Pretransplant Assessment

The pretransplant assessment is an essential part of the transplantation process as it helps identify patients with contraindications or potential complicating factors, those patients who may benefit from further medical or device management, and those who have an unrecognized reversible condition. This assessment includes a thorough cardiac evaluation to delineate the cardiac anatomy and to define the hemodynamic profile (contraindications are discussed later in this article). Cardiac catheterization is often performed to assess the overall anatomy and pulmonary vasculature. Assessment of the other organ systems is included to ensure that there are no contraindications to transplantation or need for modification of standard treatments before or after transplantation. All noncardiac diseases should be evaluated and appropriate consultations should take place to help determine the associated long-term outcomes and morbidities. As part of the transplant assessment, the patient should undergo HLA typing, as the results may alter the intra- and postoperative management. Detailed psychosocial assessment of patients and their family members is essential to understand their support system, risk factors for noncompliance, and issues that would preclude transplantation, especially in the adolescent population. As these assessments are comprehensive, they are best performed within the context of a transplant-knowledgeable multidisciplinary team. Components of a typical assessment are outlined in Table 1 .

Assessment of patients being considered for listing as fetuses differs somewhat because of the limitations in the diagnostic testing available. The workup includes a detailed maternal, prenatal, and family history. A detailed fetal echocardiogram and anatomic antenatal ultrasonography are required to define anatomy and to rule out associated anomalies. Additional testing includes amniocentesis for chromosomes, other genetic testing as indicated, and maternal screening for infectious diseases. Indications for fetal listing are similar to those in the postnatal period and include single-ventricle anatomy with risk factors for surgical palliation (severe atrioventricular valve regurgitation, decreased function), HLHS in centers where transplantation is offered as primary therapy, unresectable cardiac tumors, right atrial isomerism syndromes, cardiomyopathies with poor ventricular function, and intractable arrhythmias. Ideally, candidates are listed once they are 35 weeks’ gestational age or older, and have an estimated fetal weight greater than 2.5 kg to optimize pulmonary maturity. If a donor heart becomes available and there are no acceptable post-natal candidates, patients are delivered by cesarean section and undergo immediate transplantation.

Contraindications and Complicating Factors

The pretransplant assessment allows for the identification of factors that may complicate or completely exclude transplantation as a treatment option. The list of contraindications has been modified over the years, and several previous factors that would have excluded a transplant are now dealt with through a variety of strategies. In patients with complex congenital heart disease, the technical difficulties arising from unusual anatomy such as abnormal situs, systemic venous abnormalities, anomalous pulmonary venous drainage without stenosis, and some pulmonary artery anomalies no longer prohibit transplantation. Previous sternotomy/thoracotomy, reversible pulmonary hypertension, noncardiac congenital abnormalities, kyphoscoliosis with restrictive pulmonary disease, nonprogressive or slowly progressive systemic diseases (genetic or isolated metabolic cardiomyopathies), and diabetes mellitus without end-organ damage no longer preclude cardiac transplantation. Although the list of contraindications has decreased over the years, there are still several that must be ruled out before transplantation can occur :

• (1)
  

  Severe and irreversible end-organ damage or multisystem organ dysfunction

  
  
• (2)
  

  Severe hypoplasia of the branch pulmonary arteries, because the distal branch pulmonary arteries are from the recipient and cannot be corrected with transplantation

  
  
• (3)
  

  Severe pulmonary vein stenosis or atresia, because the recipient’s pulmonary veins are connected to the donor’s left atrium. Transplantation would not cure this anatomic problem and patients would be at high risk for pulmonary hypertension

  
  
• (4)
  

  A severe or progressive noncardiac disease, such as a chromosomal, neurologic, or syndromic condition, that is associated with limited survival (eg, Duchenne muscular dystrophy, a systemic mitochondrial disorder, or an untreatable and multisystem metabolic disorder)

  
  
• (5)
  

  Active infection

  
  
• (6)
  

  Severe irreversible pulmonary hypertension

  
  
• (7)
  

  Psychological issues: smoking, drug/alcohol abuse, unstable or chronic psychiatric conditions, life-threatening noncompliance

  
  
• (8)
  

  Others: coexisting malignancy; morbid obesity; diabetes mellitus with end-organ damage; hypercoagulable states; retransplantation during an acute rejection episode.

