Organ Transplantation

Cardiac Considerations

Cardiac disturbances occur because of altered physiology, congenital heart defects, and toxic medication adverse effects. A hyperdynamic circulation with a compensatory increase in cardiac output (CO) secondary to vasodilation characterizes the altered cardiac physiology from liver disease. Vasodilation is central to the hyperdynamic circulation that accompanies portal hypertension. It likely is the result of the presence of vasoactive mediators. These mediators or gut-derived “humoral factors” (nitric oxide [NO], tumor necrosis factor [TNF]-α, endocannabinoids) enter the systemic circulation through portosystemic collaterals and bypass the hepatic detoxification that usually occurs. Shunting also occurs in the skin and lungs. Mixed venous saturation is increased in patients with liver disease. Poor oxygen extraction and increased CO likely explain the increased mixed venous saturation. The arterial-venous oxygen difference is reduced because of decreased oxygen consumption and hypoxia from arterial-venous shunting.

Cardiomyopathy associated with portal hypertension is well described in adults but is not well characterized in children with liver disease. However, children with liver disease can have a cardiomyopathy for other reasons. Inborn errors of metabolism and other syndromes are associated with cardiomyopathies and cardiac anomalies. Some of the inborn errors include Wilson disease, oxalosis, glycogen storage disease type III, tyrosinemia, and Gaucher disease. Tacrolimus and cyclosporine A have also been associated with hypertrophic cardiomyopathy in animal studies and in pediatric liver transplant recipients. Other studies have demonstrated that the cardiac function is generally well preserved in pediatric liver transplant patients who are receiving tacrolimus, but there may be evidence of subtle cardiovascular changes that predispose a small percentage of patients to develop hypertrophic cardiomyopathy. Alagille disease is commonly associated with congenital heart disease (CHD) such as pulmonary stenosis, coarctation, tetralogy of Fallot, and atrial and ventricular septal defects. Diastolic dysfunction has been associated with increased mortality after transplantation.

QT prolongation of the electrocardiogram (ECG; see Chapter 16 ) has been described in adult patients with alcoholic liver disease and may be associated with sudden cardiac death. A decrease in K ⁺ currents in cardiomyocytes in rats with cirrhosis may provide a possible mechanism for the QT prolongation. Children with liver failure have also been shown to have an increase in QTc interval. A QTc greater than 450 msec has been reported in 18% of children with liver disease. These findings may increase the risk of ventricular arrhythmias; however, there are conflicting data regarding resolution after liver transplantation. Nonselective β-blockade has also been shown to reduce the QT prolongation, but it is unclear if this reduces the risk of arrhythmias or improves survival. Although previous data suggested prolonged QT did not predict survival, more recently the presence of prolonged QT was associated with a greater PELD score and portal hypertension. Pediatric patients with chronic liver disease and prolonged QT may be at increased risk of mortality while waiting for a transplant.

Pulmonary Considerations

Pulmonary hallmarks of liver disease are hypoxia and pulmonary hypertension. Hypoxia can occur for several reasons including hepatopulmonary syndrome (HPS) and V̇/Q̇ mismatch from atelectasis owing to ascites, hepatosplenomegaly, or pleural effusions. HPS is characterized by hypoxia from intrapulmonary arteriovenous shunting (caused by increased angiogenesis) and intrapulmonary vascular dilatation. The diagnosis is made by demonstrating either arterial hypoxia (Pa o ₂ <70 mm Hg) or an increased alveolar-arterial gradient greater than 20 mm Hg in the setting of pulmonary vascular dilatation. Intrapulmonary vascular dilatation can best be demonstrated using echocardiography or a lung perfusion scan with macroaggregated albumin. HPS occurs in at least 15% to 20% of adults with cirrhosis. HPS has been reported in infants 6 months of age and is described in 0.5% to 20% of all children with liver disease. It appears to be more prevalent in children with biliary atresia and polysplenia syndrome. When adjusted for the severity of hepatic disease, HPS does not affect mortality. A normal pulse oximetry value in children with cirrhosis does not necessarily rule out HPS. Children with normal pulse oximetry may exhibit other criteria for the diagnosis (intrapulmonary vasodilatation and alveolar-arterial gradient greater than 15 mm Hg) and may be at increased risk for morbidity and mortality.

