aandachtspunten bij anesthesie voor ... - uz leuven · 29-11-2019 7 details of othermaindiseases:...

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Marleen Verhaegen27-11-2019

Aandachtspunten bij Anesthesie voor Levertransplant atie

Liver Transplantation (LTX): Topics

• Introduction• Pathophysiological effects of end-stage liver disease (ESLD)

• Anesthesia for LTX– Preoperative care

– Induction and monitoring– Preanhepatic phase

– Anhepatic phase– Reperfusion phase

– Neohepatic or postreperfusion phase

Liver Transplantation (LTX): Topics

• Introduction– Liver transplantation: some data

– MELD score• Pathophysiological effects of end-stage liver disease (ESLD)

– Cardiovascular system• Cirrhotic cardiomyopathy

• Portopulmonary hypertension– Respiratory system

• Hepatopulmonary syndrome– Renal system

• Hepatorenal syndrome– Neurological system

• Hepatic encephalopathy– Coagulation system

– Electrolyte disturbances• Anesthesia for LTX

I Will Not Talk About…

• Acute liver failure• Pediatric LTX

• Combined organ procedures• Retransplantation

• Organ allocation• Organ shortage

• Living donor LTX• …..

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Liver

• 25 % of resting cardiac output goes to the liver– 100 – 130 mL/100 g/min

• Dual blood supply– 25 % by hepatic artery

• 50 % of O2 supply• Arterial pressure

– 75 % by portal vein• Nutrients• Low pressure (5 – 10 mmHg)

• Arterioles and venules both drain into sinusoids• Hepatic veins drain into the inferior vena cava• Bile canaliculi drain bile into bile ducts and intestine

Liver Cirrhosis

• Injury (ischemia, viral / bacterial infection, drug or alcoholic toxicity)• Hepatocellular necrosis• Kupffer cell activation• Inflammation

→ Healing→ Fibrosis

→ Hepatocyte proliferation (HCC)• Loss of liver function• Increased resistance to blood flow

→ Portal hypertension→ Oesophageal varices

Nguyen-Lefebvre and Horuzsko, Enzym Metab J 1(1): 101

LTX: History

• Thomas Earl Starzl, MD, PhD (1926 - 2017)– 1963: the first human LTX (unsuccessful)

• First 5 human LTX: no survival > 23 days

– 1967: the first successful human LTX

• 1970s: 1 year survival < 25 %– Immunosuppression: steroids, azathioprine

• 1980s: improved results

– Cyclosporine– 1983: LTX accepted as definitive therapy for endstage liver disease (ESLD) (US NIH)

1989: eerste LTXUZ Leuven

Number of Liver Transplants in Europe

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Jaarverslag 2018, Raad voor Transplantatie UZ Leuven

LTX: Results

Continuous improvements resulted in increased long-term survival of liver graft recipients• Surgical techniques• Anesthetic management• Postoperative immunosuppressive management

Adam et al., J Hepatol 2012; 57: 675–688

Jaarverslag 2018, Raad voor Transplantatie UZ Leuven Jaarverslag 2018, Raad voor Transplantatie UZ Leuven

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Jaarverslag 2018, Raad voor Transplantatie UZ Leuven Jaarverslag 2018, Raad voor Transplantatie UZ Leuven

LTX: Long-Term Morbidity

• Hepatic problems– Recurrence of primary liver disease

– Biliary problems– Rejection

Åberg et al,, Scand J Surg 2011; 100: 14-21

LTX: Long-Term Morbidity

• Hepatic problems• Non-hepatic complications: life-long immunosuppression long-term toxicity

– Cardiovascular disease• Major adverse cardiovascular events are the main cause of post-LTX morbidity and mortality• Hypertension, myocardial infarction, heart failure, atrial fibrillation, pulmonary embolism, stroke

• 3-fold increased risk

– Renal dysfunction• GFR < 30 mL/min

• 10 years: up to almost 30 % of patients

– Malignancy• 2- to 4-fold increased risk

• Highest risk: non-melanoma skin cancer, lymphoma

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LTX: Indications (1)

• Various indications for LTX– Advanced chronic liver disease– Benign tumors and polycystic liver disease– Unresectable hepatic malignancies– Metabolic liver disease– Fulminant hepatic failure

• Regional variations


• Advanced chronic liver disease– Predominantly hepatocellular disease

• Alcoholic liver disease• Chronic viral-induced liver disease (hepatitis B, C, D, E)

• Chronic drug-induced liver disease• Idiopathic autoimmune liver disease

– Predominantly cholestatic disease• Primary biliary cirrhosis (PBC)• Primary sclerosing cholangitis (PSC)

• Biliary atresia• Familial cholestatic syndrome

– Predominantly vascular• Budd-Chiari syndrome• Veno-occlusive disease


• Polycystic liver disease– Symptoms due to liver volume

• Unresectable hepatic tumors / malignancies– Hepatocellular carcinoma

• Cirrhosis

– Cholangiocarcinoma (highly selected patients)– Rare hepatocellular or bile duct tumors within the hepatic parenchyma– Isolated hepatic metastatic disease– Carcinoid tumor– Pancreatic islet cell tumor

Generally no hepatic failure


• Metabolic liver disease– Hereditary hemochromatosis– Alpha-1-antitrypsin deficiency– Wilson’s disease– Homozygos type II hyperlipoproteinemia– Crigler-Najjar syndrome type I– Erythropoietic protoporphyria

– Urea cycle deficiencies– Glycogen storage diseases, type I and IV– Tyrosinemia

• Fulminant hepatic failure– Acute viral hepatitis, Epstein-Barr virus– Drug-induced liver toxicity

• Acetaminophen• Non-acetaminophen

– Unknown

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Details of other main diseases:

Other liver diseases)-unprecised 2246 TPN-induced cholestasis 11Benign liver tumors or Polycyctic disease 1658 HIV 1Budd Chiari 1020 Microangiopathy 1Parasitic disease 91 Small for size syndrome 1Hepatopulmonary syndrome 18



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LTX: Exclusion Criteria

Relative exclusion criteria: individualized decision (multidisciplinary)

American Association for the Study of Liver Diseases (AASLD) guidelines

LTX: MELD

MELD = Model for End-stage Liver Disease:10 x [0.957 x log(creatinin mg/dL) + 0.378 x log(bilirubin mg/dL) + 1.120 x log(INR) + 0.643

• Numerical score based on 3 standard laboratory values– Serum creatinin– Serum bilirubin– International normalized ratio (INR)

• Range: 6 (less ill) – 40 (gravely ill)• Objective criteria used to prioritize candidates for LTX

– Estimate of 3-month probability of death on the waiting list– Identification of LTX candidates with the highest risk of mortality on the waiting list

• Recertification at specified intervals

Eurotransplant Liver Allocation System (ELAS) manual

LTX: MELD

• Implementation of MELD score Fewer deaths on the waiting list Patients having LTX: increased severity of illness

• Increased use of blood products• Increased use of vasopressors

• Adaptations to MELD score have been proposed: MELD-Na score– Hyponatremia is an independent predictor of mortality in patients with cirrhosis listed for LTX

[Na+] < 126 mEq/L: increased risk of death (~ x 7)

– January 2016: MELD-Na score replaced MELD score in the U.S.MELD-Na = MELD + 1.32 x (137 – Na) – [0.033 x MELD x (137 – Na)]

LTX: MELD

LabMELD does not always accurately reflect disease severity Exceptional MELDInitiative of transplant center to request exceptional MELDRequires approval

Martin and O’Brien, Clinical Liver Disease 2015; 5: 105-107.

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LTX: Exceptional MELD

• Exceptional MELD is not based on lab values• Eligible patients

– Standard exception (SE)• Eurotransplant criteria (e.g. HCC, POPH)

– Non-standard exception (NSE)• Patients not eligible for SE

• Disease and country-specific rules– Must be approved by national audit group


PATHOPHYSIOLOGICAL EFFECTS OF ESLDAnesthesia for Liver Transplantation: Attention Points

Organ response to hepatic dysfunction.

