Cardiac Manifestations

Cardiac disturbances occur in children with liver disease because of altered physiology, congenital heart defects, and toxic side effects. A hyperdynamic circulation secondary to vasodilation characterizes the altered cardiac physiology from liver disease, with a compensatory increase in cardiac output (CO). Vasodilation is central to the hyperdynamic circulation that accompanies portal hypertension. It likely occurs because of the presence of vasoactive mediators. These mediators or gut-derived “humoral factors” (e.g., nitric oxide [NO], tumor necrosis factor α, endocannabinoids) enter the systemic circulation through portosystemic collaterals and bypass hepatic detoxification.¹⁴ Shunting also occurs at the level of the skin and the lungs. Mixed venous saturation increases in children with liver disease because of poor tissue oxygen extraction. Arterial-venous oxygen difference is reduced because of the combination 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 develop 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, and Gaucher disease.¹⁵ Tacrolimus and cyclosporine A have also been associated with hypertrophic cardiomyopathy in animal studies and in pediatric liver transplant recipients.^16,17,18 Echocardiographic assessment of cardiac function is generally well preserved in children receiving tacrolimus, but there may be evidence of subtle cardiovascular changes, which predispose a small percentage of children to develop hypertrophic cardiomyopathy.¹⁹

Other diseases that may lead to liver failure are associated with congenital heart disease. For example, children with Alagille disease may have pulmonary stenosis, coarctation, tetralogy of Fallot, atrial and ventricular septal defect.

QT prolongation has also been described in adults with alcoholic liver disease and may be associated with sudden cardiac death.²⁰ A decrease in K⁺ currents observed in rat cardiomyocytes with cirrhosis may provide a possible mechanism for the QT prolongation. Children with liver failure have also been shown to have an increase in QT interval (QTc greater than 450 msec in 18% of children with liver disease), possibly increasing the risk of ventricular arrhythmias, however, there is no evidence of an increased dispersion of repolarization (see Chapter 14). These changes appear to be transient and reversible after liver transplantation.²¹ Nonselective β-adrenergic blockade has also been shown to reduce the QT prolongation, but it is unclear if this reduces the risk of arrhythmias or improves survival.²² Although previous data suggested that prolonged QT did not predict decreased survival,²³ more recent evidence suggests that the presence of a prolonged QT was associated with an increased PELD score and portal hypertension. Children with chronic liver disease and prolonged QT may be at increased risk of mortality while waiting for a transplant.²⁴

Pulmonary Manifestations

The hallmarks of the pulmonary manifestations of liver disease are hypoxia and pulmonary hypertension. Hypoxia is secondary to hepatopulmonary syndrome (HPS) and ventilation/perfusion () mismatch from atelectasis caused by tense ascites, hepatosplenomegaly, and/or pleural effusions. HPS is characterized by hypoxia from intrapulmonary arteriovenous shunting and intrapulmonary vascular dilatation.²⁵ The diagnosis is predicated on either arterial hypoxia (Pao₂ less than 70 mm Hg in room air) or an increased alveolar-arterial gradient of more than 20 mm Hg in the setting of pulmonary vascular dilatation. Intrapulmonary vascular dilatation can best be demonstrated on echocardiography or lung perfusion scan with macroaggregated albumin.²⁶ HPS occurs in 15% to 20% of adults and in 0.5% to 20% of infants and children with cirrhosis²⁷ as young as 6 months of age. It appears to be more prevalent in children with biliary atresia and polysplenia syndrome.^28,29

Treatment for hypoxia is long-term supplemental oxygen; definitive treatment is liver transplantation. In a case series of seven children with HPS who were successfully transplanted, all recovered postoperatively with their hypoxia resolving within an average of 24 weeks.³⁰

