Heart Transplantation

The indication for heart transplantation in children is influenced by the age of the child. Approximately 55% of infants younger than 1 year of age who are listed for cardiac transplantation have complex congenital heart disease, whereas the 44% to 54% of older children (1 to 17 years of age) suffer from cardiomyopathy, with the percentage transplanted for congenital heart disease decreasing steadily as patients age ( Fig. 73.1 ). There has also been a shift in the type of lesions primarily palliated with transplantation. In the 1980s heart transplantation had better long-term survival than staged palliation for hypoplastic left heart syndrome (HLHS), which was the most frequent indication for neonatal heart transplantation with some centers using transplantation as the primary therapy for this disease. However, with improved surgical techniques and alternate options such as the “hybrid procedure” and surveillance programs all leading to increased survival, HLHS is now less common as an indication for heart transplantation than non-HLHS congenital heart disease. Other congenital malformations that can lead to consideration of heart transplantation include pulmonary atresia with intact ventricular septum and right ventricular dependent coronary circulation, the more complex forms of single ventricle, truncus arteriosus, double-outlet right ventricle, Ebstein anomaly, unbalanced atrioventricular canal, and transposition of the great arteries. Once palliative or corrective surgery has been undertaken, patients may develop heart failure requiring transplantation. This may be due to systemic ventricular dysfunction (systolic or diastolic), pulmonary ventricular dysfunction, cyanosis, intractable arrhythmias, or complications of single-ventricle palliation such as plastic bronchitis, protein-losing enteropathy, or chronic effusions.

Indications for heart transplantation broken down by recipient age.

(From Rossano JW, Cherikh WS, Chambers DC, et al. The Registry of the International Society for Heart and Lung Transplantation: Twentieth pediatric heart transplantation report-2017; focus theme: allograft ischemic time. J Heart Lung Transplant. 2017;36[10]:1060-1069.)

Whereas cardiomyopathy is the second most common indication for transplantation in infants, it is the most frequent diagnosis of children requiring transplantation beyond infancy. Idiopathic dilated cardiomyopathy is the most common diagnosis followed by idiopathic restrictive cardiomyopathy, familial dilated cardiomyopathy, and myocarditis. Unresectable cardiac tumors and chemotherapy-induced myocardial dysfunction are less common indications for transplantation in older children.

Lung Transplantation

Guidelines from the International Society for Heart and Lung Transplantation (ISHLT) recommend that lung transplantation should be considered in adult patients when predicted 2-year survival is less than 50%, whereas in children it is less specific and rather states “a short predicted life expectency.” As with heart transplantation, the indications for pediatric lung transplantation are related to the age of the child at presentation. Infants (<1 year of age) most commonly present with pulmonary hypertension of various causes, interstitial lung disease, and surfactant protein deficiency. Cystic fibrosis begins to play a role, albeit small, from ages 1 to 5 years and is responsible for half or more of the cases after age 6 years ( Table 73.1 ). Despite improvements in the treatment and prognosis of cystic fibrosis, some children develop early pulmonary dysfunction and should be considered for transplantation when they develop progressive hypercapnia or oxygen dependence, increasing frequency of hospitalizations, or poor weight gain despite adequate nutrition. Another problem that patients with cystic fibrosis face is the development of multidrug-resistant pseudomonal infections. Given the difficulties in treating infections with these organisms in immunocompromised patients, some consideration must be given to transplant listing before development of panresistant strains.

Patients with primary pulmonary hypertension typically do not present for lung transplantation until adulthood; however, some children can develop rapidly worsening symptoms. Children with pulmonary hypertension due to pulmonary vein stenosis are at increased risk for sudden death while waiting for transplantation. Children with secondary pulmonary hypertension due to cardiac disease (Eisenmenger syndrome) can be considered for bilateral lung transplantation with concomitant cardiac repair, if the cardiac defect is amenable to surgical correction, rather than combined heart-lung transplantation.

