Chapter 94 Liver transplantation

Liver transplantation has revolutionised the care of patients, with both acute and chronic end-stage liver disease becoming the treatment of choice in the absence of contraindications. It has become an almost routine procedure, with the majority of patients having a short postoperative intensive care unit (ICU) stay and 1-year survival > 90%.¹^–⁴ Indications have widened, and contraindications decreased. As a consequence, the number of patients awaiting transplantation continues to outstrip cadaveric donor rates; waiting times lengthen, hence patients become critically ill before receiving a transplant, increasing risk and perioperative complications, and impairing long-term outcome.⁵ Innovative strategies have evolved as possible solutions to the lack of cadaveric donor organs, including widening the donor pool to include previously unsuitable donors (so called marginal donors), paediatric and adult living-related donation, reduced size and splitting techniques and the use of ‘non-heart beating donation’.

PATIENT SELECTION

There are currently relatively few absolute contraindications to liver transplantation and no specific age limitation. Guidelines are available in regard to hepatocellular carcinoma and liver transplant. Such patients increasingly, if not inevitably, require disease-modifying treatments, (transarterial chemoembolisation and radio frequency ablation) whilst waiting for a suitable cadaveric donor.

Portopulmonary and hepatopulmonary syndromes are now an active indication for transplantation as opposed to a contraindication.⁶ Such patients are likely to have a more complex postoperative course, especially if graft function is borderline or they develop sepsis. Monitoring of patients whilst on the waiting list is essential to ensure that their disease does not progress such that transplantation is no longer a feasible option. Patients must have the required cardiorespiratory reserve to tolerate the procedure. Much work has gone into the development of prognostic tools to allow accurate prediction of the need and timing for transplantation, and increasingly the model used is the model for end-stage liver disease (MELD) system. This system was initially developed for predicting survival following transjugular intrahepatic portosystemic stent (TIPS) shunt but has been shown to be equally useful in predicting survival in those awaiting liver transplantation. Once multiorgan failure has developed in a debilitated patient awaiting transplantation, survival rates decrease to 20–30% and these patients often require weeks to months of postoperative hospitalisation.^2,⁷

PERIOPERATIVE ASPECTS

OPERATIVE TECHNIQUE

Orthotopic liver transplantation (OLT) involves recipient hepatectomy, revascularisation of the donor graft and biliary reconstruction.

Two main techniques are used in adult liver transplantation – those with vena cava preservation (‘piggyback technique’) and those using portal bypass (either internal, temporary portocaval shunt or external, veno-venous bypass). The advantages of the piggyback technique include haemodynamic stability during the anhepatic phase, without large volume fluid administration, and the negation of the need for veno-venous bypass with its associated risks and complications. Decreased transfusion requirements, shorter anhepatic time and shorter total operating time are also observed. There is no observed difference in renal function between the two techniques.⁸^–¹⁰ The donor hepatic artery is directly anastomosed, utilising an ‘end-to-end’ technique, or a conduit is constructed. Portal venous anastomosis must also be undertaken. In most patients this is an end-to-end anastomosis; however, portal venous thrombosis is no longer a contraindication to transplantation. These patients may under go a re-cannulisation procedure or require a jump graft technique. Such conduits and grafts are normally fashioned from donor vessels.

It is imperative that all those caring for the patients are aware of the surgical technique undertaken, as complications may vary. The radiologist must be aware of the technique used to allow appropriate interpretation of subsequent investigations and vascular imaging. This applies not just to the vascular anastomosis but also to the presence of a full graft, reduced size graft, right or left split graft or indeed an auxiliary graft. The biliary anastomosis is normally also undertaken as an end-to-end procedure, the donor bile duct being directly joined to the recipient duct. It is no longer standard for this to be undertaken over a T-tube, but this may be required where there is marked discrepancy between donor and recipient duct size. Some conditions (e.g. extrahepatic biliary atresia, primary sclerosing cholangitis) may preclude end-to-end anastomosis and formation of choledochojejunostomy may be required.