Portopulmonary hypertension (PPH) is defined by the World Health Organization as pulmonary artery hypertension (pulmonary systolic pressure of 25 mm Hg or greater) in the setting of a normal pulmonary capillary wedge pressure and portal hypertension.³¹ The incidence of PPH is 0.2% to 0.7% in adults with cirrhosis but increase to 3% to 9% in adults presenting for liver transplantation.³² The incidence in children is unknown, with accounts limited to case reports and one case series. Signs and symptoms on presentation are new heart murmurs, dyspnea, and syncope. Echocardiography can successfully identify pulmonary hypertension in pediatric and adult patients with PPH³³; the severity of PPH predicts mortality. In a retrospective review, mild PPH did not increase mortality; however, those children who underwent liver transplantation with moderate PPH (pulmonary artery pressure [PAP] is 35 to 45 mm Hg) had a 50% mortality rate and those with severe PPH (PAP greater than 50 mm Hg) had a 100% mortality rate.³⁴

There are no definitive guidelines for the management of children with PPH. Early identification is essential, and this may be accomplished with echocardiography. If PPH appears likely, cardiac catheterization should be performed to confirm the diagnosis, measure pulmonary artery pressures, and assess the response to NO and epoprostenol. Children who respond to medical management may be candidates for liver transplantation.³⁵ Otherwise, severe PPH is generally a contraindication for liver transplantation because of the increased risk of mortality.

Neurologic Manifestations

Hepatic encephalopathy (HE) is a significant neurologic complication that is classified as either acute (seen in fulminant hepatic failure) or chronic (seen in chronic cirrhosis or chronic portal hypertension). The classification of the severity of acute and chronic HE is similar and is shown in Table 29-1. The pathophysiology is not entirely known, but cerebral edema appears to be a feature of both acute and chronic HE. Cerebral edema is more severe in acute HE and can result in increased intracranial pressure. Ammonia is repeatedly implicated in the pathogenesis of HE and may participate in the process by causing astrocyte swelling and low-grade cerebral edema.^36,37 The two major sources of ammonia in humans are catabolism of endogenous protein and gastrointestinal absorption. Bacterial breakdown of nitrogen-containing products in the gut results in ammonia formation, which is then absorbed in the portal circulation. Factors that increase blood ammonia concentrations can exacerbate the signs and symptoms of HE. These typically include increased catabolism from infection, increased gut absorption from high-protein diets, constipation, and gastrointestinal bleeding. Other neurotoxins that have been implicated in the exacerbation of HE include endogenous production of benzodiazepines, hyponatremia, and inflammatory cytokines; these may all share the final common pathway of increasing cerebral edema.

TABLE 29-1 West Haven Staging Classification of the Severity of Acute and Chronic Hepatic Encephalopathy

Management of HE should begin with assessing the child’s ability to manage their airway. Children with grade 3 (somnolence to semi-stupor, responsive to verbal stimuli but confused) and 4 (coma, unresponsive to verbal or noxious stimuli) HE may require tracheal intubation to protect the airway and to provide adequate oxygenation and ventilation. Otherwise, management typically focuses on reducing gastrointestinal production and absorption of ammonia. Lactulose is often prescribed to create an osmotic gastrointestinal diuresis and to acidify the lumen of the gut to trap ammonia and minimize absorption. Antibiotics (e.g., neomycin and metronidazole) kill the gastrointestinal bacteria that are involved in metabolizing nitrogen products to ammonia. Other medications include sodium benzoate, which combines in the liver with ammoniagenic amino acids, like glycine, to facilitate their excretion.³⁸ Ornithine aspartate may also provide a substrate to the liver for enhancing urea cycle and glutamine synthesis, and reduce ammonia levels. Flumazenil may reduce the symptoms of HE by inhibiting endogenous benzodiazepines and γ-aminobutyric acid, although 0.01 mg/kg in children with fulminant hepatic failure failed to correct the HE.³⁸

Children with fulminant hepatic failure can have increased intracranial pressure (ICP), which is the major cause of mortality and may be a contraindication for liver transplantation. Intracranial hypertension occurs in 38% to 81% of adult patients with fulminant hepatic failure³⁹ and is often monitored in those with fulminant hepatic failure (grade 3 to 4 HE). The risk of intracranial hemorrhage secondary to coagulopathy can be reduced by replacing clotting factors and platelets, and by placing an epidural rather than a subdural monitor.⁴⁰ Management strategies for children with increased ICP should focus on maintaining cerebral perfusion pressure above 60 mm Hg, and ICP at less than 20 mm Hg. Management strategies often include tracheal intubation and ventilation with the head in midline position and slightly elevated to 30 degrees to facilitate venous drainage. Ventilation is adjusted to achieve a Paco₂ of 30 to 35 mm Hg with minimal positive end-expiratory pressure (PEEP). Medical management to reduce ICP includes administering barbiturates or propofol to minimize stimulation and to directly reduce ICP.⁴¹ Mannitol can be administered if ICP remains increased. Hypothermia has also been described, and in a small trial with 14 patients with fulminant hepatic failure, ICP was reduced by maintaining core body temperature at 32° C to 33° C.⁴² Orthotopic liver transplantation is the definitive treatment for children with acute or chronic HE.

