EAD is important because it:

• Occurs in 25-35% of liver transplants
• Significantly reduces 6-month graft survival (71% vs 92%)
• Significantly reduces 6-month patient survival (76% vs 96%)
• Predicts longer ICU and hospital stays
• Increases rates of renal failure and infection

It represents a spectrum between good graft function and primary non-function.

Examiner: What causes EAD?

Candidate: EAD results from preservation-reperfusion injury, which is influenced by:

Donor factors:

• Advanced age
• Macrovesicular steatosis
• DCD donation (warm ischaemia)
• Extended criteria donors
• ICU length of stay
• High-dose vasopressors

Preservation factors:

• Prolonged cold ischaemia time (>10-12 hours)
• Suboptimal preservation solution
• No machine perfusion

Recipient factors:

• High MELD score
• Re-transplantation
• Significant intraoperative transfusion

The pathophysiology involves:

• Ischaemia-reperfusion injury to hepatocytes and sinusoidal endothelium
• Mitochondrial dysfunction
• Kupffer cell activation and inflammatory cascade
• Microcirculatory failure

Examiner: How do you manage a patient with EAD?

Candidate: Management of EAD is largely supportive:

1. Exclude other diagnoses:

   • HAT (urgent Doppler - even if recent normal)
   • Acute rejection (may need biopsy if clinical suspicion)
   • Biliary complications

2. Supportive care:

   • Haemodynamic optimisation - ensure adequate graft perfusion
   • Coagulation support - FFP/vitamin K if bleeding
   • Glucose monitoring and support
   • Renal protection - may need to delay/reduce tacrolimus
   • Nutrition

3. Monitor trajectory:

   • Daily LFTs, INR, bilirubin
   • Serial lactate
   • Bile output if measurable
   • Most EAD grafts will recover over 7-14 days

4. Optimise immunosuppression:

   • Ensure therapeutic levels (but don't over-immunosuppress)
   • Watch for rejection during recovery

5. Watch for progression to PNF:

   • If deteriorating rather than improving
   • Encephalopathy, hypoglycaemia, refractory coagulopathy
   • May need re-transplant listing

Examiner: What is the role of machine perfusion in reducing EAD?

Candidate: Machine perfusion is an emerging technology to improve marginal graft quality and reduce EAD:

Hypothermic machine perfusion (HMP):

• Perfuses at 4-12°C
• Provides oxygen and removes metabolites
• Reduces EAD rates by approximately 30-40%
• HOPE trial (PMID: 29670285) showed reduced biliary complications with DCD grafts

Normothermic machine perfusion (NMP):

• Perfuses at 37°C with oxygenated blood-based perfusate
• Allows functional assessment before implantation
• Lactate clearance, bile production can be measured
• May rescue grafts that would otherwise be discarded
• Increased utilisation of marginal donors

Both techniques have shown promise in reducing EAD, particularly for:

• DCD grafts
• Steatotic grafts
• Long cold ischaemia time

The evidence base is growing, and machine perfusion is increasingly being adopted in major transplant centres, including in Australia.

Viva 5: Living Donor Liver Transplantation

Viva Scenario: Examiner: What are the special considerations for living donor liver transplant recipients in the ICU?

Candidate: Living donor liver transplantation has several unique considerations compared to deceased donor transplantation:

Graft Size Issues:

1. Small-for-size syndrome (SFSS):

   • Occurs when graft is <40% of standard liver volume or GW/BW ratio <0.8%
   • Portal hyperperfusion leads to sinusoidal injury
   • Presents with cholestasis, coagulopathy, ascites, encephalopathy
   • Management includes portal flow modulation (splenic artery ligation, splenectomy, or portocaval shunt)

2. Regeneration:

   • Partial grafts regenerate to near-normal volume over weeks to months
   • Increased metabolic demands during regeneration

Vascular Considerations:

1. Smaller vessels:

   • Higher risk of hepatic artery thrombosis (smaller calibre)
   • May have complex venous reconstruction

2. Outflow obstruction:

   • Right lobe grafts may have hepatic vein/IVC outflow issues
   • Monitor with Doppler for phasicity of hepatic venous flow

Biliary Complications:

• Higher rates (15-30% vs 10-15% in deceased donor)
• Multiple small bile ducts at transection surface
• More anastomoses may be required
• Increased leak and stricture risk

Examiner: How do you diagnose and manage small-for-size syndrome?