Kiamanesh D et al. Br. J. Anaesth. 2013;111:i50-i61

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Organ response to hepatic dysfunction.


Portal Hypertension

• Elevated pressure within the portal venous system (normal portal venous pressure: 5 – 10 mmHg)– Hepatic venous pressure gradient (HVPG) (Portal pressure – pressure v cava inf) > 5 mmHg– Portal venous system: low pressure, low resistance highly compliant system– Various causes of increased portal resistance (pre-hepatic, intra-hepatic, post-hepatic)

• Cirrhosis: sinusoidal PH– Static component: structural changes due to liver fibrosis and nodule formation– Dynamic component: contraction of myofibroblasts

• Inflammation hepatocytes: cytokine release recruitment and transdifferentiation of hepatic stellate cells into contractile and fibrogenic myofibroblasts

Activated hepatic stellate cells (HSCs) in liver ci rrhosis increase intrahepatic vascular resistanceQuiescent HSCs are vitamin A storage cells and found in normal livers. In response tofibrogenic stimuli, such as transforming growth factor beta, HSCs are activated to becomemyofibroblasts, which exhibit a contractile and fibrogenic (collagen-producing) phenotype. These activated HSCs, located underneath liver sinusoidal endothelial cells, exert a contractile effect on the hepatic microcirculation, resulting in an increase in intrahepatic resistance.

Iwakiri, Clin Liver Dis 2014; 18: 281-291.

Pathogenesis of portal hypertension (NO nitric oxide, RAS renin–angiotensin system,ADH antidiuretic hormone)

Ismail B.E.S., Rivas J.M., Zervos X.B. (2017) Pathophysiology of Cirrhosis and Portal Hypertension. In: Eghtesad B., Fung J. (eds) Surgical Procedures on the Cirrhotic Patient. Springer, Cham

Portal Hypertension: Complications

• Complications– Clinically significant portal hypertension: HVPG > 10 mmHg– High morbidity and mortality

• Esophageal varices– Risk of upper GI bleeding and aspirationR/ β-blockers reduced risk of bleeding

• Ascites

– Associated problems• Pleural effusion

– R/ Pleural evacuation• Pericardial effusion and cardiac tamponade (TTE)

– R/ Pericardiocentesis

R/ Sodium restriction and diureticsAlbumin IV Paracentesis (repeatedly)

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Portal Hypertension: Anesthesia

• Induction– Ascites– Esophageal varices (nasogastric tube)

• Renal insufficiency– Avoid nephrotoxic drugs

• Hyponatremia– Risk of osmotic demyelination syndrome

• Collateral circulation: surgical bleeding• Fast intravenous volume loading risk of PH increase

ESLD: Cardiovascular System

• Hyperdynamic circulation• Cirrhotic cardiomyopathy• Coronary artery disease (CAD)• Portopulmonary hypertension (POPH)

ESLD: Hyperdynamic Circulation

• Approximately 70 % of patients with ESLD• Characteristics

– Low systemic vascular resistance– Increased heart rate– Normal or slightly decreased blood pressure– High cardiac output

• Pathophysiology

– Splanchnic and systemic arterial vasodilation• Enhanced endogenous production and diminished clearance of vasodilating substances

– NO, CO, endogenous cannabinoids, tumor necrosis factor-α, adrenomedullin, hydrogen sulfide• Inflammatory response to bacterial translocation

Activation of renin-angiotensin-aldosteron system and ADH production with retention of sodium and water with increased plasma volume

– Venous capacitance increase• Portal hypertension with formation of portosystemic shunts

• Anesthesia– Hypotension: R/ vasopressor

Vasodilation from hepatic dysfunction


Cirrhotic Cardiomyopathy

Cirrhotic cardiomyopathy (CCM) is an impaired contractile responsiveness to physiologic or pharmacologic stress, impaired left ventricular diastolic relaxation, and electrophysiologic abnormalities

Møller and HenriksenGut 2008;57:268–278. doi:10.1136/gut.2006.112177

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Cirrhotic cardiomyopathy (CCM) is an impaired contractile responsiveness to physiologic or pharmacologic stress, impaired left ventricular diastolic relaxation, and electrophysiologic abnormalities • CCM is often overlooked

– At rest, many patients with CCM appear to have a preserved left ventricular function• No signs or symptoms in basal circumstances

– Problems occur during stress and in case of volume overload• Risk of acute decompensated heart failure • Liver transplantation

• Prevalence in cirrhosis: ≈ 50 % – Often silent presentation until unmasked by stress, TIPSS, LTX

• CCM is progressive without LTX

– LTX may reverse CCM– Increased risk of graft failure and mortality


Cirrhotic cardiomyopathy (CCM) is an impaired contractile responsiveness to physiologic or pharmacologic stress, impaired left ventricular diastolic relaxation, and electrophysiologic abnormalities

Markin et al., J Cardiothorac Vasc Anesth 2019; 33: 3239-3248

Zardi et al., J Cardiol 2016; 67: 125-130.

Cirrhotic cardiomyopathy: Pathophysiology

Zardi et al., J Cardiol 2016; 67: 125-130.

Cirrhotic cardiomyopathy: Diagnosis

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ESLD and Coronary Artery Disease

Prevalence of CAD in patients with LTX candidates: ? (literature: 2.7 – 60 %)• Common, but often undiagnosed• Higher incidence than in the general population

– Increased prevalence of traditional risk factors in patients with non-alcoholic fatty liver disease (NASH)– Increasing age of recipients more risk factors for CAD

• LTX candidates with ≥ 2 traditional risk factors: 50 % prevalence of CAD– Hypertension, smoking, DM, hypercholesterolemia, obesity, genetic history

Evaluation for CAD in LTX candidates Management of flow-limiting CAD in LTX candidates

Lentine et al., Circulation 2012; 126: 617-663.

ESLD: Pretransplant Evaluation for CAD

• Noninvasive functional testing• Limited predictive value for obstructive CAD in patients with ESLD• Not possible in many ESLD patients• Poor correlation with angiographic findings and postoperative complications from CAD

– Dobutamine stress echocardiography• ESLD are often inable to reach target heart rate x blood pressure

• Study data are inconclusive• Screening of patients with risk factors? (3 or more risk factors?)

– Single photon emission computed tomography (SPECT) perfusion imaging• Poor specificity and sensitivity for detecting CAD in LTX candidates

• Coronary artery calcium score (CACS)?

– Correlation with severity of plaques– Preoperative CACS > 400 predicts cardiovascular complications 1 month after LTX– Data are limited

ESLD: Pretransplant Evaluation for CAD

• Coronary angiography– Gold standard, but not routinely indicated (too high cost/benefit ratio)– In case of an abnormal noninvasive CAD test, high risk factors for CAD, clinical suspicion of CAD– Concerns

• Bleeding complications• Renal dysfunction contrast-induced nephropathy

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ESLD and Coronary Artery Disease: Therapy

• Management of CAD in LTX candidates remains controversial• Many different therapeutic strategies

– High risk of LTX in patients with CAD• High perioperative risk of cardiac morbidity and mortality• Immunosuppression: increased long-term risk of CAD

• Obstructive CAD not amenable to revascularization may be a contraindication

– High risk of CABG in patients with ESLD

– Coronary stenting during waiting period for LTX• Bare-metal stent and dual anti-platelet therapy: (6 weeks –) 3 months

Portopulmonary Hypertension (POPH): Definition

Portopulmonary hypertension is a combination of portal hypertension and pulmonary arterial hypertension

• Portal hypertension– Chronic liver disease– Non-cirrhotic (extrahepatic) portal hypertension ≈ 10% of patients with POPH

• Portal vein thrombosis, hepatic vein sclerosis, congenital portal circulation abnormalities, periportal fibrosis without cirrhosis