Hematologic Manifestations

There are several hematologic alterations associated with liver disease. Anemia is common because of a combination of gastrointestinal bleeding, poor nutrition, and decreased erythropoietin production from renal failure. Portal hypertension can result in splenomegaly, which causes platelet sequestration and thrombocytopenia. All of the coagulation factors (except factor VIII) are synthesized in the liver. As synthetic functions decline, 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 increase in prothrombin time (PT) and partial thromboplastin time (PTT). Children with acute or fulminant hepatic failure can present with a hematologic profile similar to disseminated intravascular coagulation.

Renal Manifestations

Renal failure is common in children 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 (HRS). Prerenal azotemia from hypovolemia is a common cause for renal failure and 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. HRS 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%; in children the incidence is even less, at approximately 5%. The reduced incidence in children may reflect the lack of definitive criteria for diagnosis of HRS in children.⁴³ HRS 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 with portal hypertension.⁴⁴ HRS presents similarly to prerenal azotemia (increased creatinine, decreased urine sodium [U_Na less than 10 mM, Fe_Na less than 1%]), but is differentiated from azotemia by its lack of response to a fluid challenge. HRS has been classified based on the rate of progression of renal failure into types 1 and 2: type 1, which has a worse prognosis, is characterized by a rapid progression of renal failure with a 100% increase in creatinine in less than 2 weeks. It usually occurs in patients with acute liver failure. In type 2, renal failure progresses over weeks to months, and usually occurs in patients with chronic liver disease. Regardless of the type, prognosis is poor in children with HRS, with a mortality of 80% to 95%.⁴⁵ The definitive treatment for HRS is liver transplantation, because the renal failure is reversible if the liver is replaced.⁴⁶

The primary goal in the management of patients with liver disease and renal failure is to exclude treatable and reversible causes, such as nephrotoxins (NSAIDs), hypovolemia (diuretics, gastrointestinal bleeding), and sepsis. All nephrotoxins should be stopped and children should be given a fluid challenge, ideally with a colloid solution. If sepsis is suspected patients should be extensively cultured and antibiotics that are not nephrotoxic administered.

Pretransplant renal function predicts mortality in adult patients undergoing transjugular intrahepatic shunt and liver transplantation, and 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.⁴⁷ At this time it is not clear that serum creatinine is a predictor of mortality in children with liver disease.⁴⁸ Before transplantation, type 1 HRS can be managed with vasoconstrictors (vasopressin analogs, norepinephrine), although there are limited data on their use in children. Critically ill children may require continuous renal replacement therapy (continuous venovenous hemofiltration or hemodiafiltration) as a bridge to transplantation.

Metabolic Manifestations

The metabolic derangements seen in liver disease include glucose, ammonia, electrolyte, and acid-base disturbances. Electrolyte abnormalities include hyponatremia, hypo- and hyperkalemia, hypocalcemia, and hypomagnesemia. Hypoglycemia may occur in children with fulminant hepatic failure or abrupt discontinuation of total parenteral nutrition, but hyperglycemia is more common in the perioperative period. During the dissection and anhepatic phase there are several causes of hyperglycemia. Typically glucose concentrations will increase immediately after reperfusion. Serum glucose increases if there is an exogenous source of glucose or if there is altered glucose metabolism. Exogenous sources include glucose from blood products,⁴⁹ dextrose containing intravenous (IV) fluids, and damaged hepatocytes from the liver graft.⁵⁰ Glucose uptake is altered by methylprednisolone steroid-induced insulin resistance. Hepatic denervation likely results in alterations in insulin and glucose clearance during the postoperative period, and may explain the frequent occurrence of impaired glucose tolerance and diabetes in liver transplant recipients.⁵¹

