Anaesthesia for hepatic

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1 Anaesthesia for hepatic transplantation Dawn Fabbroni MBChB MRCP FRCA Mark Bellamy MBBS MA FRCA Liver transplantation has become the treatment of choice for end-stage liver failure and some cases of acute liver failure. This can be orthotopic (same place) or heterotopic (other place). The first successful orthotopic liver transplant was performed by Starzl in Since then, advances in surgical, anaesthetic and immunological management have resulted in prolonged graft survival and overall 1 yr survival rates >80%. 1 Liver transplantation is performed in patients of all ages. Paediatric liver transplantation has a 10 yr survival rate of 80 90%. Good success rates are also seen in the >70-yr-old population, providing they are carefully selected to take account of co-morbidities. 1 Indications for liver transplantation Indications for liver transplantation include chronic progressive liver disease (predominantly, but not exclusively, cirrhosis) and acute hepatic failure (Table 1). The decision to list a patient for transplantation is based more on the severity of hepatic dysfunction than the underlying aetiology. Priority is based on specific prognostic criteria using a number of scoring systems. Commonly used scores include the model for end-stage liver disease Table 1 Indications for orthotopic liver transplantation 1 Cirrhotic disease Virus-related cirrhosis Alcoholic cirrhosis Primary biliary cirrhosis Cryptogenic cirrhosis Autoimmune hepatitis Cancers Hepatocellular carcinoma Cholangiocarcinoma Biliary tract carcinoma Metastases Cholestatic disease Acute hepatic failure Metabolic disease Wilson s Disease Haemochromatosis Other Budd Chiari syndrome Benign liver tumours Failure of previous transplant (rejection, primary non-function) (MELD) score and paediatric end-stage liver disease (PELD) scores. 2 The MELD/PELD scores are numerical scales based on the patient s risk of dying while awaiting transplantation. The MELD score for patients older than 12 yr is based on bilirubin, international normalized ratio (INR) and creatinine. The PELD score is based on bilirubin, INR albumin, growth failure and age when listed. Indicators of poor prognosis include renal impairment, hyponatraemia, muscle wasting, impaired cardiopulmonary function and severe pulmonary hypertension. Mild to moderate pulmonary hypertension (mean <35 mm Hg) is not a contraindication to transplantation; however, mortality increases to around 100% in severe pulmonary hypertension (mean pulmonary artery pressure >50 mm Hg). New proven hepatopulmonary syndrome (triad of liver disease, hypoxaemia on room air and pulmonary vascular dilatation) is not a contraindication to liver transplantation as it may resolve after successful grafting in a high proportion of cases. 3 Transplantation for primary hepatobiliary malignancy is considered in the absence of metastasis and based on tumour bulk; however, results are poor (25 40% 2 yr survival). Selection is based on either the Milan criteria (single tumour 5 cm or up to three tumours, none >3 cm) 4 or the San Francisco criteria (single lesion 6.5 cm or up to 3 lesions, none >4.5cm and total tumour diameter 8 cm). Preoperative assessment A multidisciplinary preoperative assessment should be performed by a hepatologist, surgeon and anaesthetist before listing for transplantation. Assessment involves evaluating hepatic dysfunction and associated pathophysiological complications and existing concomitant disease. Preoperative investigations A number of investigations are used to establish cardiovascular fitness and risk profile. Key points Liver transplantation is the treatment of choice for endstage liver failure. Pre-assessment and careful patient selection should be performed by a multidisciplinary, anaesthetic, surgical and hepatology team. There are three phases in the physiology of a transplant (resection or pre-anhepatic phase, anhepatic phase and post-reperfusion phase). These must be understood and managed appropriately. Blood loss is unpredictable; it can be insignificant or massive. Perioperative care should be provided in an appropriate level 3 facility. Dawn Fabbroni MBChB MRCP FRCA Specialist Registrar in Anaesthesia St James s University Hospital Beckett Street Leeds LS9 7TF UK Mark Bellamy MBBS MA FRCA Consultant in Anaesthesia and Intensive Care St James s University Hospital Beckett Street Leeds LS9 7TF UK Tel: Fax: m.c.bellamy@leeds.ac.uk (for correspondence) doi: /bjaceaccp/mkl040 Continuing Education in Anaesthesia, Critical Care & Pain Volume 6 Number Downloaded from ª The Board of Management and Trustees of the British Journal of Anaesthesia [2006]. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org 171