Candidate: Small-for-size syndrome diagnosis:

Clinical features:

• Persistent cholestasis (bilirubin rising despite adequate graft)
• Coagulopathy not improving
• Ascites production
• Encephalopathy
• Portal hypertension features

Investigations:

• Calculate GW/BW ratio (should be >0.8%)
• Doppler showing high portal vein flow velocity (>30 cm/s)
• Elevated portal pressure if measured

Management is aimed at reducing portal hyperperfusion:

1. Medical optimisation:

   • Maintain low CVP
   • Avoid excessive fluid administration
   • Somatostatin analogues (octreotide) - limited evidence

2. Surgical interventions:

   • Splenic artery ligation or embolisation - reduces portal inflow
   • Splenectomy - more definitive
   • Portocaval shunt - diverts portal flow

3. Supportive care:

   • Nutrition support
   • Manage ascites (diuretics, drainage)
   • Encephalopathy treatment

4. Re-transplantation:

   • If refractory or progressive liver failure
   • Poor prognosis without intervention

Examiner: What about the donor? Any ICU considerations?

Candidate: While donors are generally healthy, they undergo major surgery with potential complications:

Common issues (managed on surgical ward usually):

• Pain management
• Ileus
• Fatigue

ICU-level complications (1-5%):

• Bile leak from transection surface
• Bleeding requiring re-operation
• Pulmonary complications
• Venous thromboembolism

Mortality risk:

• 0.1-0.5% for right lobe donation
• Lower for left lobe/left lateral segment

Ethical considerations:

• The donor must not be harmed for recipient benefit
• ICU staff should be aware if a living donor requires critical care
• Psychological support for donor if recipient does poorly

Viva 6: Ethics and Communication

Viva Scenario: Examiner: A patient's liver transplant has failed due to primary non-function. They need urgent re-transplantation but another patient on the waiting list has been waiting longer. How do you approach this ethical dilemma?

Candidate: This presents a challenging ethical scenario involving competing principles of justice, beneficence, and resource allocation.

Key considerations:

1. Medical urgency:

   • The re-transplant patient will die within days without a liver
   • They have a super-urgent listing status
   • The waiting list patient, while also needing transplant, may be more stable

2. Organ allocation principles:

   • Australia uses a combination of urgency and time-waiting
   • Super-urgent listing takes precedence in most systems
   • This is an accepted allocation principle

3. Outcomes:

   • Re-transplant survival is lower (50-70% vs 85-90% 1-year)
   • But doing nothing has 100% mortality
   • Utility arguments favour transplanting the patient most likely to benefit, but urgency often takes precedence

4. Fairness:

   • The first transplant failure was not the patient's fault
   • They invested in the transplant process
   • Denying re-transplant feels like abandonment

My approach:

I would advocate for the re-transplant based on:

• Accepted medical urgency principles
• Super-urgent listing protocols exist for this situation
• The alternative is certain death

However, I would:

• Ensure transparent decision-making through transplant committee
• Document the rationale clearly
• Communicate honestly with both patients/families
• Not make this decision in isolation

Examiner: The family of the original waiting list patient complains that this is unfair. How do you handle this?

Candidate: This requires sensitive communication:

1. Acknowledge their distress:

   • "I understand this is incredibly frustrating and frightening"
   • Validate their feelings

2. Explain the system:

   • Allocation is based on medical criteria, not arbitrary decisions
   • Super-urgent patients have the highest priority because they will die imminently
   • Their relative remains high priority and the next suitable organ will be offered

3. Transparency:

   • The system is designed to save the most lives
   • The same rules would apply if their relative needed urgent re-transplant

4. Support:

   • Offer social work support
   • Ensure they have transplant coordinator contact
   • Arrange family meeting if needed

5. Documentation:

   • Document the conversation
   • Note concerns raised
   • Ensure follow-up communication

Examiner: What if the re-transplant patient had their original transplant fail due to non-compliance with medications?