• Pulmonary arterial hypertension (PAH)– Increased mean PAP (PAPm): ≥ 25 mmHg at rest

– Low or normal PCWP: ≤ 15 mmHg at rest – Increased PVR: ≥ 3 wood units (≥ 240 dynes.s.cm-5)Exclusion of alternative causes of PAH (eg, heritable PAH, collagen vascular disease, congenital heart disease, human immune deficiency virus, or drugs)

POPH: Prevalence and Epidemiology

• Prevalence ≈ 2 - 16 % of patients with portal hypertension• There appears to be no correlation between the severity of liver disease (Child-Pugh score, MELD) and

the risk of POPH

• There is no correlation between the degree of portal hypertension (measured by the hepatic venouspressure gradient) and the severity of POPH

• Overt POPH develops 4 – 7 years after the diagnosis of portal hypertension

POPH: Classification

• Mild POPH: mPAP 25 – 34 mmHg → No influence on perioperative mortality• Moderate POPH: mPAP 35 – 44 mmHg → Increased risk of perioperative mortality• Severe POPH: mPAP ≥ 45 (-50) mmHg → Extremely high risk of perioperative mortality

Porres-Aguilar et al, Annals of Hepatology, 2008; 7

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POPH: Histology

Obstruction of pulmonary arterial blood flow • Proliferation of the intima• Hypertrophy of the media• Fibrosis• In situ thrombosis

→ Thickening of the arterial wall→ Blood vessel occlusion

→ Increased pulmonary vascular resistance

POPH: Pathophysiology

The mechanism of POPH is unknown.• Hyperdynamic circulation of ESLD increasing flow through pulmonary vascular bed with increased sheer

stress on vascular wall leading to endothelial injury and dysfunction with vasoconstriction and progressivevascular remodeling

– Is this the initiating stimulus?• Dysregulation of vasoactive, proliferative, angiogenic, and inflammatory substances with remodeling of

the pulmonary arterial endothelium– Serotonin, IL-1, IL-6, angiotensin-1, endothelin-1, glucagon, thromboxane B2, glucagon, VIP– Produced by the diseased liver or normally metabolized by the healthy liver– Reaching the pulmonary circulation through portosystemic shunts (precluding hepatic inactivation)

• Genetic predisposition• Viral infection with natural killer cell-mediated immune deficiency

• (Thromboembolism from portal venous system)– Not confirmed by autopsy data

Multifactorial mechanism?

POPH: Symptoms

• Patients remain asymptomatic for a long time• The first symptoms are commonly fatigue and dyspnea on exertion• Evolution to chest pain, dyspnea at rest, syncope, orthopnea and peripheral edema

POPH diagnosis can be missed easily preoperatively– Clinical signs and symptoms are generally aspecific and occur late – Dyspnea is common in advanced liver disease, even in patients without POPH

Screening for POPH is indicated in patients with portal hypertension considered for LTX

POPH: Screening

There is no good screening method for POPH• General screening tests may indicate right heart strain (advanced cases of POPH)

– ECG: right ventricular hypertrophy, right atrial hypertrophy, right axis deviation, RBBB– Chest X-ray: enlargement of right heart chambers, dilatation of the pulmonary arteries

• Arterial blood gasses: possibly mild to moderate hypoxemia, hypocapnia, increased A-a gradient• PFT: often normal, sometimes decreased diffusion capacity and reduced lung volume• TTE (every patient considered for LTX)

– No diagnosis of POPH, but rules out POPH or indicates need for further investigation• RVSP < 30 mmHg: rules out POPH

• RVSP > 50 mmHg: predictive for POPH Right heart catheterisation

– Optimal repeat interval is unclear. POPH may develop within 2 – 3 months. • Patients with portal hypertension on LTX waiting list without symptoms of POPH: every 6 - 12 months

• Symptoms suggestive of POPH TTE• Patients on LTX waiting list with diagnosis of POPH: every 3 - 6 months progression?

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POPH: Diagnosis

Right heart catheterization: gold standard for definitive diagnosis and staging of POPH • In case of TTE indicating elevated PAP or right ventricular dysfunction

– RVSP > 30 - < 50 mmHg: consider RHC– RVSP > 50 mmHg: RHC is indicated

• Differentiation from ESLD patients with an increased PAP due to a high cardiac output (20 - 50 % of ESLD patients) and/or a postcapillary factor

– Up to 20 % of patients with portal hypertension and mPAP between 25 and 35 mmHg• Exclusion of other causes of PAH• Severity of POPH: therapeutic implications (decision to consider the patient for LTX)

POPH: Prognosis

• POPH patients without medical treatment and without LTX have a poor outcome– Complications of ESLD and right ventricular failure– Survival is worse in patients with POPH than in patients with other causes of group I PAH

• 2 year survival rate (with PAH treatment): 67 % (POPH) vs 85 % (PAH of other causes)5 year survival rate (with PAH treatment): 40 % (POPH) vs 64 % (PAH of other causes)

Krowka et al. Chest 2012; 141 (4): 906 - 15

• Delayed treatment of PAH in POPH patients?

• Waitlist mortality in POPH is associated with severity of liver disease (MELD), severity of pulmonaryhypertension (right heart failure, low cardiac index, low central venous saturation), and lack of treatment

Survival curves comparing patients who were not selected to receive medical therapy for pulmonary hypertension (natural history) with those who were in the absence of liver transplantation.

Survival curves for the entire cohort broken down by the type of treatment for pulmonary hypertension or liver disease.

5 y survival = 14 %

5 y survival = 45 %

Total patients n = 74 5 year survival (%)

No liver transplantation (n = 62)

No treatment (n = 19) 14

PAH therapy (n = 43) 45

Liver transplantation (n = 12)

LTX alone (n = 3) 33 2 intraoperative deaths

LTX + PAH therapy (n = 9) 67 3 deaths < 1 month of LTX

5 y survival = 67 %

5 y survival = 14 %

5 y survival = 45 %

Swanson et al, Am J Transplant 2008; 8: 2445-2453

POPH: Treatment

Limited data from studies in POPH patients: most treatments are copied from studies in patients with PAH of other causes• General management of patients with PAH

• Specific therapy for PAH– Bridge to LTX (criteria)?– Improved survival?– Decreased symptoms and imrpved functionality?

• Liver transplantation is not a treatment for POPH per se– Criteria for LTX must be met

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POPH: General Management (1)

• Oxygen supplementation to correct hypoxemia• Diuretics

– Maintenance of euvolemia in patients with RV failure and fluid retention– POPH

• Treatment of ascites and/or peripheral edema• Concerns: too rapid fluid removal (hypovolemia) and electrolyte disturbances (hypokalemia intracellular

acidosis hyperammonemia hepatic coma)

• Anticoagulation– Long-term benefit in patients with PAH (IPAH, heritable PAH, PAH due ot anorexigens)– No good data on efficacy and safety in patients with POPH– Contraindications related to liver disease Not routinely recommended in POPH patients Decision on an individual basis

• Digoxin may be considered in patients with tachyarrhythmias

POPH: General Management (2)

• Calcium channel blockers (CCBs): avoid in POPH– Indicated in PAH patients demonstrating an acute vasodilator response to CCBs during right heart

catheterization (generally patients with IPAH)

– Avoid in POPH patients due to risk of • Mesenteric dilatation worsening of portal hypertension

• Increased fluid retention• Reduced RV function

• Stop β-blockade– Patients with PAH: stopping β-blockade has a beneficial effect on pulmonary hypertension– POPH: β-blockade is often started to prevent bleeding from esophageal varices

• There are no data on the effect of stopping β-blockade on esophageal variceal hemorrhage

• TIPSS: avoid– Risk of acute increase in cardiac output and mPAP– Absolute contra-indication in severe pulmonary hypertension