2 As a minimum, an ECG and echocardiography should be performed in all patients. Underlying ischaemic heart disease and alcohol-related cardiomyopathy are not uncommon, so full functional assessment is often required. The assessment regimen varies between centres. Dobutamine stress echocardiography and cardiopulmonary exercise testing show promise as indicators of perioperative risk. Exercise ECG, echocardiography and radionucleide angiography may assist in identifying patients with significant ischaemic heart disease or cardiomyopathies and quantifying their risk of undergoing liver transplantation. Chest X-ray and pulmonary function tests may reveal existing lung pathology and pleural effusions. They allow measurement of a patient s respiratory reserve and can assist planning ventilatory management after operation. Formal pulmonary artery catheter studies are performed in patients suspected of pulmonary hypertension. Up to 10% of patients with cirrhosis suffer pulmonary hypertension, often in association with portal hypertension. Hyponatraemia is commonly associated with portal hypertension and ascites as a result of water retention. A serum sodium <125 mmol litre 1 is carefully corrected preoperatively over days or weeks to reduce the risk of pulmonary oedema and central pontine myelinolysis associated with acute perioperative sodium shifts. This is achieved through fluid restriction and use of the aldosterone antagonist, spironolactone. Hypoalbuminaemia, coagulopathy and thrombocytopenia are not generally corrected preoperatively except where there is a specific indication (e.g. active bleeding). There appears to be relatively little relationship between coagulopathy and intraoperative blood loss. However, increased perioperative blood loss is associated with portal hypertension and previous surgery resulting in higher complication and mortality rates. 5 In end-stage liver disease, the hepatorenal syndrome results in renal impairment and ultimately failure. Albumin and terlipressin are protective in those with or at risk of hepatorenal syndrome. 6 Perioperative haemofiltration may be required. Intraoperative management Premedication Benzodiazepine premedication appears safe in elective cases but should be avoided in patients with hepatic encephalopathy. Monitoring Routine monitoring ECG, oxygen saturations (S p O 2 ) and noninvasive blood pressure (NIBP) are established before induction. Further invasive cardiovascular monitoring may be established either pre- or post-induction depending on the cardiovascular stability of the patient. Pulmonary artery flotation catheters, PiCCO and LIDCO and transoesophageal echocardiography (TOE) are all used in different centres. TOE is the gold standard and provides continuous information on ventricular wall motion and embolic phenomena. A nasogastric tube, urinary catheter and oesophageal temperature probe are inserted. Patients at risk of raised intra-cranial pressure (ICP) (e.g. fulminant liver failure) are generally transferred from ICU with ICP monitoring in situ. Positioning The patient is positioned supine with one or both arms abducted to a maximum of 70. Abduction beyond this angle can result in brachial plexus injury. A warming hot air overblanket is used. The lower chest and abdomen are exposed for surgical access. Induction of anaesthesia An i.v. crystalloid infusion is commenced before induction and continued as maintenance fluid. The main requirement of induction is cardiovascular stability. A variety of induction agents are used in different centres. Increasing interest in early extubation has lead to the use of shorter-acting drug combinations, including midazolam, propofol and remifentanil. Maintenance of anaesthesia After intubation, IPPV is established with a suitable volatile agent, for example desflurane % end-tidal concentration in oxygen-enriched air. Desflurane has the advantage of a quick recovery time and low hepatic metabolism. Many centres use either isoflurane or sevoflurane. Nitrous oxide is avoided to reduce cardiovascular depression, gut distension and bubble formation if on veno-venous bypass (VVB). Total i.v. anaesthesia with propofol has been used successfully, but may be associated with cardiac depression after reperfusion. A remifentanil infusion ( mg kg 1 min 1 ) provides intraoperative analgesia with the advantage of a very short context-sensitive half-life. Alternatives include alfentanil infusion or boluses of morphine. Muscle relaxation with atracurium (at 30 mg h 1 ) provides adequate relaxation and reliable reversal after prolonged