Liver and Heart Transplantation

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Chapter 70 Liver and Heart Transplantation

Claus U. Niemann, MD , Abbas Ardehali, MD, FACS

Liver transplantation

1 How many liver transplantations are performed in the United States annually?

Approximately 6000 to 6500 liver transplantations are performed annually in the United States. This includes a small number (3%-5%) from living liver donors. An estimated 17,000 to 18,000 patients are on the waiting list for liver transplantation. Approximately 1600 to 1800 patients die annually while awaiting liver transplantation. One-year, 3-year, and 5-year patient survival after primary transplantation is approximately 88%, 80%, and 74%, respectively.

2 What are the reasons for liver transplantation?

The list of diseases treatable by liver transplantation has expanded steadily over the last decade. Most commonly, the disease process leading to liver transplantation is chronic. Less frequent is acute-on-chronic disease and acute liver failure. Chronic viral hepatitis B or C and alcoholic liver remain the most common reasons for transplantation. Increasingly, nonalcoholic fatty liver disease is an indication for liver transplantation.

Overall, the etiology of chronic liver disease can be classified as follows:

Noncholestatic cirrhosis: Alcohol; hepatitis A, B, C, D; cryptogenic; autoimmune.

Cholestatic cirrhosis: Primary biliary cirrhosis, secondary biliary cirrhosis, primary sclerosing cholangitis.

Metabolic disease: Wilson disease, hemochromatosis, primary oxalosis, glycogen storage disease, α₁-antitrypsin deficiency, tyrosinemia, homozygous hyperlipidemia.

Malignant neoplasm: The single most common neoplasm presenting for liver transplantation is hepatocellular carcinoma. Eligibility for transplantation is most commonly based on tumor burden as defined by the Milan or University of California, San Francisco (UCSF) criteria. Cholangiocarcinoma, hepatoblastoma, and hemangiosarcoma are all very rare indications for transplantation.

Miscellaneous: Biliary atresia (in children most common indication), cystic fibrosis, polycystic liver disease, Budd-Chiari syndrome, neonatal hepatitis.

Acute hepatic necrosis: Etiology unknown, drug induced, acute hepatitis, environmental exposure (i.e., Amanita phalloides mushrooms).

The severity of liver disease is calculated on a numeric scale that ranges from 6 (less ill) to 40 (gravely ill). The scoring system, model for end-stage liver disease (MELD), was introduced almost a decade ago and is also used for allocation of organs. The MELD risk score is a mathematical formula that includes creatinine, bilirubin, and international normalized ratio. It does not include the cause of liver disease. Exception points can be earned with hepatocellular carcinoma and comorbidities such as hepatopulmonary syndrome.

Priority exception to MELD is category status 1, which defines acute severe onset of liver failure (fulminant hepatic failure).

3 Why is a patient rejected for liver transplantation?

Reasons to deny transplantation may be due to medical conditions and psychosocial reasons and may vary from center to center. Liver transplantation is considered a medium- to high-risk procedure. Significant coronary artery disease, compromised cardiac function (reduced ejection fraction), and uncontrolled pulmonary hypertension are considered contraindications for liver transplantation. Nevertheless, patients may be eligible once cardiopulmonary disease is adequately treated (i.e., percutaneous transluminal coronary angioplasty). Significant vasopressor support and intubation (other than airway protection) immediately before transplantation may exclude eligibility for transplantation. Uncontrolled infection or sepsis is also considered a contraindication. A positive HIV test, without evidence of AIDS, is not a contraindication, and reasonable survival has been reported. Advanced hepatocellular carcinoma (outside Milan or UCSF criteria) or metastatic disease is generally considered to be a contraindication because of high risk of recurrence and poor 5-year survival. In fulminant hepatic failure, uncontrolled and markedly elevated intracerebral pressure (ICP) is the most common reason for exclusion.

Psychosocial factors such as active drug or alcohol abuse or the lack of a good social support system may lead to the exclusion of the patient from transplantation. Thorough preoperative evaluation and periodic review of the patient’s medical and psychosocial condition are crucial for successful transplantation and long-term survival.

Older age per se is not a reason to deny liver transplantation. Increasingly, patients older than 65 years of age receive liver transplants.