Treatment for hypoxia is long-term supplemental oxygen. Definitive treatment may occur with liver transplantation. One case series described seven children with HPS who had successful transplants; all seven children recovered from their HPS postoperatively. The average time required to correct hypoxia after transplantation was 24 weeks.

Portopulmonary hypertension (PPH) is defined by the World Health Organization (WHO) as pulmonary artery hypertension (pressure >25 mm Hg) in the setting of normal pulmonary capillary wedge pressure and portal hypertension. The incidence of PPH is 0.2% to 0.7% in adults with cirrhosis but increases to 3% to 9% in adults presenting for liver transplantation. The number is not known in children and is limited to case reports and case series. Evidence from case series and autopsy data suggest that the incidence of PPH is 0.5% to 5% in children with portal hypertension. Signs and symptoms on presentation were new heart murmurs, dyspnea, and syncope. Echocardiography can successfully identify pulmonary hypertension in children and adult patients with PPH. The severity of PPH predicts mortality. Adult patients with mild PPH had no increase in mortality during liver transplantation. However, those patients who underwent OLT with moderate PPH (pulmonary artery pressure [PAP] = 35–45 mm Hg) had a 50% mortality rate and those with severe PPH (PAP >50 mm Hg) had a 100% mortality rate.

There are no definitive guidelines for the management of children with PPH. Early identification is essential, and all children who present for liver transplantation should be evaluated for the presence of PPH with echocardiography. If present, cardiac catheterization needs to be performed to confirm the diagnosis, measure PAPs, and assess the response to NO and epoprostenol. Children who respond to medical management may be candidates for liver transplantation. Otherwise, severe PPH is generally a contraindication for liver transplantation because of the increased risk of mortality.

Neurologic Considerations

Hepatic encephalopathy (HE) is a neurologic complication of liver disease classified as either acute (seen in fulminant hepatic failure) or chronic (seen in chronic cirrhosis or chronic portal hypertension). Minimal encephalopathy, diagnosed with neuropsychological testing, may be present in as many as 50% of children with chronic liver disease. The pathophysiology is not entirely known but cerebral edema is a feature of both acute and chronic HE. The cerebral edema is more severe in acute HE and can result in increased intracranial pressure (ICP). Ammonia is repeatedly implicated in the pathogenesis of HE and may participate in the process by causing astrocyte to swell, resulting in low-grade cerebral edema. The two major sources of ammonia in humans are catabolism of endogenous protein and gastrointestinal absorption of exogenous protein. Bacterial breakdown of nitrogen-containing products in the gut results in ammonia formation, which is then absorbed in the portal circulation. Factors that can increase blood ammonia concentrations can exacerbate the signs and symptoms of HE. These typically include increased catabolism from infection or increased gut absorption from high-protein diets, constipation, and gastrointestinal bleeding. Other factors that have been implicated in the exacerbation of HE include benzodiazepines, hyponatremia, and inflammatory cytokines, which may all share a final common pathway to increase cerebral edema.

Management of HE should begin with assessing the child's ability to manage his or her airway. Children with grade 3 and 4 HE may require tracheal intubation to protect the airway to ensure adequate oxygenation and ventilation. Otherwise, management typically focuses on reducing gastrointestinal production and absorption of ammonia. Lactulose is often prescribed to create an osmotic diarrhea and to acidify the lumen of the gut to trap ammonia and minimize absorption. Antibiotics such as neomycin and metronidazole have been used to kill the gastrointestinal bacteria involved in metabolizing nitrogen products to ammonia. Other medications include sodium benzoate, which combines in the liver with ammoniagenic amino acids, such as glycine, to facilitate their excretion. Ornithine aspartate may also provide a substrate to the liver for enhancing the urea cycle and glutamine synthesis and to reduce ammonia concentrations. Flumazenil has been postulated to reduce the symptoms of HE by inhibiting endogenous benzodiazepines and γ-aminobutyric acid. However, this benefit was not demonstrated in children who received 0.01 mg/kg flumazenil for HE in the setting of fulminant hepatic failure.