use. Most relaxants are safe provided neuromuscular block is monitored to prevent delayed recovery. I.V. fluids and blood products Large bore cannulae are required for rapid transfusion of blood and fluids. A 3 5 lumen central line is inserted under ultrasound guidance, including a wide bore port (8G). An alternative is to use two large bore peripheral cannulae (8F). Where VVB is used, 18 Fr cannulae are inserted percutaneously into an internal jugular and femoral vein. A rapid infusion system (e.g. Level-1 ) allows rapid transfusion of warmed fluids (37 38 C) at rates of up to 1500 ml min 1. Fresh frozen plasma (FFP), colloid and electrolyte solutions are used with packed red cells to achieve a haematocrit of FFP, cryoprecipitate and platelet infusions are administered if required according to measures of coagulopathy 172 Continuing Education in Anaesthesia, Critical Care & Pain Volume 6 Number

3 Table 2 Summary of surgical and anaesthetic aspects of liver transplantation Surgical details Anaesthetic problems Anaesthetic management Phase I Phase II anhepatic phase Phase III reperfusion phase Inverse T or Mercedes incision Dissection of the structures around the liver and porta hepatis, achieving mobilization Division of hepatic artery, portal vein and bile duct. The vena cava is cross-clamped both at the diaphragm and immediately below the liver. or the hepatic vein isolated, With or without veno-venous bypass The liver and portion of vena cava is removed New liver inserted. Caval and portal anastomoses fashioned Blood re-enters the portal vein and caval clamps are removed Hepatic artery is anastomosed and biliary system reconstructed Haemorrhage may occur from dissection, varices and adhesions Cardiovascular instability from ascitic decompression Worsening coagulopathy. No production of clotting factors, fibrinogen deficiency. Thrombocytopenia Absent citrate/lactate metabolism, reduced gluconeogenesis and glucose uptake, worsening acidosis Hypotension and #SVR Initial K þ increase then decrease as graft takes up K þ Metabolic acidosis begins to correct Fibrinolysis prevented/attenuated by antifibrinolytics (e.g. aprotinin or tranexamic acid) Methylprednisolone 10 mg kg 1 before reperfusion to protect against graft dysfunction and renal injury 10 mmol CaCl 2 immediately before reperfusion to protect the myocardium from "K þ. Epinephrine ( mg) boluses with or without infusions of vasopressor or inotropic support K þ supplementation after the initial plasma increase and clinical bleeding. The rationale for the target haematocrit is to allow adequate oxygen delivery but to prevent hepatic artery thrombosis. Many centres use thrombo-elastography (TEG), Sonoclot or other near patient analysers to guide their management. Monitoring of full blood count, clotting, electrolytes and blood gases is carried out hourly or as clinically indicated. This guides management of ventilation, calcium and potassium supplementation, glycaemic and acid base management, and blood replacement therapy. Occasionally 10 50% dextrose may be required to treat hypoglycaemia; this is more likely to occur in cases of severe acute liver failure. Surgery falls into three phases (Table 2). Each of the three phases of liver transplantation poses particular problems for the anaesthetist. Phase I (pre-anhepatic) The surgical approach normally utilizes an inverse T or Mercedes incision. Dissection may be complicated by steady and sometimes rapid haemorrhage caused by varices in the abdominal wall or adhesions within the abdominal cavity. Fluid shifts may result from ascitic decompression. Phase II (anhepatic phase) During the anhepatic phase, there is further physiological derangement. No hepatic clotting factors are produced, fibrinogen is deficient and anti-thrombin concentrations decrease, leading to worsening coagulopathy and the onset of fibrinolysis. Thrombocytopenia can develop owing to massive blood transfusion and platelet consumption, exacerbating preoperative thrombocytopenia. Fibrinolysis may be prevented or attenuated by antifibrinolytic agents, such as aprotinin and tranexamic acid. 7 Absent citrate and lactate metabolism results in progressive acidosis. Hypocalcaemia because of citrate accumulation is treated by slow i.v. calcium infusion. Ionized calcium should be maintained between 0.84 and 1.4 mmol litre 1 to prevent coagulopathy and cardiac depression. Magnesium may also need to be supplemented. There is also reduced gluconeogenesis and glucose uptake. Protection from gastrointestinal tract antigens is lost. Phase III (reperfusion phase) On reperfusion of the preserved liver there is a sudden massive release of cold, hyperkalaemic, acidotic