Acid-base disturbances commonly occur during liver transplantation. Children with renal disease may have a preexisting metabolic acidosis from bicarbonate elimination. A metabolic acidosis is typically present during the dissection and anhepatic phase, but it is usually most pronounced immediately after reperfusion. Lactic acid and citrate (from blood products) are not metabolized during the anhepatic phase and contribute to the acidosis. Cross clamping of the inferior vena cava (IVC) and aorta alters blood flow to gut and lower extremity tissue beds and may also contribute to the lactic acidosis. Once the liver graft begins to function, the metabolism of lactate and citrate may lead to a metabolic alkalosis.⁴⁹

Hepatectomy (Stage 1)

The initial description of orthotopic liver transplantation is referred to as the “classic” technique. In the “classic” approach the liver is dissected to its vascular supply and the supra- and infrahepatic IVC are clamped, along with the portal vein and hepatic artery. The liver is removed enbloc (Fig. 29-1). The disadvantage of this approach is that the IVC is cross clamped, thus reducing 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 only requires partial clamping of the IVC.⁶⁶ The liver is dissected away from the IVC, the short hepatic veins, portal vein, and left, right, middle hepatic vein. The infrahepatic vena cava of the donor is oversewn and the suprahepatic vena cava is anastomosed to the native hepatic veins (Figs. 29-2 and 29-3). This only requires partial clamping of the IVC. A portacaval shunt can be established for children who do not tolerate clamping of the portal vein (see Fig. 29-3). Typically these are recipients who have not developed collateral flow secondary to portal hypertension (e.g., maple syrup urine disease).

FIGURE 29-1 The classic approach for orthotopic liver transplantation. The suture lines are visible at the suprahepatic and infrahepatic anastomoses.

(From Starzl TE, Iwatsuki S, VanTheil DH, et al. Evolution of liver transplantation. Hepatology 1982;2:614-36.)

FIGURE 29-2 The piggyback technique preserves the inferior vena cava (IVC). This is the view of the liver graft after the recipient’s hepatic confluence is anastomosed to the donor’s IVC (the infrahepatic IVC of the donor is ligated).

(From Tzakis A, Todo S, Starzl TE. Orthotopic liver transplantation with preservation of the inferior vena cava. Ann Surg 1989;210:649-52.)

FIGURE 29-3 The native liver has been removed. There is a clamp across the right, middle, and left hepatic veins. The black arrow shows the portacaval shunt. The white arrow shows the hepatic artery. The dashed white arrows show the short hepatic veins.

(From Kuo PC, Davis RD. Comprehensive atlas of transplantation. Philadelphia: Lippincott Williams & Wilkins; 2005, p. 132.)