Patients with fulminant hepatic failure can have increased ICP, which is the major cause of mortality and may be a contraindication for liver transplantation. Intracranial hypertension occurs in 38% to 81% of patients with fulminant hepatic failure. ICP is often monitored in patients with fulminant hepatic failure with grade 3 to 4 HE. However, there is a risk of intracranial hemorrhage secondary to coagulopathy. This risk can be reduced by replacing clotting factors and platelets and by placing an epidural rather than a subdural ICP monitor. Management strategies for patients with increased ICP should focus on maintaining a cerebral perfusion pressure greater than 60 mm Hg and an ICP less than 20 mm Hg. Often this includes tracheal intubation and ventilation. Patients should be positioned with their heads midline and slightly elevated to 30 degrees to facilitate venous drainage. Ventilation should focus on achieving a Pa co ₂ of 30 to 35 mm Hg with minimal positive end-expiratory pressure (PEEP). Medical management to reduce ICP includes administering thiopental or propofol to minimize stimulation and to reduce ICP. Mannitol can be administered if ICP remains increased. Hypothermia has also been described in a small trial with 14 patients with fulminant hepatic failure; maintaining core body temperature at 32°C to 33°C reduced ICP, but the impact on outcome is less certain. Orthotopic liver transplantation is the definitive treatment for patients with acute or chronic HE.

Hematologic Considerations

Anemia is common and occurs because of a combination of gastrointestinal bleeding, poor nutritional state, and decreased erythropoietin production from renal failure. Portal hypertension can result in splenomegaly, which causes platelet sequestration and thrombocytopenia. All the coagulation factors (except factor VIII) are synthesized in the liver. As synthetic function declines, coagulation factor production diminishes. The reduction in bile salt also decreases the absorption of fat-soluble vitamins (A, D, E, K) and contributes to the deficiency of factors II, VII, IX, and X. The result is an elevated prothrombin time (PT) and partial thromboplastin time (PTT). Patients with acute or fulminant hepatic failure can present with a hematologic profile similar to disseminated intravascular coagulation (DIC).

Renal Manifestations

Renal failure is common in patients with acute and chronic liver disease and its cause is multifactorial. Renal failure can be classified as prerenal azotemia, acute tubular necrosis (ATN), or hepatorenal syndrome. Prerenal azotemia from hypovolemia occurs secondary to diuretic therapy, gastrointestinal bleeding, splanchnic pooling, and sepsis. ATN occurs because of decreased central blood volume secondary to central splanchnic pooling and decreased prostaglandin synthesis. The hepatorenal syndrome is characterized by renal failure in the setting of liver failure and portal hypertension. The incidence in adults with chronic liver disease is approximately 10% to 15%. The lower incidence in children (5%) possibly reflects the lack of criteria for the diagnosis of hepatorenal syndrome in children. It occurs secondary to intense renal vasoconstriction from activation of the renin-angiotensin, arginine vasopressin, and sympathetic nervous systems. This activation is a homeostatic response to the profound splanchnic vasodilation that occurs in patients with portal hypertension. Hepatorenal syndrome appears similar to prerenal azotemia (increased serum creatinine, decreased urine Na (U _Na <10 mM, fractional excretion of sodium [FE _Na ] <1%]) but it is differentiated by its lack of response to a fluid challenge (see Chapter 28 ). Hepatorenal syndrome is classified into two types. The rate of progression of renal failure distinguishes the two types. Type 1, which has a worse prognosis, is characterized by a rapid progression of renal failure with a 100% increase in serum creatinine in less than 2 weeks. It usually occurs in acute liver failure. Type 2 progresses over weeks to months and usually occurs in children with chronic liver disease. Regardless of the type, prognosis is poor in patients with hepatorenal syndrome with a mortality rate of 80% to 95%. The definitive treatment for hepatorenal syndrome is liver transplantation because the renal failure is reversible if the liver is replaced.