POPH and Specific Therapy for PAH

Fig. 4. Mechanism of action of current vasodilator therapies as treatment of PPHT. Three major pathways contribute to the obstruction of pulmonary arterial blood flow and vasoconstriction in PPHT: the prostacyclin pathway, the endothelin pathway and the NO pathway. PPHT is characterized by decreased prostacyclin and NO levels and increased ET-1. PGI2 is produced from arachinodic acid through enzymatic reactions involving prostacyclin synthase and COX. Binding of PGI2 to its G-coupled receptor results in increased cAMP, which in turn activates protein kinase A. Prostacyclin therapy triggers higher intracellular cAMP levels, resulting in smooth muscle cell relaxation and subsequent vasodilation. In endothelial cells, NO is produced from L-arginine through the enzyme eNOS. NO diffuses towards the smooth muscle cell layer, where it activates GC which converts GTP to cGMP. PDE-5 catabolizes cGMP, thereby decreasing smooth muscle cell relaxation. PDE-5 inhibitors block the PDE-5 enzyme thereby inhibiting breakdown of cGMP and increasing the effect of NO promoting smooth muscle cell relaxation and vasodilation. In PPHT, ET-1A receptors are upregulated. Binding of ET-1 to this receptor triggers cleavage of phosphatidylinositol 4,5-biphosphate into diacylglycerol and IP3, after which intracellular Ca2+ levels increase and the cell contracts. ETR antagonists target ET-1 receptors, resulting in decreased IP3 and Ca2+, thereby reducing the degree of vasoconstriction.

Abbreviations: PPHT, portopulmonary hypertension; NO, nitric oxide; ET-1, endothelin-1; COX, cyclooxygenase; PGI2, prostacyclin; cAMP, cyclic adenosine monophosphate; eNOS, endothelial nitricoxide synthase; GC, guanylate cyclase; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate; PDE-5, phosphodiesterase type 5; IP3, inositol 1,4,5-trisphosphate; Ca2+, calcium; ETR, endothelin receptor; AC, adenylate cyclase; ATP, adenosine triphosphate; GMP, guanosine monophosphate; ECE, endothelin-converting enzyme; ET-1A receptor; endothelin-1A receptor.

Raevens et al. Liver Int. 2015; 35: 1646-60

POPH: Specific Therapy for PAH

Vasodilatatory, anti-proliferative, anti-thrombotic effects• Prostacyclin analogues

– Epoprostenol (iv pump): Flolan®, Veletri®

– Iloprost (inhaled): Ventavis®

– Treprostinil (po, sc, iv)

• Endothelin receptor antagonists– Bosentan (po): Bosentan Teva®, Tracleer®

– Ambrisentan (po): Volibris®

– Macicentan (po): Opsumit®

• Phosphodiesterase type-5 inhibitors – Sildenafil (po): Balcoga®, Revatio®, Sildenafil Teva®

– Tadalafil (po): Adcirca®

– Vardenafil (po)

• Guanylate cyclase stimulator– Riociguat (po): Adempas®

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POPH: Specific Therapy for PAH

• Prostacyclin analogues• Phosphodiesterase type-5 inhibitors• Endothelin receptor antagonists

No extensive data from RCTs in patients with POPH– Case series, small observational studies– Some data indicate improved survival with specific therapy for PAH, but other data do not confirm this

• Greater survival benefit for patients with milder liver disease?

– Risk of hepatotoxicity• POPH patients excluded in PAH studies• Only patients with moderate liver disease in POPH studies

Treatment to enable LTX– Target: mPAP < 35 mmHg and PVR < 400 dynes.s.cm-5

POPH: Liver Transplantation (1)

• Patients with an indication for LTX – MELD score underestimates the mortality risk of POPH patients on waiting list for LTX

• Severity of POPH and mortality after LTX

– Mild POPH: no contraindication for LTX– Moderate POPH: medical treatment of PAH LTX?

• Goal: mPAP < 35 mmHg

– Severe POPH: contraindication for LTX• Pulmonary problems

• Reversibility of PAH is unlikely• Liver congestion and primary graft dysfunction• Mortality is high

Severity of POPH mPAP Perioperative mortality

Mild < 35 mmHg No influence

Moderate 35 - 45 mmHg Up to 50 %

Severe ≥ 45 mmHg ≈ 100%


• Careful selection, treatment and follow-up of patients is necessary– Well-defined selection criteria: mPAP < 35 mmHg

• Regular echocardiographic follow-up while on waiting list (interval?)

– Medical treatment for PAH before LTX• Moderate POPH: treatment goal: = mPAP < 35 mmHg and PVR < 400 dynes.s.cm-5

• Reversibility of POPH after LTX? If PAH resolves, it may take months to years


• Intraoperative management– Avoid hypothermia, hypoxemia, acidosis, hypocalcemia– Continue PAH specific therapy througout the transplant procedure– Monitoring

• Pulmonary artery catheter• Transesophageal echocardiography

– Vasoactive drugs• Dobutamine• Adrenaline • Noradrenaline• Milrinone (right heart failure)

– Reperfusion may cause major hemodynamic changes• Hypotension• PAP increase• Right heart failure

– Management of acute increase of pulmonary hypertension• Nitric oxide• Inhalation therapy (ilomedine, milrinone)

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ESLD: Pulmonary Problems

• ESLD: up to 50 % prevalence of pulmonary dysfunction• Major pulmonary problems in ESLD

– Hepatopulmonary syndrome– Hepatic hydrothorax– Compression atelectasis (ascites)– Hemorrhagic hereditary teleangiectasia– Interstitial lung disease

– Alpha-1 antitrypsin deficiency

Hepatopulmonary Syndrome: Definition

Hepatopulmonary syndrome is a triad of

• Liver disease– +/- portal hypertension– +/- cirrhosis

• Intrapulmonary vascular dilatation

• Impaired oxygenation– Alveolar-arterial O2 gradient ≥ 15 mmHg breathing room air

• Age ≥ 64 y: A-a O2 gradient > 20 mmHg

– Or: PaO2 < 80 mmHg while breathing room airExclusion of intrinsic cardiopulmonary pathology

HPS: Intrapulmonary Vascular Dilatation

Arteriovenous malformations in the lungs• Vasodilation of pulmonary (pre-)capillary vessels

– 15 – 160 µm (normal < 8 – 15 µm)• An absolute increase in the number of dilated vessels• Pleural and pulmonary arteriovenous shunts and portopulmonary venous anastomoses

HPS: Impaired Oxygenation

• Gas exchange abnormalities leading to hypoxemia1. Ventilation-perfusion mismatch

• Increased pulmonary vascular blood flow without increased alveolar ventilation

2. Intrapulmonary R-L shunting• Deoxygenated, mixed venous blood

3. Limitation of O2 diffusion• In severe pulmonary vasodilation• O2 therapy may improve oxygenation

• Impaired hypoxic pulmonary vasoconstriction– 30% of patients

Rodríguez-Roisin R, Krowka MJ. N Engl J Med 2008;358:2378-2387

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HPS: Staging

• Classification according to the degree of hypoxemia in patients with an A-a O2 gradient ≥ 15 mmHg

(Patients breathing room air)

• There is discussion about a relationship between the severity of liver disease and the presence or severityof HPS

Stage PaO2

Mild ≥ 80 mmHg

Moderate ≥ 60 and < 80 mmHg

Severe ≥ 50 and < 60 mmHg

Very severe < 50 mmHg

HPS: Prevalence

A wide range of prevalence has been reported in patients with chronic liver disease: 4 – 47 %– Heterogenous diagnostic criteria: various cutoffs for gas exchange abnormalities– Diagnostic methods– Patient population

HPS: Clinical Signs

• Spider naevi: cutaneous marker for intrapulmonary vascular dilatation?– More systemic and pulmonary vasodilatation?– More impaired hypoxic pulmonary vasoconstriction?– Higher grades of hypoxemia?