There are several physiologic considerations that take place during the hepatic dissection that affect the anesthetic management. Hypotension is common and can occur for a variety of reasons. These include 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 (Kasai procedure), and coagulopathy.⁶⁷ Blood conservation during this portion of the surgery by maintaining low central venous pressure (decrease of 30% from baseline) has been described in adults. The reported benefit of a low central venous pressure is less bleeding, with subsequent decrease in allogeneic blood requirements and decreased morbidity. Some studies have suggested an overall reduction in 1-year mortality.^68,69 The technique is controversial and the potential risks include end-organ injury, such as renal or graft failure.⁷⁰ 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 include hyperkalemia, hypocalcemia, hypomagnesemia, and acidosis from 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 IVC cross-clamp, which causes a decrease in preload. Hemodynamically, there is a decrease in cardiac output, central venous pressure, and pulmonary artery pressure, with an increase in systemic vascular resistance.⁶⁷ Preload should be gently augmented to maintain mean arterial pressure (MAP) with the lowest filling pressures possible. Hypervolemia may cause hepatic congestion during reperfusion. Inotropic agents like dopamine or epinephrine may need to be used to maintain MAP. A portacaval shunt, if performed, may moderate some of these hemodynamic changes by preserving preload from the portal vein (if venovenous bypass is going to be used, it is initiated during this period). Unmetabolized citrate causes hypocalcemia and hypomagnesemia because it chelates both. Acidosis occurs from the unmetabolized citrate, lactate, and other acids. Bicarbonate may be administered if there is a significant metabolic acidosis (base deficit less than 5 mEq/L). Once the liver is on the surgical field warm ischemia time begins. The time to reperfusion should be brief, and steps should be in place for reperfusion. Before reperfusion, potassium should be in the low-normal range and calcium and bicarbonate should be in the high-normal range. 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 may be achieved by increasing the serum pH with hyperventilation, and the administration of sodium bicarbonate (1 to 3 mEq/kg). Glucose and insulin can be administered to acutely reduce potassium (see Chapter 8). Potassium-wasting diuretics like furosemide (0.5 to 1 mg/kg) can also be used. Administering fresh blood or washed red blood cells will minimize the increase in potassium during transfusion therapy. β₂-Adrenoceptor 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. Postreperfusion syndrome is characterized by a decrease in MAP of greater than 30%.⁷¹ Several factors participate in this event, including myocardial dysfunction, arrhythmias, and bleeding. The myocardial dysfunction is thought to occur from release of NO and tumor necrosis factor α.⁷² Cardiovascular collapse can occur and the child may require epinephrine to correct the hemodynamic effects of reperfusion.⁷¹ Hyperkalemia is a common event immediately after reperfusion and may cause ventricular arrhythmias. It should be treated with calcium chloride (10 to 30 mg/kg) initially to stabilize the cardiac membrane and then insulin and dextrose, hyperventilation, furosemide, β₂-adrenoceptor agonists, and sodium bicarbonate to decrease the serum potassium concentration (see previous section). The high potassium content of the preservation solution is the cause of the hyperkalemia. University of Wisconsin (UW) solution, a very commonly used preservation solution contains large amounts of potassium (120 mmol/L). Histidine-tryptophan-ketoglutarate (HTK) solution was introduced in 1980 as a cardioplegic solution, and contains substantially less potassium (10 mmol/L) than the UW solution.⁷³ A recent study comparing the two found equal 1-month and 1-year graft survival with HTK and UW solutions. The viscosity is reduced with HTK and may introduce itself more easily into the vascular spaces in the donor liver.⁷⁴ 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.⁷⁵

Fibrinolysis can occur after reperfusion, and in one study it occurred in 60% of children and 80% of adults.⁷⁶ This results from increased tissue plasminogen activator activity and decreased synthesis of fibrinolysis inhibitors. Heparin effect is produced by endogenous heparinoids from the graft, residual heparin from the preservation, and release of tissue plasminogen activator from endothelial cells of the revascularized graft. Aprotinin blunts this response by inhibiting kallikrein and plasmin, which led to the wide spread use of aprotinin. The beneficial effects of aprotinin to reduce blood loss in orthotopic liver transplant in adults and children had been considered inconclusive until the European Multicenter Study on the Use of Aprotinin in Liver Transplantation (EMSALT) study in 2000.⁷⁷ However, the benefits of aprotinin in pediatric patients are not as clear. A retrospective study in 18 pediatric transplant patients receiving a high or regular dose of aprotinin demonstrated a reduction of red cell and fresh frozen plasma transfusion by half, but it was not found to be statistically significant. There is concern that there may be an association between aprotinin and intraoperative thrombotic events (hepatic artery and portal vein thrombosis) in pediatric recipients of liver transplants. Children may be at increased risk for developing intraoperative thrombi or emboli. Children are hypercoagulable after liver transplantation because of a decrease in protein C and antithrombin III,⁷⁸ and they may be more likely to develop hepatic artery thrombosis.^79,80,81 Aprotinin has been removed from the market because of the increased risk of death in adult cardiac patients. Tranexamic acid, an alternative antifibrinolytic is being used in adults for liver transplants; a nonrandomized prospective study did not find a difference in transfusion requirements or thromboembolic events after changing from aprotinin to tranexamic acid.⁸² Currently there are no pediatric data to support or refute the use of tranexamic acid or ε-aminocaproic acid.