Heart-Lung Transplantation

Though some children with Eisenmenger syndrome have cardiac defects that are amenable to surgical repair, those with poor ventricular function, serious valvular disease, or uncorrectable cardiac anomalies must be considered for combined heart and lung transplantation. Heart-lung transplantation has been employed for patients with cystic fibrosis, occasionally with use of the recipient’s heart for subsequent “domino” transplantation; however, the majority of institutions perform bilateral lung transplants in cystic fibrosis patients with normal cardiac function.

Recipient Evaluation

When a patient is referred for transplant evaluation, initial steps include determination of disease severity and whether there are any reversible or treatable factors responsible. This is all highly dependent on the cause of heart or respiratory failure, which itself is variable by age-group (see Fig. 73.1 and Table 73.1 ). If there are no alternative treatment options, then a complete evaluation is undertaken, which includes medical, surgical, and psychosocial evaluation. The first, and possibly most important, step in the process is to have an in-depth discussion with the family/caregivers, and patient if appropriate, to fully inform them of the benefits, risks, and outcomes expected with transplantation. Only after they have provided their informed consent should the evaluation proceed.

Specific laboratory testing in patients is indicated to identify end-organ dysfunction, active infections, historical infectious exposures, coagulopathy, neoplasm, blood type, nutritional deficiencies, effects of chronic medications, and sensitization to human leukocyte antigens (HLAs) as represented by panel-reactive antibodies (PRAs). Based on initial testing, diagnosis, or other comorbid conditions, further diagnostic studies, particularly imaging, may be indicated to assess end-organ function, vascular access, surgical approach, or presence of neoplasm.

The ISHLT recommends right heart catheterization should be performed on all adult candidates for heart transplant listing and periodically thereafter until transplantation. In cases of suspected myocarditis, biopsy can help determine the extent of involvement and potential for reversibility ; however, recent advances in cardiac magnetic resonance imaging have led to less dependence on invasive studies. The same may be said of determination of complex anatomy by computed tomography and cardiac magnetic resonance imaging, but data regarding hemodynamics remain the unique purview of catheterization, especially when a potential intervention is discovered. Determination of PVRI by catheterization is of particular importance in pediatric patients given the potential impact on outcomes after transplantation.

The inclusion of cardiopulmonary exercise testing (CPET) in evaluation for transplantation in pediatric and adolescent patients is variable. For those in whom CPET can be performed, assessment of peak oxygen consumption (VO ₂ ) may be useful in the decision to list for heart transplantation. Guidelines from ISHLT use VO ₂ cutoff values of less than 14 mL/kg/min or 50% or less predicted as guides to consider listing for adult patients but offer no specific guidance on pediatric patients. Pulmonary and musculoskeletal disease can negatively affect results. Normal values for pediatric patients are different than in adults, and patients with palliated single-ventricle physiology may have a depressed baseline. Other parameters, such as heart rate reserve, minute ventilation/carbon dioxide production, and peak systolic blood pressure during CPET have been shown to predict risk in patients with congenital heart disease. Pulmonary function testing and 6-minute walk test may also be indicated, particularly for lung transplant evaluation.

The goal of the psychosocial evaluation is to assess whether there are sufficient social supports to achieve compliant care in the outpatient setting to maximize the chances for a successful outcome. This assessment includes the parents/caregivers and patient if appropriate and addresses home environment, extended support networks, history of compliance with medical management recommendations, and history of illicit drug use or social welfare concerns. It is important to stress to families that there is no bias based on race, ethnicity, socioeconomic status, or family structure.

Determination of pretransplant HLA sensitization by PRAs is necessary to assess risk of rejection and to identify donor HLA to avoid. A number of factors, including use of human homograft material in surgical palliation, frequent blood transfusions, MCS, and prior transplantation can contribute to antibody generation. These preformed, circulating antibodies can engage in cell- and antibody-mediated rejection and lead to graft loss or death. The current combination of flow cytometry using beads coated with single HLA antigens and a C1q complement-fixing assay allows detection of clinically significant antibodies, yielding the calculated PRA (cPRA). In patients who are highly sensitized and can expect long wait times as a result of many identified antibodies to HLA, desensitization protocols have shown efficacy in reducing the cPRA.