• Cyanosis• Digital clubbing

HPS: Symptoms

• Patients may be asymptomatic• Dyspnea

– Insidious onset: initially dyspnea at exertion• Platypnea

– Dyspnea induced by moving from supine into upright position• Orthodeoxia

– PaO2 decrease > 4 mmHg or SaO2 > 5% when the patients moves from supine to upright position– Pulmonary arteriovenous malformations occur predominantly at the base of the lungs increased

perfusion of the lower lobes with more ventilation/perfusion mismatching and increased shunting in the upright position

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Fig. 2. Pathogenesis and pathophysiology of hepatopulmonary syndrome.

Experimental HPS is induced by the technique of CBDL cirrhosis, which leads to pulmonary vasodilation,

intravascular accumulation of activated macrophages and monocytes and angiogenesis.

Pulmonary vasodilation is caused by NO production, following eNOS and iNOS activation and CO

production. In CBDL lungs, ET-1 binding to its ET-1B receptor induces eNOS activation while iNOS and

HO activation occurs in intravascular monocytes/macrophages. Activated monocytes and macrophages

are recruited to the lungs because of bacterial translocation and endotoxaemia after CBDL, in which

CX3CL1/CR3CR1 signalling is responsible for correct monocyte/macrophage adherence to the

pulmonary endothelium.

In addition, increased production of VEGF-A leads to endothelial cell survival and proliferation through

angiogenic Akt/ERK signalling, when it binds to its VEGFR2 on pulmonary endothelial cells.

This combination of pulmonary vasodilation, angiogenesis, pulmonary capillary proliferation and

formation of intrapulmonary arteriovenous shunts results in ventilation-diffusion mismatch, right-to-left

shunting and diffusion restriction, finally contributing to gas exchange disturbances with arterial

hypoxaemia, which characterizes HPS.

Abbreviations:

HPS, hepatopulmonary syndrome;

CBDL, common bile duct ligation;

NO, nitric monoxide;

eNOS, endothelial nitric oxide synthase;

iNOS, inducible nitric oxide synthase;

CO, carbon monoxide;

ET-1, endothelin-1; ET-1B receptor, endothelin-1 B receptor;

HO, haem oxygenase;

CX3CL1, chemokine fractalkine; CX3CR1, chemokine fractalkine receptor;

VEGF-A, vascular endothelial growth factor A;

Akt, protein kinase B;

ERK, extracellular signal-regulated kinase;

VEGFR2, VEGF receptor 2.

Raevens et al, Liver International 2015;35: 1646 - 1660

HPS: Pathogenesis

Nitric oxide appears to play a key role in the of pulmonary vascular changes of HPS, but several othermediators and mechanisms have been proposed• Pulmonary vasodilation

– Increased NO production in the lungs– Increased CO production in the lungs

• Angiogenesis• Pulmonary capillary proliferation• Formation of intrapulmonary capillary shunts

Possible mechanisms of hepatopulmonary syndrome: TNF-α: Tumor necrosis factor-alphaET-1: Endothelin-1ETBR: Endothelin B receptorsNO: Nitric oxideeNOS: Endothelial NO synthaseiNOS: inducible NO synthaseHO-1: Heme oxygenase-1CO: Carbon monoxideVEGF: Vascular endothelial growth factor.

Tumgor; World J Gastroenterol. 2014 Mar 14; 20(10): 2586–2594

HPS: Natural History

• Spontaneous resolution is unlikely• Hypoxemia is progressive

– Mean PaO2 decline: 5.2 (0.4 – 8.3) mmHg/year• HPS worsens the prognosis of patients with ESLD

HPS patients and no LTX *(n = 37)

Matched controls ** (no HPS, no LTX)

(n = 47)p

Median survival 24 months 87 months

5-year survival rate 23 % 63 % 0.0003

* No LTX because of age or co-existing conditions** Matched for cause and severity of liver disease

Swanson et al., Hepatology 2005; 41: 1122-1129

HPS: Natural History

• Spontaneous resolution is unlikely• Hypoxemia is progressive

– Mean PaO2 decline: 5.2 (0.4 – 8.3) mmHg/year• HPS worsens the prognosis of patients with ESLD• Cause of death: multifactorial

– Generally related to complications of liver disease• Hepatic failure, multisystem organ failure due to sepsis, hepatocellular carcinoma, gastrointestinal bleeding

– Progressive hypoxemic failure• Development of concomitant portopulmonary hypertension is unlikely

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HPS: Diagnosis (1)

Detection of intrapulmonary vascular dilatations: Contrast-enhanced echocardiography• Agitated saline

– Microbubbles > 10 µm diameter normally do not pass through the pulmonary capillary bed– Bubbles in left atrium appear within 3 - 6 heart cycles after iv injection when shunts typical of HPS

are present• Intracardiac shunts: bubbles appear in the left heart within 1 - 2 cardiac cycles

• Sensitive• Non-invasive• Detection of other problems (e.g. pulmonary hypertension)

Impaired oxygenation?

HPS: Diagnosis (2)

Impaired oxygenation: A-aO2 gradient, arterial PO 2

• Patient in upright position if possible, breathing room air• PaO2 < 80 mmHg indicates impaired oxygenation

– Patients > 65 y: PaO2 < 70 mmHg• More accurate: calculation of alveolar-arterial O2 gradient (compensates for hyperventilation)

– A-a O2 gradient ≥ 15 mmHg (> 64 y of age: ≥ 20 mmHg)– Problem: calculation assumes normal cardiac output

Forde et al., Hepatology 2019; 69 (1): 270-81

HPS: Screening

Patients with ESLD listed for LTX should be screened for HPS screening for hypoxemia• Pulse oximetry

– SpO2 < 96 % was considered sufficient to detect severe HPS (PaO2 < 60 mmHg) • Sensitivity 100 %, specificity 88 % (Arguedas et al., Clin Gastroenterol Hepatol 2007; 5: 749-54)

–

Forde et al., Hepatology 2019; 69: 270-81

• Normal SpO2 is possible with hypoxemia in liver cirrhosis

• Normal SpO2 is possible with mild HPS and an increased A-a O2 gradient

SpO2 is not sufficiently sensitive to screen for HPS in LTX candidates

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HPS: Screening

Patients with ESLD listed for LTX should be screened for HPS screening for hypoxemia• Pulse oximetry

– SpO2 < 96 % was considered sufficient to detect severe HPS (PaO2 < 60 mmHg)– Forde et al.: SpO2 is not sufficiently sensitive to screen for HPS in LTX candidates

• A combination of spider naevi, digital clubbing, cyanosis, and severe hypoxemia (PaO2 < 60 mmHg) in the absence of cardio-pulmonary disease strongly suggests HPS

HPS: Treatment

• There is no good medical therapy to improve gas exchange and hypoxemia– Supplemental O2 as symptomatic therapy– Various medications have been tried (mostly anecdotically or in uncontrolled case series): no

(sustained) improvement in oxygenation– Several medical interventions have been tried

• TIPSS: variable response with a few case reports indicating improvement, but there may be a risk of worsening HPS due to an increased hyperkinetic state

• Other interventions (embolization, plasma exchange): unsuccessful

HPS: Liver Transplantation

Liver transplantation is the only definitive treatment for HPS

Figure 1. (A) Survival curves from the time of HPS diagnosis for HPS patients and controls (from time of PaO2 determination) undergoing OLT (P = .69); and HPS patients and controls not undergoing OLT (P = .0003); (B) Survival from the time of OLT for HPS patients with severe hypoxemia and controls (P = .67). Swanson et al., Hepatology 2005; 41: 1122-1129

HPS and 5-year survival

HPS and no LTX *(n = 37)

HPS and LTX(n = 24)

23 % 76 %

* P = 0.0001

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HPS: Liver Transplantation

Liver transplantation is the only definitive treatment for HPS• Usually there is resolution of dyspnea and hypoxemia (80% of patients)

– Highly variable time course (6 – 12 months)• Delayed recovery is common

– Refractory HPS is possible after LTX• Most problems occur in the early postoperative period

– Early postoperative mortality is higher in patients with HPS • Risk factors: preoperative PaO2 (room air) ≤ 50 mmHg and preoperative shunt fraction ≥ 20%

– Long-term survival rates are similar for patients with or without HPS• HPS is not considered in MELD score

– Standard exception policy for patients with severe HPS (PaO2 < 60 mmHg)

Schiffer et al., Am J Transplant 2006;6: 1430-1437

ESLD: Renal System

• Hospitalized decompensated liver cirrhosis patients: 20 % AKI• Acute kidney injury (AKI) in ESLD and ascites

– Volume unresponsive AKI– Acute tubular necrosis

• Caused by hypovolemia, nephrotoxic drugs, infection

– Hepatorenal syndrome (HRS)• Most characteristic type of AKI in ESLD

• Renal dysfunction in ESLD has a high postoperative morbidity and mortality– Pretransplant renal impairment is a predictor of cardiac events after LTX– Significant renal dysfunction not expected to recover combined liver-kidney transplantation?