Split-liver grafts allow one liver to provide an organ for two recipients. Initially comprised of a child receiving the left lateral segment and an adult the remaining liver, nowadays two adults may receive grafts from one liver if the anatomy and size match allow. Such splits may be less than ideal when the recipient has a high MELD score, as is increasingly the case with the prioritisation of sick patients awaiting liver grafts. Such grafts are at increased risk of postoperative complications such as bile leaks from the cut surface and haematoma/collections at the cut surface.^3,¹¹

Auxiliary liver transplantation is a technique that involves subtotal recipient hepatectomy and implantation of a reduced size graft. It is a technically difficult procedure, as both portal and arterial supplies have to be constructed de novo. In addition, a duplicate biliary drainage system needs to be constructed. Hepatic venous outflow is anastomosed as usual. In acute liver failure, it has significant potential, since regeneration of the native liver may obviate the need for donor function, potentially allowing withdrawal of immunosuppression. It also has application in the treatment of some hereditary metabolic disorders where adequate metabolic function may be achieved with an auxiliary graft. The major advantage is withdrawal of immunosuppressive therapy if the patent develops severe complications, or when applicable gene therapy becomes available. The disadvantage of auxiliary transplantation in the face of acute liver failure is that the postoperative course is frequently more complicated; reasons are multifactorial, and can be due to the continued presence of a regenerating native liver or due to a smaller donor graft attempting to cope with a critical illness.

Non-heart beating transplantation (NHBD) has emerged in recent times as a potential way of increasing organs for transplantation.^12,¹³ The success in renal transplantation has lead to exploration of its application in the fields of liver, pancreas and lung retrieval. Most retrievals are undertaken in the context of controlled NHBD, i.e. in the context of planned withdrawal of care. Warm ischaemia can be accurately assessed and cold ischaemia minimised. Early experience with NHBD was associated with inferior survival for patients and grafts but recent experience suggests that survival is approaching that for heart beating donation. There are, however, continuing concerns over biliary and vascular complications. Prolonged cold ischaemia is associated with poor graft function and biliary complications, as are warm ischaemia times of greater than 30 minutes.¹⁴ With regard to postoperative care, an understanding of the pre- and perioperative factors is essential in anticipating potential complications, initiation of monitoring and proactive management.

Adequate function of undersized transplanted liver grafts is essential to successful outcome. Primary graft non-function is relatively rare and one of the main areas of concern is that of the so-called ‘small for size syndrome’.^15,¹⁷ This was first recognised in the post transplant setting but also occurs following liver resection. It is still an area under discussion but the clinical entity is that of hyperbilirubinaemia, graft dysfunction, ascites, and portal hypertension with associated end-organ dysfunction/failure. The clinical picture is that of portal hyperaemia, with portal flow passing into a small liver remnant/graft with associated pathophysiological consequences, and at a histological level there is evidence of arteriolar constriction. In some patients consideration should also be given to the potential compounder of hepatic venous outflow limitation.^18,¹⁹ Other factors that predispose to the syndrome are an inappropriate graft weight to recipient and steatotic grafts. In regard of management of this syndrome most trials have focused on optimising venous outflow and limiting/preventing portal hyperaemia and limiting portal hypertension.^15,²⁰ Animal studies have also examined the role intrahepatic vasodilators with good effect. Management of the syndrome remains controversial but its early consideration allows the clinical team time to consider therapeutic options and interventions.

BLOOD LOSS AND COAGULOPATHY

Orthotopic liver transplantation may be associated with massive blood loss. The causes of this are multifactorial and include preoperative coagulation disorders secondary to end-stage liver disease, portal hypertension, surgical technique, adhesions related to previous surgery and intraoperative changes in haemostasis. Activation of the fibrinolytic system, especially during the anhepatic and post-reperfusion phases, occurs in some recipients. Platelet dysfunction, both quantitative and qualitative, is also common. The consequences of massive bleeding and replacement are significant, not only in terms of postoperative morbidity and mortality, but also intraoperatively, when issues such as acute hypovolaemia, reduced ionised calcium due to citrate intoxication, hyperkalaemia, acidosis and hypothermia become important. Transfusion-related acute lung injury (TRALI) is a potentially devastating complication. It is believed to result from neutrophil antibodies preformed in donor serum. The immunosuppressive effects of large volume blood transfusions are well recognised and pertinent in a group of patients who are already functionally immunosuppressed. In addition to these immediate problems is the risk of transmission of, as yet, unidentified viral infections.

Much effort has gone into reducing the amount of exogenous blood products required intraoperatively. This includes the use of cell salvage techniques with autologous transfusion, near patient testing of haemostasis, utilising both laboratory-based tests and thromboelastography. The appropriate use of antifibrinolytic drugs such as aprotinin and tranexamic acid may then be considered. These therapies appear to reduce intraoperative blood loss and transfusion requirements and possibly reduce the reperfusion injury sustained without increasing the incidence of thromboembolic complications or renal impairment.