The primary goal in the management of patients with liver disease and renal failure is to exclude treatable and reversible causes of renal failure such as nephrotoxins (e.g., nonsteroidal antiinflammatory drugs), hypovolemia (e.g., diuretics, gastrointestinal bleeding), and sepsis (e.g., spontaneous bacterial peritonitis [SBP]). All nephrotoxins should be stopped and patients should be given a fluid challenge, ideally with a colloid solution. If sepsis is suspected, extensive cultures should be obtained and nonnephrotoxic antibiotics should be started.

Pretransplant renal function predicts mortality in adults undergoing transjugular intrahepatic shunt and liver transplantation. This underscores the importance or renal function and explains why serum creatinine is used in the MELD score. Preexisting renal failure is also a major determinant of survival after liver transplantation in adults. Efforts to improve renal function pretransplant may improve posttransplantation outcome. It is not clear whether serum creatinine is a predictor of mortality in children with liver disease. Type 1 hepatorenal syndrome can be managed by treating reversible causes such as providing antibiotic treatment for spontaneous bacterial peritonitis before transplantation. Critically ill children may require continuous renal replacement therapy (continuous venovenous hemofiltration, continuous venovenous hemodiafiltration) and vasopressors as a bridge to transplantation.

Metabolic Considerations

Metabolic derangements include glucose, ammonia, electrolyte, and acid-base disturbances. Electrolyte abnormalities include hyponatremia, hypokalemia and hyperkalemia, hypocalcemia, and hypomagnesemia. Hypoglycemia may occur in patients with fulminant hepatic failure or abrupt discontinuation of TPN, but hyperglycemia is more common in the intraoperative and postoperative period.

Hepatectomy (Stage 1)

The initial description of OLT is referred to as the “classic” technique. In the classic approach, the liver is dissected to its vascular supply and the suprahepatic and infrahepatic vena cava (VC) are clamped along with the portal vein and hepatic artery. The liver is removed en bloc ( Fig. 31.1 ). The disadvantage of this approach is the VC cross-clamp and the associated reduction in preload. The piggyback technique was described 1989 and is the preferred approach for pediatric transplants because there is more flexibility with the organ size and it requires only partial clamping of the VC. The liver is dissected away from the IVC, the short hepatic veins, portal vein, and left, right, and middle hepatic vein. The infrahepatic VC of the donor is oversewn and the suprahepatic VC is anastomosed to the native hepatic veins ( Figs. 31.2 and 31.3 ). This requires only partial clamping of the IVC. A portocaval shunt can be established for patients who do not tolerate clamping of the portal vein (see Fig. 31.3 ). Typically, these are patients who have not developed collateral flow secondary to portal hypertension (e.g., MSUD).

Several physiologic considerations that take place during the hepatic dissection affect the anesthetic management. Hypotension is common and can occur as the result of changes to the cardiovascular, hematologic, and metabolic systems. The most common cause of hypotension includes hypovolemia secondary to hemorrhage and third-space volume losses. Resuscitation with citrated blood products can result in hypocalcemia and surgical manipulation can cause mechanical compression of the IVC or right ventricle. Bleeding occurs from fragile collaterals, adhesions from prior surgery (e.g., Kasai procedure), and coagulopathy. Blood conservation with a reduction in allogeneic blood exposure may have a significant benefit on perioperative morbidity including infections, intensive care unit (ICU) stay, and hospital stay. One technique to reduce blood loss is the maintenance of low CVP (decrease of 30% from baseline) as has been described in adults. The reported benefit of a low CVP is less bleeding with subsequent decrease in allogeneic blood requirements and decreased morbidity. Some studies have also suggested an overall reduction in morbidity and 1-year mortality. The technique is controversial and the potential risks include end-organ injury, such as renal or graft failure. This technique has not been described in the pediatric liver transplant population.

Hematologic abnormalities include anemia, thrombocytopenia, coagulation factor deficiency, and low fibrinogen. A progressive coagulopathy can develop during this stage. Metabolic derangements including hyperkalemia, hypocalcemia, hypomagnesemia, and acidosis occur from volume resuscitation with blood products.