• Identifying patients who will have recovery of renal function after LTX is important

Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a functional renal impairment in patients with advanced liver disease or severe fulminant liver injury, without other causes of kidney failure

• Increased renal vasoconstriction• Reduced glomerular filtration rate• Increase in creatinine• Impaired sodium and water excretion.

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The basic mechanism of the hepatorenal syndrome.

GFR, glomerular filtration rate; NASH, nonalcoholic steatohepatitis; SNS, sympathetic nervous system; TIPS, transjugular intrahepatic portosystemic shunt. (From Shah N, Silva RG, Kowalski A, et al. Hepatorenal syndrome.Dis Mon 2016;62(10):367)

Adelmann et al., Anesthesiology Clin 35 (2017) 491–508.

Portal hypertension

Splanchnic arterial vasodilatationIntravascular volume depletion

Renal vasoconstriction

Pathophysiology of Hepatorenal Syndrome

Hepatorenal Syndrome

• Type 1 HRS– Rapid decline in GFR

• Serum creatinine reaching > 2.5 mg/dL within 2 weeks, or• 50 % reduction in creatinine clearance to < 20 mL/min within 2 weeks

– Precipitating clinical event• Typically spontaneous bacterial peritonitis

– Extremely unstable condition

– Also rapidly deteriorating of hemodynamic and hepatic function, encephalopathy• Type 2 HRS

– More moderate and progressive renal failure– Main clinical problem: refractory ascites– Untreated median survival: 4 – 6 months

• Worse than patients with cirrhosis and ascites without HRS

– Precipitating event risk of developing type 1 HRS

HRS: Criteria for Diagnosis

EASL Clinical Practice Guidelines, J Hepatol 2010, 53

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HRS: Diagnosis

Diagnosis of exclusion• Absence of primary kidney disease, proteinuria, systemic hypovolemia causing renal hypoperfusion• Oliguria• Lab tests

– Low urinary sodium (< 10 mEq/L)– Uremia– Normal urinary sediment

– Increased serum creatinine• Aspecific because ESLD patients are often cachectic with muscle wasting

HRS: Treatment

• Optimalization of intravascular volume– Avoid fluid overload– Albumin

• 1 g/kg (max. 100 g) followed by 20-40 g/d• + Vasopressor therapy (terlipressin)

• Pharmacological treatment: vasoconstrictors• Terlipressin• Vasopressin

Improved renal function without survival benefit Bridge to LTX

• Paracentesis to reduce intra-abdominal pressure• Renal replacement therapy

• LTX usually reverses HRS• In case of prolonged endothelial damage and suspicion of irreversible tubular necrosis: consider

combined liver-kidney transplant

HRS: Terlipressin

• Glypressin®

• Type 1 HRS– Studies: varying dosage, route of administration (sc infusion, iv bolus or infusion) and duration of

therapy– Significant decrease in plasma renin and aldosterone, and improved GFR– Most studies show no overall survival benefit, but an improved renal function (as a bridge to LTX?)

• ≈ 50 % respond to therapy

– Benefit only in combination with albumin– Risk of ischemia

• Less ischemic complications than vasopressin

– Continue during liver transplantation

Hepatic Encephalopathy

Hepatic encephalopathy (HE): a brain dysfunction caused by liver insufficiency and/or portosystemicshunting; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging fromsubclinical alterations to coma.

• Subdivision according to underlying disease– Type A: Acute liver failure– Type B: Portosystemic bypass or shunting– Type C: Cirrhosis

• Prevalence in cirrhosis– Minimal HE: 20 - 80% of patients– Overt HE: 30 - 40 % at some time, often repeatedly

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Hepatic Encephalopathy: Signs and Symptoms

Very variable clinical signs and symptoms• Chronic or episodic symptoms in patients with cirrhosis

– Mild confusion coma• Acute, rapidly progressive syndrome in acute liver failure

– Risk of cerebral edema and intracranial hypertension

AASLD / EASL, J Hepatol 2014; 61: 642-659

West Haven Classification of Hepatic Encephalopathy

Hepatic Encephalopathy: Pathophysiology

Complex pathophysiology• Increased arterial and venous ammonia in cirrhosis

– Neurotoxin produced by bacteria in the intestinal tract– Ammonia is shunted from the portal system to the systemic circulation– Ammonia passes the blood-brain barrier into astrocytes: metabolized to glutamine– Increased glutamine levels swelling of astrocytes and impaired neurotransmission

• Astroglial and neuronal modifications caused by

– Accumulation of ammonia and manganese– Inflammation– Nutritional/metabolic factors– Neurosteroid-induced activation of the GABAergic system

Hepatic Encephalopathy: Precipitating Factors

Precipitating factors• Infection• GI bleeding• Hyponatremia


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Hepatic Encephalopathy: Differential Diagnosis


Hepatic Encephalopathy: Treatment

Treatment of overt HE (recurrent/episodic)• Identification and treatment of reversible triggers• Treatment of increased ammonia levels

– Lactulose• Decreased ammonia absorption from the gut• Dehydration

– Rifaximin (neomycin, metronidazole): add-on drug• Oral antibiotic reducing ammonia-producing enteric bacteria

• Preventive therapy after an episode of overt HE – Lactulose (+ rifaximin after second episode)

• Not after TIPSS

– Discontinuation of prevention is sometimes possible• Well-controlled precipitating factors

• Improved liver function or nutritional status

• Avoid benzodiazepines

ESLD: Coagulation System

• Routine laboratory tests in ESLD patients– Generally indicate hypocoagulation

• Prolonged aPTT, INR, PT• Thrombocytopenia

– These tests assess only part of the coagulation system and do not represent the clinical hemostaticstatus of an ESLD patient

• Clinical data– There is no correlation between routine coagulation test abnormalities and blood loss during LTX– Administration of blood products to correct abnormal coagulation tests do not reduce intraoperative

blood loss during LTX

• Liver disease has complex effects on the balance between prohemostatic and antihemostatic processes The net effect is difficult to predict and to measure “Rebalanced hemostatic system”

• Balance can be disturbed easily

Tripodi and Mannucci, N Engl J Med 2011; 365: 147-156.

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ESLD: Coagulation System

• In many patients with ESLD the coagulation system is rebalanced, without an impaired hemostasis– Not reflected in routine laboratory tests– Viscoelastic testing to assess hemostasis in ESLD?

• Thromboelastography• Rotem

– Acute events easily disturb the balance between procoagulant and anticoagulant factors• Patients with ESLD may be at risk of thromboembolic events

(portal vein thrombosis, deep vein thrombosis, pulmonary emboli)– Abnormal function of the vascular endothelium– Even in the presence of a prolonged INR/PT and aPTT

– Hypercoagulation (PBS, PSC, Budd-Chiari syndrome)– Thromboembolic events are the most frequent cause of hemodynamic collapse and mortaltity

during liver transplantation

Hyperfibrinolysis

Hyperfibrinolysis during LTX is can contribute to severe bleeding• ESLD: abnormal fibrinogen structure and function• Reduced fibrinogen polymerization• Enlarged vascular endothelial area increased activation of tPA increased fibrinolysis

Fibrinolysis activation and inhibition.Tripodi and Mannucci, N Engl J Med 2011; 365: 147-156. Kim et al., Acute and Critical Care 2018; 33(3): 162-169.