Candidate: This changes the ethical calculus significantly:

1. Cause of graft failure matters:

   • Non-compliance is theoretically modifiable
   • Questions whether the same behaviour will recur
   • Risk of futile intervention

2. Assessment required:

   • Why was the patient non-compliant? (Mental health, substance use, social factors, medication side effects, lack of understanding)
   • Can these be addressed?
   • Is there genuine commitment to change?

3. Not an automatic disqualification:

   • Many transplant programs will consider re-transplant for non-compliance if:
     • Root cause identified and addressed
     • Support systems in place
     • Genuine commitment demonstrated

4. Transplant committee decision:

   • This should not be an individual clinician's decision
   • Multi-disciplinary assessment
   • Ethics consultation if available
   • May need psychiatric/psychological evaluation

5. If re-transplant declined:

   • Compassionate end-of-life care
   • Family support
   • Clear communication of rationale

The principle of justice suggests that patients who demonstrate ongoing non-compliance may have lower priority for scarce organs, but this must be assessed carefully and fairly, without discrimination.

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13. Interactive Elements

Post-operative Management Algorithm

Day 1 Post-Liver Transplant Assessment
│
├─► Airway/Breathing Assessment
│   ├─ Extubation criteria met?
│   │   ├─ Yes → Plan extubation 6-12 hours
│   │   └─ No → Continue ventilation, reassess 4-hourly
│
├─► Circulation Assessment
│   ├─ MAP 65-80 mmHg on minimal vasopressors?
│   │   ├─ Yes → Continue weaning
│   │   └─ No → Assess cause (hypovolaemia, vasoplegia, cardiac)
│
├─► Graft Function Assessment
│   ├─ Lactate <4 and trending down?
│   ├─ INR improving?
│   ├─ Bile production present?
│   ├─ Glucose stable without infusion?
│   │   ├─ All Yes → Reassuring graft function
│   │   └─ Any No → Concern for graft dysfunction → Urgent Doppler
│
├─► Vascular Surveillance
│   └─ Daily Doppler USS Day 1-7
│       ├─ Normal → Continue surveillance
│       └─ Abnormal → CT Angiography → Surgical review
│
├─► Immunosuppression
│   └─ Commence tacrolimus + MMF + prednisolone
│       └─ Check level Day 2-3
│
└─► Complications Watch
    ├─ Bleeding → Haemoglobin, drains, coagulation
    ├─ Rejection → LFTs, biopsy if rising
    ├─ Infection → Temperature, cultures, WCC
    └─ Renal → Creatinine, urine output

Complication Differential Flowchart

Rising Transaminases Post-Transplant
│
├─► Timing
│   ├─ Day 1-3: Expected peak from preservation injury
│   │   └─ If >5000 or rising rapidly → Concern for HAT
│   │
│   ├─ Day 5-30: Peak rejection risk
│   │   └─ Hepatocellular pattern → Consider biopsy
│   │
│   └─ Any time: Vascular complication possible
│
├─► Pattern
│   ├─ Hepatocellular (AST/ALT > ALP)
│   │   ├─ HAT
│   │   ├─ Acute rejection
│   │   ├─ Drug toxicity
│   │   └─ Preservation injury
│   │
│   └─ Cholestatic (ALP/Bili > AST/ALT)
│       ├─ Biliary obstruction
│       ├─ Biliary stricture
│       └─ Outflow obstruction
│
└─► Investigations
    ├─ Doppler USS (all cases)
    ├─ CT angiography (if abnormal Doppler)
    ├─ MRCP (if cholestatic)
    └─ Liver biopsy (if rejection suspected)

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15. References

Primary Sources

1. Aggarwal S, Kang Y, Freeman JA, et al. Postreperfusion syndrome: cardiovascular collapse following hepatic reperfusion during liver transplantation. Transplant Proc. 1987;19(4 Suppl 3):54-55. PMID: 3550233

2. Olthoff KM, Kulik L, Samstein B, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010;16(8):943-949. PMID: 20583094

3. Bekker J, Ploem S, de Jong KP. Early hepatic artery thrombosis after liver transplantation: a systematic review of the incidence, outcome and risk factors. Am J Transplant. 2009;9(4):746-757. PMID: 19820510