Biliary and Hepatic Artery Reconstruction (Stage 4)

The final step is reestablishing hepatic artery blood flow and reconstructing the biliary system. In smaller children, the hepatic artery may require an anastomosis via a conduit to the infrarenal aorta. This requires temporary cross clamping of the aorta. Biliary reconstruction is established by 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 metabolic alkalosis may develop. The hemodynamic goals include maintaining a normal central venous pressure. If the central venous pressure is high (greater than 8 mm Hg), there is a concern that the liver graft can become congested and may not function normally. The risk of hepatic artery thrombosis ranges from 0% to 25% and is greater in infants and children.^80,81 This risk increases if the PT and PPT are corrected. 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. In fact, maintaining the hematocrit at 8 to 9 g/dL is safe and reasonable. Anticoagulation strategies with heparin, dextran, aspirin, and alprostadil may reduce the risk of hepatic artery thrombosis.

Split Liver Techniques and Living Donor Liver Transplants

Advances in surgical technique, tissue preservation, and immunosuppression have resulted in improved survival in children undergoing liver transplantation. The result is more children are awaiting liver transplantation, but the number of available organs has not increased significantly. Children are at a particular disadvantage because of size limitations. Two techniques have attempted to address these issues. 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.^83,84 The technique has evolved, and today the graft is split while still in vivo (in the heart-still-beating donor), as compared to 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 child and graft survival,⁸⁵ which has increased from 60% to 70% in the 1990’s to 80% to 90% in 2003. In one series, 218 split-liver grafts were transplanted between 1995 and 2002. Overall child survival at 1 year was 81.7%, and overall graft survival was 75.8%. Surgical complications that caused a return to the OR were bleeding (9.2%), bowel perforation (8.3%), and biliary problems (7.5%); hepatic artery complications occurred in 6.7%.⁸⁵

Living-donor liver transplantation was first described in 1989.⁸⁶ This approach has reduced mortality among children awaiting liver transplantation. The benefit of a living donor (especially if related), is improved posttransplant results because of better graft quality, smaller ischemic times, and better immune compatibility. In fact, these improved results have been observed in several institutions that perform this procedure.⁸⁷ In a recent study, the 1- and 5-year patient survivals were 94% and 92% respectively.⁸⁸ 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, peripheral nerve injuries, biliary leakage, abdominal wall defects, pleural effusions, pneumonia, pulmonary emboli, and death.^88,89,90 Other than death, these complications were without long-term sequelae, except for a peripheral nerve injury.⁸⁸

Outcomes

The Studies of Pediatric Liver Transplantation (SPLIT) registry was initiated in 1995 and consists of 38 centers in the United States and Canada. These centers contributed 85% of the pediatric liver transplants in 2002. Transplants performed more recently had greater survival rates. In the past, age less than 1 year was considered an increased risk factor for mortality, but over the past 20 years there is little mortality difference between children less than 2 years of age and those greater than 2 years of age at transplant.⁹¹

Survival also depends on the preoperative MELD/PELD score. Patients stratified to status 1 had a significantly smaller 1-year survival rate when compared to other transplant recipients (76% vs. 87%). Adults with MELD scores greater than 35 demonstrated decreased 1-year patient and graft survival. There is a suggestion that pediatric patients with greater PELD scores have decreased 1-year patient and graft survival, but that association was not statistically significant. The overall 1-year survival remained excellent, at more than 85%⁹² (E-Fig. 29-2).

E-FIGURE 29-2 Kaplan-Meier plots of patient survival for pediatric recipients receiving deceased-donor liver transplants, stratified by calculated PELD score. M, MELD score; P, PELD score.

(From Freeman RB, Harper A, Edwards EB. Excellent liver transplant survival rates under the MELD/PELD system. Transplant Proc 2005;37:585-8.)