INTEM EXTEM

APTEMFIBTEM

LTX: Coagulation Management (1)

• Blood loss is a major cause of morbidity and mortality– Transfusion of blood (products) is independently correlated with outcome– Hemoglobin: generally maintain at 6.5 – 7 g/dL

• Low hematocrit level reduced incidence of hepatic artery thrombosis?

• Prophylactic pro-hemostatic therapy based on routine coagulation tests is not indicated– No good evidence showing a correlation between routine coagulation tests and clinical bleeding

• The intraoperative administration of agents aimed at improving coagulation should be based on– Clinical signs of abnormal coagulation

• Bleeding from puncture sites, oozing in the surgical field, absence of clots

– Viscoelastic monitoring (TEG / Rotem)?• Normal range in ESLD / LTX?

• No good clinical data showing outcome benefit• Diagnosis of

– Hypercoagulation– Hyperfibrinolysis


• Hyperfibrinolysis: tranexamic acid– TEG / Rotem– 30 mg/kg IV– Prophylactic benefit remains controversial

• Dosage?

– (Increased risk of thromboembolic complications?)

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• Coagulation factors– Factor concentrate

• Cofact® (factor II, VII, IX and X)• Low volume

– FFP requires high volume ( bleeding risk in portal hypertension)• Literature

– Clinical effect on transfusion requirements remains unclear in liver transplantation– No thromboembolic complications

• More studies are needed

– Fibrinogen• Riastap®

• Expensive

– Recombinant factor VIIa• Thromboembolic complications

• Expensive

ESLD: Electrolyte Disturbances

• Hyponatremia• Hypocalcemia

– Low serum albumin with reduced calcium binding– Malnutrition– Vit D deficiency– Packed red blood cell transfusion with failure to clear citrate

• Hypomagnesemia

– Loop diuretics– Significant blood loss

ESLD and Hyponatremia

• Degree of hyponatremia increases with severity of hepatic disease– Develops slowly with progression of liver disease– Common in patients with advanced cirrhosis

• Clinical symptoms: Serum [Na+] < 120 mEq/L (~1 % of cirrhosis patients)

Serum [Na+](mEq/L)

Prevalence(%)

< 135 50

< 130 22

< 125 6

< 120 1 Angeli et al., Hepatology 2006; 44: 1535-1542

ESLD and Hyponatremia

• Association with severe ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, renal dysfunction, hepatorenal syndrome

• Prognostic value– Hyponatremia is a risk factor for death on the LTX waiting list– Serum [Na+] < 125 mEq/L: impending HRS– Serum [Na+] < 130 mEq/L: increased risk for osmotic demyelination syndrome with severe

neurologic dysfunction after LTX

Angeli et al., Hepatology 2006; 44: 1535-1542

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ESLD and Hyponatremia: Pathogenesis

• Systemic vasodilatation– Most pronounced in the splanchnic circulation decreased MAP and renal perfusion HRS

• Activation of endogenous sodium- and water-retaining neurohumoral mechanisms– Renin-angiotensin system– Sympathetic nervous system– Antidiuretic hormone

• Water retention (ADH) Ascites Hyponatremia

ESLD and Hyponatremia: Treatment

• No proven benefit• Indications for treatment

– Neurologic symptoms due to hyponatremia– Serum [Na+] < 120 mEq/L

• Avoid rapid correction (osmotic demyelination syndrome)– Goal: serum [Na+] increase 4 – 6 mEq/L per day (maximum 8 mEq/L per day)

• Fluid restriction? (difficult to achieve, low diuresis)• Correction of hypokalemia increase of serum [Na+]

– Cirrhosis: hypokalemia due to diuretics, diarrhea, vomiting• (Hypertonic NaCl)

LTX and Osmotic Demyelination Syndrome

• Prevalence of ODS after LTX: 5 – 29 % of patients with hyponatremia• Generally in patients with a preoperative [Na+] < 130 mEq/L followed by a rapid increase during and

after surgery

• Increase occurs without specific therapy for hyponatremia– Improved hepatic function– Intravenous fluids

• Median onset time: 5 – 7 days• Neurologic complications

ANESTHESIA FOR LIVER TRANSPLANTATIONAnesthesia for Liver Transplantation: Attention Points

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LTX: Anesthesia

Complex, prolonged surgery and anesthesia• Metabolic, electrolyte and acid-base disturbances• Coagulopathy• Hypoxemia• Renal dysfunction• Hemodynamic instability• Massive blood loss

• Graft reperfusion• Timing of procedure and time pressure

Zarrinpar, A. & Busuttil, R. W. (2013) Liver transplantation: past, present and futureNat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2013.88

LTX: Anesthesia

Management of anesthesia for LTX varies widely between institutions• Preoperative care • Induction and monitoring• Distinct surgical stages

1. Preanhepatic phase2. Anhepatic phase3. Reperfusion phase

4. Neohepatic or postreperfusion phase

LTX: Preoperative Considerations (1)

• Pretransplant work-up– Practice guidelines

• EASL• AASLD (American Association for the Study of Liver Diseases)

• Local institutional guidelines

– Interval between work-up and LTX? Indication to repeat testing?• Progression of liver disease (long time on waiting list)

• Progression of established co-morbidity (e.g. POPH)• Development of new co-morbidity

– Cirrhotic cardiomyopathy– Coronary artery disease

– Pulmonary hypertension

– UZ Leuven• Hepatology: supervision of pretransplant work-up

• Multidisciplinary review before listing• Regular consultations hepatology and abdominal transplantation surgery

• Preoperative anesthesia consultation

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• Pretransplant work-up: baseline screening tests relevant for anesthesia– Laboratory tests– Oxygenation– ECG– Chest X-ray– Transthoracic echocardiography (contrast enhanced)

• Left and right ventricular size and function

• Valvular function• Presence of left ventricular outflow tract obstruction

• Pericardial effusion• Intracardiac shunt

• Pulmonary artery pressure• Intrapulmonary shunting


• Pretransplant work-up: additional investigations (recommendations vary)– Pulmonary function tests

• Clinical indications• Not always possible to perform correctly

– Cardiopulmonary exercise testing• Preoperative cardiopulmonary reserve as a predictor of early survival after LTX?• Not always possible to perform

– Evaluation for (occult) CAD• History of CAD, diabetes mellitus, ≥ 2 cardiovascular risk factors• Coronary angiography

• Dobutamine stress echocardiography? Limitations

– Right heart catheterization to investigate pulmonary hypertension suspected on TEE

J Am Coll of Cardiol 2011; 58 (3): 223 - 231


• Attention points when LTX is anounced– Indication for LTX

• Indication of hemodynamic changes• Risk of co-existing diseases

– Co-morbidity?• Portal hypertension, portal thrombosis• Cardiovascular system

– Cirrhotic cardiomyopathy– Coronary artery disease

– Portopulmonary hypertension• Respiratory system

– Hepatopulmonary syndrome• Renal insufficiency

– Hepatorenal syndrome• Encephalopathy

• Esophageal varices• Ascites

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• No sedative premedication• Check availability of blood products• Timing of the procedure may be critical

– E.g. Non-heart beating donor, acute liver failure

LTX: Induction of Anesthesia (1)

• Warm operating room– Absolutely avoid hypothermia by all means!

