Indications

Heart transplantation is performed in infants and children with end-stage cardiomyopathy who have become refractory to medical therapy, in patients with previously repaired or palliated congenital heart disease who have developed ventricular dysfunction or other nonoperable late-term complications, and (less frequently) in patients with complex congenital heart disease (pulmonary atresia with intact septum and coronary arterial stenoses, some forms of hypoplastic left heart syndrome) for whom standard surgical procedures are extremely high risk. Cardiomyopathies account for >50% of heart transplants in pediatric patients older than 1 yr, although the percentage of patients with previously repaired complex congenital lesions (≈30%) is gradually increasing. In infants younger than 1 yr, congenital heart lesions used to represent >80% of transplants; this fraction has dropped to 65% as standard surgical results for complex congenital heart disease (hypoplastic left heart syndrome) have improved.

Recipient and Donor Selection

Potential heart transplant recipients must be free of serious noncardiac medical problems such as neurologic disease, systemic infection, severe hepatic or renal disease, or severe malnutrition. Many children with ventricular dysfunction may have pulmonary hypertension and even pulmonary vascular disease, which would preclude heart transplantation; pulmonary vascular resistance must be measured at cardiac catheterization, both at rest and in response to vasodilators. Patients with fixed elevated pulmonary vascular resistance are at higher risk for heart transplantation and may be considered candidates for either heterotopic heart transplantation (see later) or heart-lung transplantation (Chapter 437.2). A comprehensive social services evaluation is an important component of the recipient evaluation. Because of the complex post-transplantation medical regimen, the family must have a history of compliance. Detailed informed consent must be obtained.

Donor shortage is a serious problem for both adults and children. At the national registry of transplant recipients in the USA (the United Network for Organ Sharing [UNOS]), allografts are matched by ABO blood group and body weight. HLA matching is not currently performed unless the recipient has preformed antibodies against a particular HLA antigen. Recent data suggests that ABO matching is not required for young infants; the exact age under which ABO tolerance develops has not yet been determined. Contraindications to organ donation include prolonged cardiac arrest with persistent moderate to severe cardiac dysfunction, ongoing systemic illness or infection, and pre-existing severe cardiac disease. Physicians caring for a patient who may be a potential donor should always contact the organ donor coordinator at their institution, who can best judge the appropriateness of organ donation and has experience in interacting with potential donor families. A history of resuscitation alone or reparable congenital heart disease is not an automatic exclusion for donation.

The decision of when to place a patient on the transplant waiting list is based on a combination of many factors, including extremely poor ventricular function (left ventricular fractional shortening <10%; normal is 28-40%), poor exercise tolerance as determined by cardiopulmonary exercise testing (Chapter 417.5), poor response to medical anticongestive therapy, multiple hospitalizations for heart failure, arrhythmia, progressive deterioration in renal or hepatic function, early stages of pulmonary vascular disease, and poor nutritional status. In patients awaiting transplantation, those with poor left ventricular function (fractional shortening <15%) are usually started on a regimen of anticoagulation to reduce the risk of mural thrombosis and thromboembolism. Patients with cardiogenic shock unresponsive to standard pharmacologic treatment may be candidates for placement of left ventricular (LVAD) or biventricular (BiVAD) assist devices, or for extracorporeal membrane oxygenation (ECMO) support, which can stabilize hemodynamics and serve as a bridge to transplantation (Chapter 436).

Perioperative Management

In the classic operation, both donor and recipient hearts were excised so that the posterior portions of the atria containing the venae cavae and pulmonary veins are left intact. The aorta and pulmonary artery are divided above the level of the semilunar valves. The anterior portion of the donor’s atria was then connected to the remaining posterior portion of the recipient’s atria, thereby avoiding the need for delicate suturing of the venae cavae or pulmonary veins. The donor and recipient great vessels were connected via end-to-end anastomoses. This has largely been supplanted by the bicaval anastomosis, with the donor right atrium (and sinus node) left intact and the suture lines at the superior and inferior vena cavae; the left atrial connection is still performed as in the classic procedure. Heterotopic heart transplantation has been used for patients with left ventricular cardiomyopathy and elevated pulmonary vascular resistance. In this operation, the donor and recipient hearts are connected in parallel, so that the recipient right ventricle (which has hypertrophied over time due to the elevated pulmonary pressures) pumps mostly to the lungs, and the donor left ventricle pumps mostly to the body. This operation is preferable to heart-lung transplant for appropriate candidates (patients with pulmonary hypertension but without parenchymal lung disease, without evidence of right ventricular failure, and without serious congenital heart disease), as it is associated with a greater survival at all post-transplant time points.

In the immediate postoperative period, immunosuppression is most commonly achieved with a triple-drug regimen, although some centers use steroid-free regimens. The most common combinations are a calcineurin inhibitor (either cyclosporine or tacrolimus), a white blood cell enzyme inhibitor (mycophenolate mofetil or azathioprine), and prednisone. Some centers are using one of the cell-cycle inhibitors that act on the protein mTOR (target of rapamycin) instead of mycophenolate because of their potential benefit in reducing graft coronary artery disease. In many centers, induction therapy (usually an antilymphocyte preparation) is added in the 1st wk, either antithymocyte globulin (ATG), monoclonal murine antihuman T-lymphocyte antibody (OKT3), or one of the humanized anti–interleukin 2 receptor antibodies (daclizumab, basiliximab). In children who do not experience significant graft rejection, steroids can be gradually eliminated after the 1st 6-12 mo. Some centers do not use steroids as part of maintenance immunosuppression, but do use them as bolus treatment for acute rejection episodes.

Most pediatric heart transplant recipients can be extubated within the 1st 48 hr after transplantation and are out of bed within 3-4 days. These patients are often discharged within the 1st 2 wk after transplantation. In patients with pre-existing high-risk factors, postoperative recovery may be considerably prolonged. For those with preoperative pulmonary hypertension, the use of nitric oxide (NO) in the postoperative period can buy time to allow the donor right ventricle to hypertrophy in response to elevated pulmonary artery pressures. Occasionally, these patients will require right ventricular assist device (RVAD) support.

Diagnosis and Management of Acute Graft Rejection

Post-transplantation management consists of adjusting medications to maintain a balance between the risk of rejection and the side effects of over-immunosuppression. Along with infection, acute graft rejection is a leading cause of death in pediatric heart transplant recipients. The incidence of acute rejection is greatest in the 1st 3 mo after transplantation and decreases considerably thereafter. Many pediatric patients experience at least 1 episode of acute rejection in the 1st 2 yr after transplantation, although modern immunosuppressive regimens have decreased the frequency of serious rejection episodes. Because the symptoms of rejection can mimic many routine pediatric illnesses (pneumonia, gastroenteritis), it is mandatory that the transplant center be notified whenever a heart transplant recipient is seen in the pediatrician’s office or emergency room for any acute illness.

Clinical manifestations of acute rejection may include fatigue, fluid retention, fever, diaphoresis, abdominal symptoms, and a gallop rhythm. The electrocardiogram may show reduced voltage, atrial or ventricular arrhythmias, or heart block but is usually nondiagnostic. Roentgenographic examination may show an enlarged heart, effusions, or pulmonary edema, but usually only in the more advanced stages of rejection. Most rejection episodes occur without any detectable clinical symptoms. On echocardiography, indices of systolic left ventricular function may be decreased; however, these usually do not deteriorate until rejection is at least moderately severe. Techniques to evaluate wall thickening and left ventricular diastolic function, which appeared to be promising, have not fulfilled their promise as predictors of early rejection. Most transplant centers do not rely on echocardiography alone in rejection surveillance.