fluid into the circulation. CaCl 2 is given to prevent potassium related arrhythmias. Before reperfusion, methyl prednisolone 10 mg kg 1 is also given as a slow i.v. infusion as immunosuppression and to protect against ischaemia-reperfusion injury. After reperfusion, there is often systemic vasodilatation and myocardial depression leading to haemodynamic instability. Excessive hypotension or decrease in cardiac output requires small boluses of epinephrine (25 50 mg). A rising central venous pressure may contribute to venous congestion in the graft. Postreperfusion syndrome (PRS) is defined as a reduction in mean arterial pressure (MAP) of 30% occurring within 5 min of graft reperfusion and persisting at least 1 min. This is thought to be mediated by cytokines, vasoactive substances released by the reperfused liver and activation of complement. Exposure to the VVB circuit may increase inflammatory cytokines and increase the incidence of PRS. Hypotension associated with a low systemic vascular resistance (SVR) may persist for >1 h. Patients with concomitant cardiac disease, ongoing bleeding or vasodilatation may require vasopressor or inotropic support. After the initial increase in serum K þ, the functioning graft avidly takes up potassium, so some patients may require aggressive potassium supplementation for several hours. Metabolic acidosis begins to correct with restoration of lactate metabolism and bicarbonate production. Primary non-function or delayed function of the graft (up to 10% of cases) is indicated by ongoing metabolic acidosis, coagulopathy and absence of bile production. Most cases require urgent re-transplantation. Continuing Education in Anaesthesia, Critical Care & Pain Volume 6 Number

4 Cell saver The introduction of cell salvage techniques has decreased blood transfusion requirements. Lost red blood cells are scavenged via a suction tube, heparinized as they enter the cell saver reservoir, washed with normal saline, centrifuged and stored directly in a blood bag ready to be re-infused. Contraindications include malignant aetiology and infected ascitic fluid. VVB Depending on the surgical technique, the portal vein, hepatic artery and the inferior vena cava, above and below the liver, may be clamped. This results in a dramatic reduction in the cardiac filling and cardiac output. The degree of haemodynamic instability is dependent on cardiovascular reserve and the extent of collateral veins (azygous, superficial abdominal and epidural veins). Cirrhotic patients tend to tolerate clamping better than expected owing to established collaterals. MAP is usually maintained for up to 1 h because of increased heart rate and a compensatory increase in SVR. The decreased venous return after cross-clamping may necessitate high volume infusions or vasopressor use during caval cross-clamping. Relative volume overload can occur on caval declamping and right heart dysfunction can result. High systemic venous pressure on crossclamping can reduce renal and splanchnic blood flow and increase portal pressure, resulting in gut oedema and increased bleeding. VVB was introduced to limit haemodynamic instability and other problems encountered on cross-clamping. It involves an extracorporeal circuit, removing blood from below the crossclamp (from femoral or inferior mesenteric veins) via heparin bonded tubing to a centrifugal pump. The blood is returned via a central vein (internal jugular or axillary). Early circuits required systemic heparinization but were abandoned because of uncontrolled bleeding. A flow equivalent to 20% of cardiac output is achieved through the bypass circuit. Adding portal bypass increases flow to about 40% of cardiac output (3 4 litres min 1 ). Flow in the circuit is produced by a pressure of mm Hg in the clamped IVC and negative pressure produced by the pump. Haemodynamic stability is improved, and the need for acute volume loading reduced by around 3 litres. 8 Complications of bypass can result from the bypass circuit or venous access. They are uncommon but there is potential for hypothermia, air embolism, clot formation, fragmentation of red cells and failure of the system. Complications from vascular access include haematoma, major vascular injury, nerve injury, air embolism and vessel thrombosis. There is little consensus between different centres when to use VVB. Some use bypass routinely, while others only on selective cases. With an overall complication rate of 1 in 350 cases (related to vascular injury and embolism), there is a strong case for using VVB selectively, that is borderline cardiac or renal function and portal hypertension where excessive bleeding or prolonged