• Routine preoperative checks• Intravenous access

– Avoid left arm (VVB)– After induction: additional large-bore IV access (fluid warming system)

• Standard preinduction monitoring

– Pulse oximetry, 5-lead ECG– Invasive blood pressure

• Antibiotics– Timely administration– Repeat in time during surgery

LTX: Induction of Anesthesia (2)

• Positioning of the patient– Surgical frame– Prolonged surgery

• Induction of anesthesia– Rapid sequence induction indicated?– Generally

• Opioid

• Propofol• Non-depolarizing muscle relaxant

– Nasogastric tube: silicone (esophageal varices)• Maintenance of anesthesia

– Generally inhalation anesthetic (sevoflurane, desflurane)• TIVA: encephalopathy with risk of cerebral edema?

– Non-depolarizing muscle relaxant– Opioid

ESLD and Drugs

• Changed pharmacokinetics and pharmacodynamics: difficult to predict– Volume of distribution– Portosystemic shunts– Impaired liver function

• Dose-effect monitoring• Avoid

– Hepatotoxic drugs

– Nephrotoxic drugs– Drugs negatively affecting coagulation

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• Hemodynamic monitoring– Invasive arterial blood pressure

• Brachial artery catheter

– Central venous pressure

– Pulmonary artery catheter (continuous cardiac output)• Cardiac output

• Pulmonary artery pressure• SvO2

– Transesophageal echocardiography may be useful• Concerns about esophageal varices bleeding, but use increases

– Avoid in case of recent variceal bleeding

• Real time information about cardiac function and volume status• POPH

• Thromboembolic events

• Additional monitoring: no outcome data– BIS– NIRS (hyperbilirubinemia)

LTX: Monitoring LTX: Preanhepatic Phase

• From incision until vascular clamping of the native liver– Dissection

• Hemodynamic effects– Significant volume shifts are possible

• Drainage of ascites• Blood loss (portal hypertension, adhesions)

– Mobilization of the native liver• Low CVP?

– Balance between adequate preload and compensation of fluid losses– Vasoconstrictor may be necessary

• Systemic vasodilation and hypotension

– Advantages vs disadvantages

LTX and Central Venous Pressure

A low CVP during the anhepatic phase is a goal in many LTX programs: 5 - 10 cm H2O (3.7 – 7.4 mmHg)• Possible advantages

– Reduced blood loss and transfusion requirements– Improved oxygen delivery to donor graft

– Less visceral edema

• Possible disadvantages– Increased risk of renal failure

• Outcome studies investigating a low CVP during LTX are inconclusive– Generally a reduced estimated blood loss– No improvement in postoperative morbidity

• Correlation between CVP changes and changes in hepatic circulation?• Optimal technique to lower CVP?Definitely avoid a severely elevated CVP

LTX: Anhepatic Phase (1)

• From vascular clamping of the native liver until reperfusion of the graft– Resection of the native liver– Implantation of the donor liver

• Clamping of IVC: reduction of venous return– Complete cross-clamping of the IVC

• Significant hemodynamic effects– Volume loading

– Vasopressors (norepinephrine, phenylephrine)• Venovenous bypass

– Improved cardiac preload– Less visceral congestion

– Piggyback technique: partial or side clamping of IVC• Reduced use venovenous bypass• Portocaval shunt

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LTX: Venovenous Bypass (1)

• Heparin-bonded circuit with centrifugal pump• From v. saphena magna or v. femoralis, and v. portae to v. axillaris or v. jugularis interna • Flow rate: 2 – 3 L/min


Literature: debate about benefit vs complications of VVB• Theoretical benefits

– Increased venous return to the heart– Less renal and intestinal congestion

– Decreased fluid administration and blood transfusion

• Possible complications– Hypothermia

– Coagulation disturbances and fibrinolysis– Increased bleeding in relation to vessel cannulation

– Gas embolism– Thrombosis

– Seroma and lymphocoele formation– Wound infection

– Nerve injury– Need for trained personnel

– Increased cost


Literature: debate about benefit vs complications of VVB• Many LTX programs have abandoned the use of a VVB

– Only in patients not expected to tolerate (even partial) cross-clamping of the IVC• UZ Leuven: VVB in most patients when technically possible

– Very low complication rate– Hemodynamically better tolerated

• Less fluids, vasopressors

LTX: Anhepatic Phase (2)

• Profound metabolic changes– Lactic acidosis: loss of lactate metabolism

• Increased plasma lactate, decreased plasma pH• Generally respiratory correction of the pH is sufficient

– Glycemia monitoring • Risk of hypoglycemia

– Hypocalcemia• Administration of CaCl2 is generally necessary (continuous infusion)

• Risk of hypothermia– Venovenous bypass– Warm room, warmed fluids, warmed air systems

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LTX: Reperfusion Phase (1)

• Reperfusion of the liver graft after completion of v. cava and v. portae anastomoses• Postreperfusion syndrome: MAP decrease of at least 30 % within 5 minutes of reperfusion and

lasting at least 1 minute– Severe cardiac dysfunction

• Systemic hypotension

• Cardiac output decrease• PAP, PcWP and CVP increase

• ECG changes• Bradyarrythmia, asystole

– Pathophysiology• Release of vasoactive substances from the ischemic liver graft into the blood stream (IL 6, TNF, K+, H+)• Release of emboli from the ischemic liver graft into the blood stream

• Preservation solution: solute release (e.g. K+)

– Risk is difficult to predict for an individual patient– Correlation with poor outcome?

• Posttransplantation renal dysfunction• Mortality


• Prevention or measures to attenuate postreperfusion syndrome– Surgeon

• Flushing of the graft (Hartmann’s solution)• Progressive unclamping of the graft outflow

– Anesthesiologist• Choice of anesthetic? No reliable data• Optimize hemodynamic and metabolic parameters before reperfusion

• Preventive pharmacological measures?– Mannitol (free radical scavenger)?

• 0.5 g/kg before reperfusion

– Vasopressor pretreatment?• Phenylephrine (100 µg) or ephedrine (10 µg)

• Reduced indicence of PRS • Reduced need for vasopressors in the postreperfusion period

• No effect on lab values, hospital LOS, mortality

– Magnesium sulphate pretreatment?• 35 mg/kg

• Reduction in incidence and duration of PRS?

– (Antihistamine agents) no• Ranitidine, diphenhydramine 15 min before reperfusion


• Postreperfusion syndrome– Prompt diagnosis is necessary.

• ECG changes are often the first indication of postreperfusion syndrome– Spiked T-tops (hyperkalemia)

– Wide QRS complexes– Bradycardia

• Hypotension• Increased PAP, PcWP and CVP

– Immediate treatment is necessary to avoid possibly fatal cardiac arrest• CaCl2 bolus if hyperkalemia is suspected• Neosynephrine, ephedrine bolus

• Epinephrine bolus in case of QRS widening, bradycardia and hypotension

– Persistent vasoplegia resistant to catecholamines• Vasopressin, terlipressin

• Methylene blue (1 – 2 mg/kg)– Inhibition of guanylate cyclase in vascular and cardiac tissue?


• Plasma bicarbonate decrease immediately after reperfusion– Adjust ventilation– (NaHCO3)

• Hypercarbia– Adjust ventilation

• Hyperglycemia• Hypothermia

– Perfusion of cold donor liver

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LTX: Postreperfusion Phase (1)

• From reperfusion until wound closure– Arterial and biliary reconstruction– Hemostasis

• Goals– Good cardiac output– Adequate perfusion pressure without venous congestion

• Low CVP

• Vasopressor

– Normothermia• Hypothermia due to reperfusion of a cold graft (drop of 0.5 - 1 °C)

• Warm room, warmed fluids, warmed air system

– Normoventilation

– Adequate coagulation • TEG / Rotem

• Hyperfibrinolysis: R/ tranexamic acid

LTX: Postreperfusion Phase (2)

• Signs of graft function– Bile production– Improvement of acid-base status– Glycemia: neoglucogenesis– Rapid increase of core temperature– Signs of blood clot formation

• Transfer to the ICU

– Sedated (propofol) and mechanically ventilated– “Fast-tracking”?

• Criteria

• Early extubation Improved outcome?– Morbidity due to prolonged ventilation

– Negative effects of mechanical ventilation on liver perfusion?

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