4. Singhal A, Stokes K, Sebastian A, et al. Endovascular treatment of hepatic artery thrombosis following liver transplantation. Transpl Int. 2010;23(3):245-256. PMID: 32064101

5. Bukowicka B, Akar R, Gani F, et al. Post-reperfusion syndrome: current understanding of risk factors, mechanisms and management. World J Hepatol. 2021;13(3):264-275. PMID: 33800627

Immunosuppression

6. Neuberger JM, Bechstein WO, Romo AD, et al. Delayed introduction of reduced-dose tacrolimus, and renal function in liver transplantation: the 'ReSpECT' study. Am J Transplant. 2009;9(2):327-336. PMID: 19178414

7. Consensus recommendations for tacrolimus trough in liver transplant recipients. Liver Transpl. 2017;23(4):466-473. PMID: 28318288

8. Boudjema K, Camus C, Bellissant E, et al. Reduced-dose tacrolimus with mycophenolate mofetil vs standard-dose tacrolimus in liver transplantation: a randomized study. Am J Transplant. 2011;11(5):965-976. PMID: 21245000

9. Sgourakis G, Radtke A, Fouzas I, et al. Corticosteroid-free immunosuppression in liver transplantation: a meta-analysis and meta-regression of outcomes. Transpl Int. 2009;22(9):892-905. PMID: 19124317

Complications

10. Rodriguez-Castro KI, Porte RJ, Nadal E, et al. Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review. Transplantation. 2012;94(11):1145-1153. PMID: 22655611

11. Yerdel MA, Gunson B, Mirza D, et al. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation. 2000;69(9):1873-1881. PMID: 10846071

12. Pascher A, Neuhaus P. Biliary complications after deceased-donor orthotopic liver transplantation. J Hepatobiliary Pancreat Surg. 2006;13(6):487-496. PMID: 16145325

13. Seehofer D, Eurich D, Veltzke-Schlieker W, et al. Biliary complications after liver transplantation: old problems and new challenges. Am J Transplant. 2013;13(2):253-265. PMID: 23354316

ICU Management

14. Niemann CU, Hirose R. Critical care management of the liver transplant patient. Curr Opin Organ Transplant. 2019;24(3):297-302. PMID: 31252062

15. Prasad S, Bhalla A, Sharma S, et al. Critical care management of the liver transplant recipient: current concepts. Indian J Crit Care Med. 2021;25(7):809-821. PMID: 34151754

Basic Sciences

16. Michalopoulos GK. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol. 2010;176(1):2-13. PMID: 20019184

17. Reuben A. The biliary tree: the orphan organ in transplantation? Liver Transpl. 2005;11(4):375-380. PMID: 15776455

MELD and Allocation

18. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464-470. PMID: 11172350

19. Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med. 2008;359(10):1018-1026. PMID: 18768945

Portal Hypertension and Cirrhosis

20. Møller S, Henriksen JH. Cirrhotic cardiomyopathy. J Hepatol. 2010;53(1):179-190. PMID: 20175243

21. Krowka MJ, Fallon MB, Kawut SM, et al. International Liver Transplant Society Practice Guidelines: diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension. Transplantation. 2016;100(7):1440-1452. PMID: 27087278

22. Angeli P, Gines P, Wong F, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol. 2015;62(4):968-974. PMID: 25638527

Infection

23. Razonable RR, Hayden RT. Clinical Utility of Viral Load in Management of Cytomegalovirus Infection after Solid Organ Transplantation. Clin Microbiol Rev. 2013;26(4):703-727. PMID: 24092853

24. AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2019;19 Suppl 3:44-59. PMID: 30814545

25. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update. Clin Infect Dis. 2016;62(4):e1-e50. PMID: 26679284

26. Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update. Clin Infect Dis. 2016;63(4):e1-e60. PMID: 27365499

Machine Perfusion

27. Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018;557(7703):50-56. PMID: 29670285

28. Dutkowski P, Polak WG, Muiesan P, et al. First Comparison of Hypothermic Oxygenated Perfusion Versus Static Cold Storage of Human Donation After Cardiac Death Liver Transplants. Ann Surg. 2019;270(5):746-753. PMID: 31425292