4 What is the patient pathophysiology before liver transplantation?

Every organ system can be affected by end-stage liver disease. Frequently, patients with end-stage liver disease have considerable comorbidities:

Central nervous system: Hepatic encephalopathy (grade I-IV in chronic and acute-on-chronic disease) and elevated ICP in acute hepatic failure.

Cardiac system: Hyperdynamic circulation with high cardiac output and low systemic vascular resistance. This may be blunted in patients receiving nonselective β-blockade for secondary prevention of upper gastrointestinal bleeding; cirrhotic cardiomyopathy.

Respiratory system:

Pleural effusions (right > left).

Hepatic hydrothorax, atelectasis, hepatopulmonary syndrome (orthodeoxia, PaO₂ < 70 mm Hg on room air, or A − aO₂ gradient > 20 mm Hg, intrapulmonary vascular dilatation).

Portopulmonary hypertension (presence of portal hypertension, precapillary or arteriolar pulmonary hypertension, mean pulmonary artery pressure > 25 mm Hg, pulmonary vascular resistance [PVR] > 240 dyne/second/cm⁻⁵). Pulmonary capillary wedge pressure < 15 mm Hg (all at rest and primary pulmonary hypertension ruled out). Estimation of systolic pulmonary pressure on transthoracic echocardiography can be used as a valuable screening tool. Increasingly, the transpulmonary pressure gradient is also used for evaluation.

Gastrointestinal system: Portal hypertension with possible upper gastrointestinal bleeding, (refractory) ascites.

Hematologic system: Anemia, thrombocytopenia (mainly sequestration into the spleen), prolonged prothrombin time–partial thromboplastin time, and decreased fibrinogen. Hypercoagulability (especially in patients with malignant disease).

Renal system: Hepatorenal syndrome type I or II, acute kidney injury.

Miscellaneous: Significant electrolyte disturbances (sodium, potassium, glucose), immunosuppression with increased risk for infection, malnutrition.

5 What are common complications of patients undergoing liver transplantation?

Perioperative complications depend largely on the medical condition and surgical history of the recipient (see question 4). Poor organ quality can also lead to a complicated perioperative course. The organ quality depends on multiple factors including donor age, organ ischemia time, and mechanism of death. Frequently the donor risk index is used to assess donor organ quality. Slow graft function may result in significantly increased resource utilization. Primary nonfunction of the implanted organ, often still manifesting during surgery, requires immediate relisting and retransplantation of the patient.

Overall, hemodynamic instability requiring multiple vasopressors, significant blood loss, severe coagulopathy, electrolyte or glucose abnormalities, renal dysfunction, and respiratory compromise are not uncommon during liver transplantation.

6 What are indicators of good graft function in the immediate perioperative period?

Bile production (during surgery), correction of negative base excess, normalization of prothrombin time, reduction of diffuse bleeding, decreasing fresh frozen plasma (FFP) requirements, and hemodynamic stability after implantation of the liver.

7 Does every patient receiving a liver transplant need to continue to have an endotracheal tube in place and be admitted to the intensive care unit (ICU) after surgery?

Postoperative intubation is not required per se, as long as commonly accepted extubation criteria are followed and good organ function is established. Blood loss alone should not be considered as an indication for postoperative intubation. Patients can have the endotracheal tube removed either in the operating room or shortly after arrival in the ICU.

Most centers still will admit patients to the ICU for monitoring purposes. However, some centers established fast-track protocols admitting patients with uncomplicated cases to the postanesthesia care unit and subsequently discharge them to the ward (step-down unit).

8 How do you manage the liver transplant patient in the immediate postoperative period?

As for the intraoperative course, the immediate postoperative course is primarily dictated by the medical condition of the recipient and donor organ function. In most cases, therapy is supportive and follows guidelines established for all intensive care patients. However, certain aspects require special attention:

Hypocoagulable or hypercoagulable states: Overall, treatment should be dictated by clinical evidence of bleeding (i.e., drain output, drop in hematocrit). Occasionally, patients require postoperative FFP therapy to offset an initially slow graft function. Platelets may be needed with persistent low platelet counts and evidence of diffuse bleeding. With the exception of a confirmed rapidly dropping hematocrit requiring red blood cell transfusion, transfusion of FFP, platelets, and cryoprecipitate should not be based on laboratory values alone. The threshold for reexploration should be low in the setting of persistent hematocrit drops. Leakage from vascular anastomosis sites and small arterial or venous bleeding should always be considered.