Although it is assumed that all patients with liver disease are subject to an increased risk of bleeding there are some subgroups that are prothrombotic. Patients with preoperative portal or hepatic venous thrombosis appear to carry a higher incidence of prothrombotic mutations than the general population, and patients with primary biliary cirrhosis and primary sclerosing cholangitis are frequently prothrombotic. Such patients may require anticoagulation in the early postoperative period. Other patient groups such as those with Budd–Chiari syndrome may have a recognised prothrombotic condition with a resultant early requirement for anticoagulation.

POST-REPERFUSION SYNDROME

The post-reperfusion syndrome is a poorly understood phenomenon that occurs after reperfusion of the portal vein through the donor graft. It is characterised by hypotension, bradycardia, vasodilatation, pulmonary hypertension, hyperkalaemia and in some cases cardiac arrest. The aetiology is unclear, but a sudden increase in venous return, release of vasoactive substances, and cold potassium-rich preservation fluids are potentially implicated. The syndrome usually resolves within the first 5 minutes of reperfusion with appropriate fluid loading and electrolyte management. However, in approximately 30% of patients it lasts for significantly longer, necessitating the use of inotropes and/or vasopressors. The post-reperfusion syndrome seems more common in organs with longer preservation times and may well be associated with initial poor graft function.

POSTOPERATIVE CARE

The postoperative care of the recipient depends to some extent on preoperative comorbidity, the presence of any of the immediate complications listed above, recipient stability during the procedure and lastly the pretransplant cause of liver failure.

Straightforward recipients who return to the ICU in a stable condition with good graft function may be woken up and weaned immediately. The tracheal tube and some of the invasive monitoring lines should be removed as soon as no longer required to reduce the risk of infection and encourage mobility. Close monitoring of all physiological systems is important in the early postoperative period (Tables 94.1 and 94.2).

Table 94.1 Routine investigation of posttransplant patient in the ICU

Table 94.2 Monitoring of graft function in ICU

	Parameter	Comment
General	Liver perfusion	Characteristics at surgery
	Bile production	Quality ± volume if T-tube in situ
	Haemodynamics	Stabilisation, with cessation of vasopressor requirements
Coagulation	INR/Prothrombin time (hours)	8-hourly for the first 24 hours, thereafter daily unless indicated. The fall in PT is more important than the actual value. FFP should be withheld to assess graft function although platelet support should be provided as usual
Biochemistry	Glucose	Hypoglycaemia is an ominous sign. 4-hourly measurement in the first 24 hours. Euglycaemia or hyperglycaemia requiring insulin infusion is the norm
	Arterial blood gases and lactate	4–6-hourly depending on ventilatory requirement. Hyperlactataemia and acid–base disturbance should rapidly resolve. Other causes of base deficit such as renal tubular acidosis and hyperchloraemia should be excluded and managed appropriately
	AST	Should fall steadily (50% fall each day). The first measurement may reflect washout and thus the next may be higher. Daily measurements. The initial measurement reflects the degree of preservation injury.
	Bilirubin	Early increases may reflect absorption of haematoma and do not reflect graft function. Haemolysis should be considered if the graft is not blood group matched, termed passenger lymphocyte syndrome
	ALP/GGT	Usually normal; increases may reflect biliary complications or cholestasis of sepsis

EARLY COMPLICATIONS

As with all postoperative surgical intensive care admissions some complications are applicable to all patients. These include haemorrhagic and pulmonary complications of any prolonged procedure in addition to specific complications pertinent to liver transplantation. These can be subdivided into technical complications, conditions and complications associated with pre-existing liver disease, and complications associated with immunosuppressive agents, graft function and massive transfusion.

CARDIOVASCULAR

End-stage liver disease is characterised by a hyperdynamic circulation, with low systemic vascular resistance, high cardiac index and a relatively reduced circulating volume. The majority of patients can be managed with adequate volume loading with or without vasopressor inotropes to maintain adequate perfusion pressures. However, in some patients this state may compensate for degrees of cardiomyopathy (which may be difficult to detect with non-invasive preoperative investigation).²¹^–²³ The massive increase in the volume of liver transplants performed in the last decade has revealed cardiac failure as an important cause of morbidity and mortality in the transplant recipient. So-called cirrhotic cardiomyopathy, quite independent of the effects of alcohol, may be multifactorial in nature, possibly due to overproduction of nitric oxide, abnormal β-adrenoceptor structure and/or function, or the presence of some as yet unidentified myocardial depressant factor. Whatever the cause, OLT can impose severe stresses on the cardiovascular system: haemorrhage, third-space loss, impaired venous return due to caval clamping, hypocalcaemia and acidosis all impair myocardial contractility. Reperfusion can also be a time of profound circulatory instability, as discussed above. In addition, the impaired exercise tolerance of the pretransplant recipient may have limited the clinical importance of coronary ischaemia which becomes pertinent in the posttransplant period.