Anhepatic Stage (Stage 2)

The anhepatic phase begins once the hepatic veins, hepatic artery, and portal vein are cross clamped. The dissection of the recipient's liver is completed and the organ is removed. This phase ends when the hepatic and portal vein cross clamps are removed and the graft is reperfused.

Cardiovascular changes that occur during this stage can result in hypotension. This occurs from the inferior vena cava cross-clamp, which decreases the preload. Hemodynamically, CO, CVP, and PAP decrease while systemic vascular resistance increases. Preload should be gently augmented to maintain mean arterial pressure (MAP) with the minimum filling pressures possible. Hypervolemia may cause hepatic congestion during reperfusion. Inotropic agents such as dopamine or epinephrine may be needed to maintain mean arterial blood pressure. A portocaval shunt may mollify some of these hemodynamic changes by preserving preload from the portal vein. (If VVBP is planned, it is initiated during this period.) Unmetabolized citrate causes hypocalcemia and hypomagnesemia since it chelates both cations. Acidosis occurs from the unmetabolized citrate, lactate, and other acids. Bicarbonate may be administered if there is a significant metabolic acidosis, although there is no evidence that this improves outcomes. In fact, a mild metabolic acidosis during reperfusion may not be detrimental since it will be later offset by the metabolism of citrate, which produces bicarbonate.

Once the liver is on the surgical field warm, ischemia time begins. The time to reperfusion will be brief and steps need to be in place for reperfusion. The potassium should be low-normal and the calcium should be high-normal, hemoglobin should be maintained between 9 and 10 g/dL. If the potassium is greater than 5 mEq/L, steps need to be taken to reduce it. This includes increasing the serum pH with hyperventilation and the administration of sodium bicarbonate (1–3 mEq/kg). Glucose and insulin can be administered to acutely reduce the potassium concentration as well (see Chapters 7 and 27 ). Potassium-wasting diuretics such as furosemide (0.5–1 mg/kg) can also be used. Administering fresh blood or washed red blood cells will minimize the increase in potassium during transfusion therapy. β ₂ -Agonists may decrease potassium and can be used. Calcium and epinephrine should be immediately available for reperfusion.

Reperfusion (Stage 3)

The liver graft can be reperfused once the hepatic and portal vein anastomosis are complete. Before reestablishing hepatic blood flow, the graft is flushed to remove the preservation solution to minimize the reperfusion syndrome.

Many changes can occur acutely during the reperfusion period secondary to cardiovascular, hematologic, and metabolic derangements. Reperfusion syndrome is characterized by a decrease in MAP of greater than 30%. Factors participating in this event include myocardial dysfunction, arrhythmias, and bleeding. The myocardial dysfunction is attributed to the release of NO and TNF-α. Cardiovascular collapse can occur and patients may require epinephrine to correct the hemodynamic effects of reperfusion. Hyperkalemia is a common event immediately following reperfusion and may cause ventricular arrhythmias. Hyperkalemia should be treated with calcium chloride (10–30 mg/kg) initially to stabilize the cardiac membrane and then insulin and dextrose, hyperventilation, furosemide, β ₂ -agonists, and sodium bicarbonate to decrease the serum potassium concentration (see previous section). The increased potassium content of the preservation solution is the cause of hyperkalemia. The University of Wisconsin solution, a very commonly used preservation solution, contains large amounts of potassium (120 mmol/L). Histidine-tryptophan-ketoglutarate solution was introduced in 1980 as a cardioplegic solution and contains significantly less potassium (10 mmol/L) than University of Wisconsin solution. A recent study comparing the two solutions found equal 1-month and 1-year graft survival with histidine-tryptophan-ketoglutarate and University of Wisconsin solution. The viscosity is reduced with histidine-tryptophan-ketoglutarate solution and may introduce itself more easily into the vascular spaces in the donor liver. Although hyperkalemia is the hallmark electrolyte disturbance in the immediate reperfusion period, hypokalemia is more common in children throughout the intraoperative period and may require correction.