Renal function: Renal dysfunction is frequently present before surgery, and acute kidney injury can develop during the immediate postoperative period. This can be due to temporary renal outflow obstruction during surgery when the inferior vena cava is entirely clamped for insertion of the donor liver. Significant hemodynamic instability requiring large doses of vasopressors and blood loss can contribute to postoperative acute kidney injury. Intraoperative venovenous bypass may ameliorate the outflow obstruction but is not used at most centers. More commonly a piggyback technique is used with preservation of the inferior vena cava. Postoperative supportive therapy of renal function follows ICU standard protocols. In some cases, continuous renal replacement therapy (continuous venovenous hemofiltration) through the immediate postoperative period will help with recovery of renal function.

Glucose and electrolytes: With adequate postoperative liver function and steroid administration, patients tend to have hyperglycemia, which may warrant a continuous insulin infusion. In most cases, the infusion can be tapered off within the first 24 to 48 hours. Depending on the renal function and diuretic or insulin therapy, potassium can be either high or low. If necessary, sodium levels should be corrected cautiously and according to implemented protocols. Calcium homeostasis is not significantly altered in the postoperative period.

Immunosuppression: Allograft rejection can occur at any given point after surgery and is classified as hyperacute, acute, and chronic. Immunosuppressive therapy is usually started immediately after surgery. Commonly used drugs, often in combination, are cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, and steroids. These agents can cause a variety of side effects, including undesired drug interactions, hypertension, hyperlipidemia, and osteoporosis.

Infection: After transplantation, recipients are at a significant risk for bacterial, fungal, and viral infections. Infections in this patient population have increased morbidity and mortality and unique infectious risks compared with immunocompetent ICU patients.

Heart transplantation

9 How many heart transplantations are performed in the United States annually?

In the year 2010, 2333 heart transplantations were performed in the United States. As of May 2011, 3138 patients were on the waiting list for heart transplantation. Approximately 402 patients die annually while awaiting heart transplantation. Nationwide, the 1-year and 3-year patient survival after transplantation is approximately 89% and 81%, respectively.

10 What are the reasons for heart transplantation?

Cardiac transplantation has become an accepted treatment for selected patients with end-stage heart failure. As with liver transplantation, the number of candidates and the waiting time have increased over the last years. The most common causes of end-stage heart disease leading to heart transplantation are cardiomyopathy and coronary artery disease. The etiology of end-stage heart disease can be classified as follows:

Dilated cardiomyopathy: viral, idiopathic, post partum, familial, doxorubicin (Adriamycin), myocarditis, ischemic

Restricted cardiomyopathy: sarcoidosis, amyloidosis, endocardial fibrosis, idiopathic, secondary radiation, chemotherapy

Retransplantation or graft failure: primary failure, hyperacute, acute, chronic rejection, nonspecific, restrictive-constrictive, accelerated allograft coronary artery disease

Other: congenital disease, valvular disease, hypertrophic cardiomyopathy

It is important to keep in mind that medical treatment of patients with end-stage heart disease continuously improves, selected patients can be managed medically, and survival outcomes have become similar to those of heart transplantation. Hence heart transplantation should be offered to patients who have severe disability due to their cardiac disease despite optimal medical treatment and also have no major contraindications for heart transplantation. More recently the ventricular assist device has emerged as another option for patients with end-stage heart disease that is refractory to medical therapy.

11 Why is a patient rejected for heart transplantation?

Contraindications may vary slightly from center to center. Common contraindications include significant or irreversible pulmonary hypertension; renal, hepatic, cerebrovascular disease; uncontrolled infection or sepsis; and cancer of uncertain status. Patients with systematic diseases that affect multiple organs, such as amyloidosis, may not be suitable candidates for heart transplantation. In addition, noncompliance, psychological instability, lack of social support, and active drug use may exclude a patient from heart transplantation. Old age per se is not a reason to deny heart transplantation. Indeed, increasingly, patients older than 65 years of age are transplant recipients.