Recipient Management

Waiting list mortality in pediatric patients is higher for heart transplantation than any other solid organ. The most important factor in predicting mortality is the level of invasive hemodynamic support. Management of patients on the waiting list can vary from standard heart failure therapy as an outpatient to MCS and mechanical ventilation and depends on a variety of factors, including severity of cardiac dysfunction, cardiac diagnosis, and end-organ dysfunction. The level of support required also factors into the listing status ( Table 73.2 ). Overall, the goal is to maintain end-organ function, optimize nutrition, and deliver the patient to transplant with as few comorbidities as possible.

The goals of medical management are to reduce fluid overload, reduce afterload, and downregulate neurohormonal responses. When patients cannot be adequately managed with oral heart failure medications, a number of inotropic and vasoactive agents are available. Milrinone, dopamine, dobutamine, and epinephrine are all options.

Certain patients will continue to deteriorate despite maximal medical therapy and ultimately may require mechanical ventilator support. Positive intrathoracic pressure benefits patients with left ventricular systolic and diastolic dysfunction by reducing afterload, as well as working to improve pulmonary edema and atelectatic lung segments. However, positive pressure can have mixed effects on the right heart if there is pulmonary distention beyond functional residual capacity. High intrathoracic pressures also increase systemic venous pressures and can worsen systemic edema, inhibit ventricular filling, and worsen secondary organ injury due to elevation of central venous pressure.

For decades the mainstay of MCS has been extracorporeal membrane oxygenation (ECMO). More recently a growing number of support devices have become available for patients in need of only circulatory support. Device selection depends on support goals, patient size, and native cardiac anatomy among other factors. For small children the primary option outside of ECMO has been the Berlin EXCOR pulsatile ventricular assist device. This pneumatically driven extracorporeal device is the only one approved in the United States by the Federal Drug Administration for use in children as a bridge to transplantation. The Berlin EXCOR comes in multiple pump sizes and is capable of supporting children as small as 3 to 4 kg. The device allows for reliable support of either or both ventricles. Overall success rate for bridge to transplant or explant and recovery is roughly 75%, with superior survival after heart transplant when compared with ECMO. It should be noted that in children under 10 kg at implantation, survival was lower than that of the entire group, predominantly due to patients with congenital heart disease, weight less than 5 kg, and evidence of biventricular failure through elevated bilirubin level. Further analysis has revealed that end-organ function at device implantation predicts adverse outcomes, and that neonates and infants with congenital heart disease, particularly those with prior heart surgery and ECMO support, may have poorer outcomes when considering bridge to transplant or weaning. When analyzing patients who went on to transplantation, posttransplant survival at 30 days, 1 year, and 5 years was equivalent between patients bridged with EXCOR and those who underwent transplant without MCS.

Beyond the EXCOR, several other MCS options exist for pediatric and adolescent patients, with the latter being eligible for most of the devices available to adult patients. Determination of the needed duration of support, patient size, one or two ventricular support, and native cardiac anatomy all effect the choice. Options include short-term versus long-term, extracorporeal versus implanted versus catheter-based, pulsatile versus continuous flow, and even options for complete cardiac replacement with a total artificial heart. Once a device is selected, advanced imaging techniques can be used to perform a virtual “fit test” to anticipate any anatomic or mechanical complications. Management after placement is contingent on the device selected, but major themes emerge based on the most common complications: bleeding, thrombus formation, infection, and right heart failure in the case of isolated left heart support. A growing body of literature supports successful use of these devices in congenital heart disease.

Children who are listed for lung transplantation are frequently critically ill with a significant percentage requiring hospitalization with or without mechanical ventilation and pressor support before donor organs become available. As a result, aggressive maneuvers may be necessary in an attempt to maintain end-organ viability and transplant candidacy for as long as possible. Over the past decade, advances in mechanical ventilation with jet and high-frequency ventilators, the availability of prostacyclin and nitric oxide, and artificial lung devices have broadened the armamentarium available for use in these children. Despite these measures, mortality on the waiting list remains in the range of 20% to 25% for infants and children.