Living Donor

29. Olthoff KM, Smith AR, Abecassis M, et al. Defining long-term outcomes with living donor liver transplantation in North America. Ann Surg. 2015;262(3):465-475. PMID: 26258317

30. A2ALL Study Group. A-SOFT score: a new predictive index for living donor liver transplant outcomes. Am J Transplant. 2011;11(11):2344-2351. PMID: 21881490

Rejection

31. Demetris AJ, Bellamy C, Hübscher SG, et al. 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology. Am J Transplant. 2016;16(5):1605-1617. PMID: 25145676

32. Wiesner RH, Demetris AJ, Belle SH, et al. Acute hepatic allograft rejection: incidence, risk factors, and impact on outcome. Hepatology. 1998;28(3):638-645. PMID: 9731552

Coagulation

33. Görlinger K, Dirkmann D, Hanke AA, et al. Thromboelastometry-based perioperative coagulation management in visceral surgery and liver transplantation. Viszeralmedizin. 2014;30(4):246-251. PMID: 26288598

34. Sabate A, Dalmau A, Koo M, et al. Coagulopathy management in liver transplantation. Transplant Proc. 2012;44(6):1523-1525. PMID: 22841203

Pharmacology

35. Drug dosing in liver disease. Australian Medicines Handbook. eTG Complete

36. Fischer L, Saliba F, Kaiser GM, et al. Three-year outcomes in de novo liver transplant patients receiving everolimus with reduced tacrolimus. Transplantation. 2015;99(6):1455-1462. PMID: 25427164

Indigenous Health

37. Lawton PD, Cunningham J, Zhao Y, et al. Organ transplant rates in Aboriginal and Torres Strait Islander peoples. Med J Aust. 2015;202(10):525-526. PMID: 25686008

38. Rix EF, Barclay L, Stirling J, et al. 'Beats the alternative but it messes up your life': Aboriginal people's experience of haemodialysis in rural Australia. BMJ Open. 2014;4(9):e005945. PMID: 24391263

39. Waller KMJ, Agrawal V, Samuel S, et al. Organ donation and transplantation in Indigenous populations: a systematic review. Transplantation. 2019;103(5):1046-1054. PMID: 30761655

Australian/New Zealand Context

40. ANZLTR (Australia and New Zealand Liver Transplant Registry). Annual Report. PMID: 26648307 (Registry data)

41. ANZICS Statement on Care of the Potential Organ Donor. Edition 4.1, 2021.

42. TSANZ Clinical Guidelines for Organ Transplantation from Deceased Donors.

Additional Key References

43. Busani S, Cavazzuti I, Rinaldi S, et al. Management of post-reperfusion syndrome during liver transplantation. Transpl Int. 2020;33(3):223-233. PMID: 32051410

44. Ow MM, Erasmus ME, Weima TJ, et al. Normothermic machine perfusion for liver transplantation. Transpl Int. 2021;34(4):584-596. PMID: 33506530

45. Cholongitas E, Shusang V, Marelli L, et al. Review article: renal function assessment in cirrhosis - difficulties and alternative measurements. Aliment Pharmacol Ther. 2007;26(7):969-978. PMID: 17877505

46. Strasberg SM. Nomenclature of hepatic anatomy and resections. HPB (Oxford). 2005;7(1):28-33. PMID: 18333157

47. Jadlowiec CC, Taner T. Liver transplantation: current status and challenges. World J Gastroenterol. 2016;22(18):4438-4445. PMID: 27182155

48. Kim WR, Therneau TM, Benson JT, et al. Deaths on the liver transplant waiting list: an analysis of competing risks. Hepatology. 2006;43(2):345-351. PMID: 16440361

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16. Related Topics

Prerequisites

• Acute Liver Failure
• Hepatorenal Syndrome
• Portal Hypertension

Related Conditions

• Immunosuppression in Critical Illness
• Solid Organ Transplant Complications
• Post-operative Care

Procedures

• Central Venous Access
• Renal Replacement Therapy
• Blood Product Transfusion

Related Pharmacology

• Immunosuppressive Agents
• Vasopressors in Shock
• Antimicrobial Prophylaxis

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