12 What is the physiology after heart transplantation?

Although baseline cardiac function is generally preserved, the cardiac response to demand is significantly altered. Cardiac denervation is nearly always permanent after transplantation. Because of the lack of sympathetic innervation, heart rate can only increase slowly via increased circulating catecholamine levels. Maintaining an adequate stroke volume therefore becomes paramount to sustain cardiac output in these patients. Hence, patients after heart transplantation are very preload dependent. Denervation also affects the pharmacologic therapy in these patients. Drugs that act indirectly on the heart, through either the sympathetic or parasympathetic nervous system, are ineffective. Drugs acting directly on the heart are the agents of choice to modify cardiac physiology. In addition, denervation of the heart usually prevents the recipient from experiencing chest pain when myocardial ischemia is present.

13 What are common complications seen in patients undergoing heart transplantation?

Long-term survival has significantly improved for patients undergoing heart transplantation. However, a number of complications may occur after transplantation. The complications include right or left ventricular failure, pulmonary hypertension, systemic hypertension, heart block, bradyarrhythmias, tachyarrhythmias, early graft failure, allograft rejection, accelerated allograft coronary artery disease, renal dysfunction, infection, and malignancy.

The postoperative stability of the patient is also affected by donor characteristics and by the operative technique chosen. The use of the bicaval techniques over the biatrial technique has resulted in less atrioventricular valve dysfunction and arrhythmia. Use of these newer techniques has also shown improvements in hemodynamics, exercise capacity, and overall patient survival.

14 How do you manage the heart transplant patient in the immediate postoperative period?

Preload dependence: As mentioned, patients are very preload dependent because of cardiac denervation. This renders them sensitive to positive pressure ventilation, bleeding or tamponade, and pneumothorax.

Increased PVR or right ventricular failure: Although fixed pulmonary hypertension will have been excluded before surgery, postoperative increased PVR may still develop. If severe and untreated, it can lead to right ventricular failure in the newly grafted heart. Management of increased PVR includes inhaled vasodilators such as prostacyclin and nitric oxide. Intravenous vasodilators such as nitroglycerin and nitroprusside are also options. Unfortunately, intravenous vasodilators are associated with systemic hypotension, and their use may require an additional α-agonist infusion. Right ventricular dysfunction can also be treated with atrial pacing, β-adrenergic agonists, and phosphodiesterase inhibitors. If these measures are ineffective, right ventricular assist devices or ECMO may be required.

Cardiac arrhythmias: In addition to bradycardia and heart block, atrial and ventricular tachyarrhythmias are also quite common after heart transplantation. Atrial arrhythmias may be associated with allograft rejection.

Rejection or graft failure: Allograft rejection can occur at any given point after surgery and is classified as hyperacute, acute, and chronic. Diagnosis of cellular rejection of the transplanted heart relies mainly on endomyocardial biopsy particularly in view of vague clinical symptoms and no reliable serologic markers. Serial biopsies are performed after surgery to detect any sign of rejection. Antibody-mediated rejection is difficult to diagnose; it is usually detected by the rising titer of donor-specific antibodies, when other causes have been excluded.

Immunosuppression: Patients usually start immunosuppressive therapy immediately after surgery. Common drugs, often used in combination, are calcineurin inhibitors (such as cyclosporine, tacrolimus), cell cycle inhibitors (such as mycophenolate mofetil, azathioprine), and steroids. These agents can cause a variety of side effects, as well as drug interactions (see Table 70-1).

^{Table 70-1} Drugs used for immunosuppressive therapy

Azathioprine	Myelosuppression
Cyclosporine	Hypertension, ↓renal function, ↑K⁺, ↓Mg⁺⁺, ↓seizure threshold
Mycophenolate mofetil	Myelosuppression, gastrointestinal bleeding
Prednisone	Hypertension, ↑Glu, adrenal suppression
Tacrolimus	↓Renal function, ↓seizure threshold, ↑Glu, ↑K⁺, ↓Mg⁺⁺