Fibrinolysis can occur after reperfusion and in one study it occurred in 60% of children and 80% of adults. This occurs from increased tissue plasminogen activator activity and decreased synthesis of fibrinolysis inhibitors. Heparin effect occurs from endogenous heparinoids from the graft and residual heparin from the preservation and the release of tissue plasminogen activator from endothelial cells of the revascularized graft. Antifibrinolytic medications blunt this process, but there is concern that there may be an association with antifibrinolytics and intraoperative thrombotic events (hepatic artery and portal vein thrombosis) in pediatric patients receiving liver transplants. Children can have a mixed coagulation picture after transplantation and may be hypercoagulable because of a decrease in protein C and antithrombin III. This may result in hepatic artery thrombosis. Tranexamic acid, ε-aminocaproic acid, and other methods to reduce transfusion needs in adult liver transplants have been advocated, but there are no pediatric transplant data to support or refute the use of tranexamic acid or ε-aminocaproic acid and the adult series have small sample sizes.

Biliary and Hepatic Artery Reconstruction (Stage 4)

The final step is reestablishing hepatic artery blood flow and reconstructing the biliary system. The hepatic artery may require an anastomosis via a conduit to the infrarenal aorta in infants. This requires temporary cross-clamping of the aorta. Biliary reconstruction is established by either directly connecting the graft and the recipient's common bile ducts or by connecting the common duct of the graft to a Roux-en- Y limb of the recipient's jejunum.

During biliary reconstruction, metabolic and hematologic alterations are addressed. As the liver graft begins to function the citrate administered during the previous three phases is metabolized and the patient can develop a metabolic alkalosis . One of the hemodynamic goals includes maintaining a normal CVP. If the CVP is increased (>8–10 mm Hg), there is concern that the liver graft can become congested and not function normally. The risk of hepatic artery thrombosis ranges from 0% to 25% and is greater in infants and children. This risk may be increased if the PT and PTT are corrected to normal values. Also, the viscosity from a greater hematocrit may increase the risk of hepatic artery or portal vein thrombosis. The hematocrit does not need to be corrected to normal values; maintaining the hematocrit at 8 to 9 g/dL is safe and reasonable. Surgical techniques to reduce the risk of hepatic artery thrombosis include anticoagulation with heparin, dextran, aspirin, and alprostadil.

Split Liver Techniques and Living Donor Liver Transplants

Advances in surgical technique, tissue preservation, and immunosuppression have improved the survival in patients undergoing liver transplantation. The result is more patients waiting for liver transplantation without an increase in available organs. Children are at a disadvantage because of the size limitations. Two techniques have attempted to address these issues. In 1984, Bismuth and Houssin split an adult liver and transplanted it into a child. The reduced liver technique does not increase the number of available grafts and efforts were made to perform split liver techniques to make two grafts from one adult donor. The initial results were poor, with an increase in complications and mortality. The technique has evolved and today the graft is split while still in vivo (in the heart-beating donor) compared with ex vivo (splitting performed after the graft is removed from the donor). This decreases cold ischemia time and facilitates hemostasis of the liver edge. The result is improved patient and graft survival. Patient survival has increased from 60% to 70% in the 1990s to 80% to 90% in 2003. In one series, 218 split liver technique grafts were transplanted between 1995 and 2002; overall patient survival at 1 year was 81.7% and overall graft survival was 75.8%. Surgical complications that caused a return to the operating room were bleeding (9.2%), bowel perforation (8.3%), and biliary problems (7.5%). Hepatic artery complications occurred in 6.7%.

Living donor liver transplantation was first described in 1989. The result has been a reduction in mortality among children awaiting liver transplantation. The benefit of a living donor (especially if related) is improved posttransplant results because of better graft quality, shorter ischemic times, and better immune compatibility. One- and five-year patient survival rates were 94% and 92%, respectively. The left hepatic segment is removed for pediatric recipients, whereas the right hepatic lobe is removed for adult recipients. The regenerative capacity of the liver allows the donor to regenerate the liver without hepatic insufficiency. Despite the success of this technique for the recipients, there is considerable risk to the donor. Complications include exposure to blood products, short- and long-term peripheral nerve injuries, biliary leakage, abdominal wall defects, pleural effusions, pneumonia, pulmonary emboli, and death.