surgery increases the potential for gut oedema. Postoperative care Transplant recipients require intensive care after operation. While some patients are suitable for early on-table extubation, 9 most will undergo a period of ventilation for a few hours. Patients are initially kept sedated with propofol and either alfentanil or remifentanil infusions until ready to extubate. This allows time to achieve normothermia, correction of metabolic acidosis and ensure haemodynamic stability. The sickest patients may require prolonged ICU management. Specific issues in liver transplant recipients include close monitoring of potassium concentrations as this may require ongoing supplementation for h. Tight glycaemic control is achieved with a sliding scale insulin infusion. Coagulation tests and full blood count guide further transfusion of blood and blood products. The haematocrit is maintained between 0.26 and Higher levels are associated with an increased incidence of hepatic artery thrombosis and graft failure. 10 In patients with known hypercoagulable states (Budd Chiari, Protein C and S deficiency), anticoagulation with heparin is required and haematocrit maintained at the lower end of the range. Some centres use prophylactic low-dose heparin to prevent hepatic artery thrombosis. Immunosuppression is commenced early in the postoperative period. Patient-controlled analgesia or a morphine infusion is used for postoperative pain relief. Paediatric liver transplantation The principles of liver transplantation in children are similar, but with a few important differences. The major aetiology in paediatric practice is predominantly biliary cirrhosis secondary to biliary atresia. Other causes include inborn errors of metabolism, cystic fibrosis and hepatoblastomas. Small children present their own problems. The donor graft is often a reduced graft from an adult liver (left lateral segment or left lobe). The large raw liver surface is sealed with fibrin glue and has the potential for major haemorrhage. Meticulous surgical technique is required as a smaller circulating volume means that even small bleeds can lead to significant blood loss. Cell salvage is rarely used as the volume of blood loss is not adequate to use the technique. VVB cannot be used in children <35 40 kg as there is inadequate flow through the small cannulae. There is a risk of overloading patients because of fluid administration during cross-clamping but paediatric patients tend to be more haemodynamically stable. The vessel calibre of patients and the donor graft is much smaller in children, enhancing the risk of hepatic artery thrombosis and graft failure. Blood and blood products are used cautiously; antifibrinolytics are usually avoided. The haematocrit is maintained at <0.30, haemoglobin of 8 g dl 1 and serum sodium <140 mmol litre Continuing Education in Anaesthesia, Critical Care & Pain Volume 6 Number

5 In smaller patients, heparin in flush lines plus release of endogenous heparin can produce a coagulopathy, demonstrated by a straight TEG. Protamine may be required. In our centre, most children are extubated at the end of surgery. However, some continue sedation and ventilation for a short period. Most require to be in ICU for h. Key References 1. European Liver Transplant Registry Available at: eltr.org 2. Freeman RB, Harper A, Edwards EB. Excellent liver transplant survival rates under the MELD/PELD system. Transplant Proc 2005; 37: Mandell MS. Hepatopulmonary syndrome and portopulmonary hypertension in the model for end-stage liver disease (MELD) era. Liver Transpl 2004; 10 (10 suppl 2): S Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: Massicotte L, Sassine MP, Lenis S, Seal RF, Roy A. Survival rate changes with transfusion of blood products during liver transplantation. Can J Anaesth 2005; 52: Danalioglu A, Cakaloglu Y, Karaca C, et al. Terlipressin and albumin combination treatment in hepatorenal syndrome. Hepatogastroenterology 2003; 50 (suppl 2): ccciii cccv 7. Xia VW, Steadman RH. Antifibrinolytics in orthotopic liver transplantation. Liver Transpl 2005; 11: Reddy K, Mallett S, Peachy T. Venovenous bypass in orthotopic liver transplantation: time for a rethink? Liver Transpl 2005; 11: Mandell MS, Lezotte D, Kam I, Zamudio S. Reduced use of intensive care after liver transplantation: patient attributes that determine early transfer to surgical wards. Liver Transpl 2002; 8: Buckels JA, Tisone G, Gunson BK, McMaster P. Low haematocrit reduces hepatic artery thrombosis after liver transplantation. Transplant Proc 1989; 21: Please see multiple choice questions 1 5. Continuing Education in Anaesthesia, Critical Care & Pain Volume 6 Number