Although discussion of all these contraindications is beyond the scope of this article, a better understanding of the role of pretransplant pulmonary hypertension is important. Pulmonary hypertension, specifically increased pulmonary vascular resistance (PVR), has been associated with significant right heart failure, graft loss, and increased mortality after transplantation. PVR is best assessed during cardiac catheterization. If the PVR is found to be increased during a cardiac catheterization, the next step is to determine whether the pulmonary vascular bed is reactive to vasodilators. Patients who respond with a decrease in their PVR have reversible pulmonary hypertension, whereas those with no response are considered to have irreversible pulmonary hypertension. Cardiac transplantation is feasible in patients with a pulmonary vascular resistance indexed (PVRi) less than 6 Woods units/m ² or a transpulmonary gradient (TPG) less than 15 mm Hg, or if inotropic support or pulmonary vasodilators are able to lower the PVRi to less than 6 Woods units/m ² and TPG to less than 15 mm Hg. The assessment of PVR may be difficult in certain forms of congenital heart disease as there are a variety of mechanisms that can lead to increased pulmonary artery pressures and resistance. Therefore, in some conditions such as single ventricle lesions or those patients who have multiple sources of pulmonary blood flow, accurate assessment may not be possible.

Recently, the concept of irreversible pulmonary hypertension has been questioned because of improving drug therapy and the positive effects of mechanical support in patients believed to have irreversible pulmonary hypertension. Therefore, the increasing use of mechanical support in the pediatric population may have the added benefit of increasing the number of patients eligible for isolated heart transplantation by lowering their PVR.

All of the above potential contraindications or complicating factors must be considered in the context of the risks of transplantation and the probability of short- (perioperative) and long-term survival given the ongoing shortage of donor organs that remains a limiting factor for solid-organ transplantation.

Sensitized Patients and Transplantation

As part of the routine testing all patients undergo a screening panel reactive antibody (PRA) test to look for the presence of anti-HLA antibodies. This is a test looking for preformed antibodies to a pool of potential donor antigens. A patient with a PRA higher than 10% is considered to be sensitized. Increased PRA titers are seen in patients with a ventricular assist device (VAD), repaired congenital heart disease with homograft material, multiple blood transfusions, platelet transfusions, previous transplantation, or pregnancy. Many of these risk factors, including the use of mechanical circulatory support, are important strategies for managing pediatric patients before and after listing for transplantation. Yang and colleagues examined HLA sensitization rates in children supported with extracorporeal membrane oxygenation (ECMO) or a VAD. Their results suggest that younger patients supported on ECMO were unlikely to develop device-related HLA antibodies despite homograft use or blood transfusions. However, 66% of the patients supported with a VAD had new or additional HLA sensitization after 5 weeks of support. These patients tended to be older and supported for a longer period of time. The reason for this difference is unclear but has been postulated to be the result of impaired immune function secondary to the ECMO circuit, briefer exposure to the ECMO circuit, or possible age-related factors. As the overall use of VADs increases in pretransplant management, and with the recent expansion of these devices to the neonatal and infant population, reevaluation of the risk factors and strategies to prophylaxically reduce sensitization will be needed.

Although the presence of HLA antibodies to a donor pool of antigens is not an absolute contraindication to transplantation, it continues to make these patients high-risk candidates. The presence of these antibodies increases the risk of antibody-mediated rejection, early graft failure, and decreased survival after transplantation. Because of these risks, some centers list these patients with the requirement of a negative virtual or prospective crossmatch for donor-specific HLA antibodies at the time of transplantation or will not offer transplantation as a treatment strategy. Waiting for a negative crossmatch significantly increases the waiting-list time and identifying donor-specific antibodies before acceptance of a donor heart limits the donor pool to the local area because of time constraints. Therefore, as an alternative several off-label treatment strategies intended to lower the pretransplant PRA levels or decrease the risk of antibody-mediated rejection after transplantation have been developed, including intraoperative plasma exchange, immune globulin, plasmapheresis, cyclophosphamide, rituximab, and antimetabolite treatment. Implementation of treatment protocols using these strategies in both adult and pediatric studies have recently shown reasonable short and intermediate results after transplantation in those patients who were highly sensitized before transplantation. As the pediatric outcomes are based on single centers studies, multicenter prospective studies are required to determine whether these results can be replicated and to decide on the optimal treatment regime. Listing a highly sensitized patient for heart transplantation should be performed in a center with experience and expertise in this high-risk population.