Haemodynamic changes after OLT are also common; hypertension with an increased systemic vascular resistance is frequent and may be due to the restoration of normal liver function and portal pressure, as well as the hypertensive effect of the calcineurin immunosuppressants. The increased afterload in the early posttransplant period may unmask cardiac dysfunction. Management of myocardial dysfunction post OLT is largely empirical; diuretics, afterload reduction and positive-pressure ventilation may all be required. In the longer term, control of cardiovascular risk factors is required and many of these patients may over the years return to the intensive care environs with other system failures and considerable burdens of hypertension, coronary ischaemia, diabetes, hyperlipidaemia and renal dysfunction.

PULMONARY

Pulmonary complications are common and occur in 40–80% of recipients. The presence of preoperative impairment (e.g. pleural effusions, hypoxaemia, pulmonary hypertension or the hepatopulmonary syndrome) is strongly associated with postoperative complications. Specific conditions related to liver transplantation include right hemidiaphragm palsy as a result of phrenic nerve damage, which can occur if suprahepatic caval clamping is used intraoperatively. The commonest postoperative problems are pleural effusions, ongoing shunting secondary to the hepatopulmonary syndrome, atelectasis and, over subsequent days, infection. De novo acute lung injury and the acute respiratory distress syndrome are relatively uncommon at this stage. Other complications such as TRALI and pulmonary oedema are almost certainly underrecognised and underreported.

Specific management of portopulmonary syndrome may be required in the postoperative period if right-sided pressures are elevated, to ensure that liver congestion and graft dysfunction do not ensue.^6,^24,²⁵ Control of pulmonary pressures may require a variety of therapeutic options, with the treatment options being similar to those utilised in primary pulmonary hypertension. Concern about potential hepatotoxicity needs to be balanced against the need to control right-sided pressures and provide optimal graft function. Similarly, hepatopulmonary syndrome may take a variable time to resolve and hypoxia during this period will require management and recognition.

Respiratory complications are also seen in patients with poor muscle bulk and subsequent weakness. Similarly, the presence of osteoporosis in the pretransplant patient is frequently associated with postoperative pain and poor cough. The role of adequate analgesia is important, as in all patients, in promoting mobilisation and adequate respiratory function. In general, the management of a protracted respiratory wean follows conventional lines.

NEUROLOGICAL

The quoted incidence of central nervous system (CNS) complications varies widely from 10 to 40% in the published series. Most neurological complications occur within the first month of transplant. The commonest causes relate to persistent encephalopathy post transplant in a patient with pre-existing encephalopathy.^26,²⁷ The causes are multiple, including hepatic, metabolic, infectious, vascular and pharmacological. A patient with acute liver failure will remain encephalopathic in the immediate posttransplant period, and is at risk for intracranial hypertension for 48 hours following transplantation, or longer in the face of graft dysfunction. De novo hepatic encephalopathy may develop in patients with severe graft dysfunction and/or primary graft non-function; again the patient is at risk of cerebral oedema. The effects of sepsis, rejection (and its treatment with high-dose steroids), drug therapy (especially the sedatives and analgesics used in the ICU setting) and the presence of renal failure may all contribute to the presence of altered conscious level. The calcineurin inhibitors are particularly associated with seizures and altered conscious level. All such patients will require brain imaging to further define the aetiology of their impaired neurology.

Other possible neurological complications are those of intracerebral haemorrhage. Such bleeds may relate to arteriovenous malformations, may be spontaneous or may be a complication of intracranial pressure monitoring, particularly in patients with acute liver failure. CNS infection normally presents later than the immediate postoperative period but should always be considered, especially in those patients with a prolonged and complicated postoperative course. All possible infecting agents, including bacterial, viral, fungal and opportunistic, should be considered. Central pontine myelinolysis is a rare but potentially devastating complication associated with rapid sodium shifts. Modern technology and the use of haemofiltration techniques allow tight control of sodium shifts in the majority of patients, and this has become a rare neurological complication.

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