Children Weighing More Than 20 kg

In larger children (more than 20 kg), the surgical approach is similar to that in the adult transplant patient; the kidney is placed in the iliac fossa, and the vascular anastomoses are to the common iliac vein and artery.^146,147 In larger children, the external iliac vessels may be used.¹⁴⁷ An extraperitoneal approach has the advantage of increased ease of future graft biopsy and ability to resume peritoneal dialysis in case of delayed graft failure.¹⁴⁵

Children Weighing Less Than 20 kg

If renal transplantation in smaller children were restricted to size-compatible organs, then the surgical approach would be similar to that of the larger patient. However, a 1992 NAPRTCS report noted an increased loss of cadaveric grafts from pediatric donors. These pediatric donor organs had a greater rate of graft thrombosis and primary nonfunction, as well as a greater risk for acute rejection.^150,151 Consequently, the use of pediatric donors has declined and living donors increased (Fig. 29-5). More importantly, the improvement in graft survival (Figs. 29-6 and 29-7) and patient survival (Fig. 29-8) with a living donor, although present across age-groups, is markedly greater in these young children.¹¹¹

FIGURE 29-5 Patient registrations, transplants, and selected characteristics.

(Exhibit 1.1 from The North American Pediatric Renal Trials and Collaborative Studies 2010 Annual Transplant Report. Available at https://web.emmes.com/study/ped/annlrept/annlrept.html [accessed June 17, 2011].)

FIGURE 29-6 Living-donor graft survival by recipient age.

(Exhibit 5.4 from The North American Pediatric Renal Trials and Collaborative Studies 2010 Annual Transplant Report. Available at https://web.emmes.com/study/ped/annlrept/annlrept.html [accessed June 17, 2011].)

FIGURE 29-7 Deceased-donor graft survival by recipient age.

(Exhibit 5.5 from The North American Pediatric Renal Trials and Collaborative Studies 2010 Annual Transplant Report. Available at https://web.emmes.com/study/ped/annlrept/annlrept.html [accessed June 17, 2011].)

FIGURE 29-8 Patient survival by age at transplant when grafts were received from living (A) and deceased (B) donors; transplant era 1996 to 2006.

(Exhibit 7.6 from The North American Pediatric Renal Trials and Collaborative Studies 2010 Annual Transplant Report. Available at https://web.emmes.com/study/ped/annlrept/annlrept.html [accessed June 17, 2011].)

For these reasons, the surgical technique for renal transplantation in the infant and small child has been modified to accommodate the adult-sized kidney. The use of a size-discrepant organ precludes the traditional approach. As Starzl et al¹⁵² describe: “the adult organ almost completely fills a child’s right paravertebral gutter, extending from the undersurface of the liver to the pelvis.” Typically, a midline incision from pubis to xiphoid is used and the cecum and right colon are mobilized.^{146,149,152,153} An alternate approach used by some centers, is a right lower quadrant incision, dissecting extraperitoneally; ^147,154 this may have the advantage of quicker return of bowel function. Depending on the size of the recipient’s vessels, the donor organ anastomoses may be made to the common iliac artery and vein, or directly to the aorta and vena cava.^{146,147,149,153}

In addition to difficulties in surgical technique, adult organs in pediatric recipients present physiologic challenges. The adult-sized organ sequesters a disproportionate amount of the infant’s blood volume and cardiac output.^145,146,155 In one study¹⁵⁶ that involved nine infant recipients of adult-sized kidneys, pretransplant, early posttransplant, and late posttransplant blood flows were determined in both the infant’s aorta and the adult graft. Pretransplant graft flow was approximately 618 mL/min, whereas 8 to 12 days posttransplant, graft flow had decreased to 385 mL/min, despite aortic blood flow increasing from 331 mL/min to 761 mL/min. A further decrease was observed at 4 to 6 months, with aortic blood flow at 665 mL/min and graft flow at 296 mL/min. At 4 months the graft size had decreased by 26%. Even with excellent conditions, optimal hydration, and a doubling of aortic blood-flow, these adult grafts are still underperfused, both during transplant and in the late posttransplant period. In addition, the transplanted kidney is vulnerable to further reductions of flow resulting from gastrointestinal illness, poor oral intake, or hypotension during nontransplantation surgery.¹⁵¹ This may explain why early graft loss in these smaller children is either primary nonfunction or thrombosis (E-Fig. 29-3).¹⁵⁷

E-FIGURE 29-3 Causes of graft loss—relationship with recipient age.

(From Hwang AH, Cho YW, Cicciarelli J, et al. Risk factors for short- and long-term survival of primary cadaveric renal allografts in pediatric recipients: a UNOS analysis. Transplantation 2005;80:466-70.)