ABO Blood Group–Incompatible (ABO-I) Transplantation

Heart transplantation is usually contraindicated if a donor and recipient have incompatible blood groups because of the high risk of hyperacute rejection from preformed anti-A and anti-B antibodies (isohemagglutinins). Nevertheless, because of the limited number of organs available, attempts to transplant across blood groups have occurred. ABO blood group–incompatible (ABO-I) heart transplantation was pioneered in Toronto in the mid-1990s with a clear effect on waiting-list mortality and excellent short- to intermediate-term outcomes. Ten-year follow-up of the largest single-center cohort revealed no difference in survival, rejection, renal dysfunction, allograft vasculopathy, or posttransplant lymphoproliferative disorder. ABO-I transplantations are increasingly being performed around the world and have been recognized as an important strategy to improve survival in infants following listing. It is still unclear which patients are best suited for this listing strategy and what is the upper age limit for tolerating an ABO-I transplant. Isohemagglutinins should routinely be checked as part of the pretransplant assessment in any patient less than 2 years of age, and in selected older patients at the discretion of an experienced transplant cardiologist. Careful administration of appropriate blood products is paramount during and following ABO-I transplants to ensure the absence of isohemagglutinins against the donor or recipient. Table 2 lists the appropriate blood products to be used, based on the donor and recipient blood groups. As this is an essential part of the transplantation process, ABO-I heart transplantation should be performed in a center with the appropriate knowledge and infrastructure for management of the unique blood product needs.

Donor Evaluation

The suitability of the donor heart for transplantation and the management of the donor are vital parts of the transplantation process. Although most pediatric donors were previously healthy, the patient’s history is essential to rule out any genetic, metabolic, or syndromic condition that may have cardiac involvement. The details of the mechanism of death are important to determine whether there has been any damage to the heart, such as a cardiac contusion after thoracic trauma or any risk of infection. Other pertinent information includes the donor’s blood group, size and age, and the results of previous investigations including any electrocardiograms and echocardiograms.

To increase the donor pool for pediatric patients, strategies have been undertaken to accept oversized grafts. Recipients with oversized grafts, defined as a donor/recipient weight ratio greater than 2.5, were reported to have similar posttransplant outcomes to those with a ratio less than 2.5. However, the one difference between these 2 groups was a higher incidence of delayed chest closure after transplantation when the weight ratio was greater than 2.5. Additional studies in patients with oversized grafts have also reported transient lobar collapse and greater left ventricle mass index. Although oversized grafts have not been shown to affect outcomes, older donor age has been identified as a risk factor for poor outcomes. The donor age affects both the 1- and 5- year survival after transplantation with decreased 1-year survival in adolescents transplanted with hearts from donors more than 40 years of age. In response to these findings, policies from the Canadian organ allocation system and the United Network for Organ Sharing in the United States specify that adolescent donor hearts are allocated to adolescent recipients preferentially.

The suitability of the donor heart for transplantation can be altered by the brain death process and the subsequent management. Brain death has been shown to have a deleterious effect on ventricular function, with the right ventricle being particularly susceptible. Therefore, the goals of treatment following brain death are to preserve ventricular function and prevent further myocardial damage. Intensive care management should focus on optimizing intravascular volume status, maintaining cardiac output with the lowest possible amount of inotropes, and preventing elevations in afterload. An additional strategy that has been used successfully in donor management is hormonal resuscitation. This strategy has been shown to decrease the amount of inotropic support required and increase the suitability of the donor hearts for transplantation.

During procurement, the donor heart is preserved using cardioplegia solution and cooled for transport. Carrying out this process efficiently serves to decrease the organ ischemic time. In adults, a donor ischemic time greater than 4 hours is a risk factor for decreased late survival. This has not been the case in pediatric patients. Ischemic times greater than 8 hours in children have not been shown to have an effect on long-term outcomes including survival, rejection, and allograft vasculopathy, and recent analysis of the ISHLT registry revealed that ischemic time was not a risk factor for short term survival (1 year).