The use of ECMO before lung transplantation has been less common than for heart transplantation; however, there has been experience reported in both the adult and pediatric populations. A recent systematic review of published data from 14 studies with adult patients bridged to lung transplant by ECMO found mortality rate of patients before lung transplant and 1-year survival ranged from 10% to 50% and 50% to 90%, respectively. In a single-center report of pediatric patients supported with ECMO, mechanical ventilation without ECMO, or neither, outcomes of transplanted patients were not statistically different regarding hospital discharge and 1-year survival. Given the risks associated with ECMO, there has recently been interest in the use of paracorporeal lung assist devices as a bridge to lung transplantation in neonates and children, including reports of isolated successful cases.

Donor Management

Initial donor evaluation must begin with determination of brain death. Involvement of an organ procurement agency should be initiated as soon as possible after brain death has been established to minimize the length of time between brain death and possible organ harvest. The hormonal and hemodynamic changes associated with brain death are detrimental to both cardiac and pulmonary function, so special consideration must be given to maintenance of donor organ function in the physiologically abnormal state produced by brain death. Treatment with thyroxine often results in decreased inotrope requirements with salvage of some organs that might otherwise not be considered for transplantation. Management of neurogenic shock requires volume resuscitation, but care must be employed in both the amount and type of volume administered. If possible, blood or colloids should be used, and volume status should be assessed using central venous or pulmonary capillary wedge pressures. Bronchoscopy can be useful both for diagnostic and therapeutic purposes such as removal of mucous plugs, which can decrease atelectasis and improve pulmonary gas exchange. Transthoracic echocardiography is usually performed on potential heart donors to rule out any intracardiac abnormalities or regional wall motion abnormality. Arterial blood gas measurement performed on potential lung donors may determine the adequacy of gas exchange, and a chest x-ray is done to rule out the possibility of pulmonary contusion or infectious infiltrate. Blood should be obtained from the potential organ donor for serologic studies to determine if there are any transmissible diseases (e.g., HIV, hepatitis) and ABO blood typing. Preference for ABO blood group matching is the general rule, but in the last decade some centers are opting for protocols to offer ABO-incompatible transplantation, primarily in infants, with the goal of decreasing waiting time.

Given the scarcity of pediatric organs available for transplantation, alternate strategies to increase the donor pool have been considered. Many patients are considered for organ donation even if organ function is initially borderline or unacceptable. Studies have shown that aggressive donor management can significantly improve donor organ function and early posttransplant results. Additionally, it is clear that some organs turned down for pediatric patients based on concerns over donor quality may be acceptable, with similar outcomes between quality-refused hearts and those offered primarily or hearts refused in pediatric patients that were successfully transplanted in adult recipients. Because of the limited donor pool, neonatal transplant programs often accept organs from a wider geographic area, and thus with longer cold ischemic times, than an adult program would consider. Ischemic times as long as 9.5 hours have not been shown to adversely affect long-term outcomes for pediatric heart transplant recipients, with greater tolerance for prolonged ischemic time in grafts from younger (<19 years) when compared with older (≥20 years) donors. Finally, over the last decade there has been interest in accepting organs from donors after circulatory death (as opposed to after brain death), with long-term results in adult lung transplants, and limited cases in pediatric heart transplants, showing promising results.

The size range of donor organs that can be accepted for pediatric heart transplants is larger than for adults. Donors up to 2.5 times the weight of the recipient can be accepted with no evidence of ill effects in most cases. Evaluations of graft growth have shown that the velocity of cardiac growth is initially slow for these oversized organs with normal growth later in life, essentially allowing the recipient to grow into the larger organ. Certain children with dilated cardiomyopathy and massive cardiomegaly can tolerate organs from donors as much as three times their weight, although care must be taken to prevent atelectasis from pulmonary compression. Contemporary data suggest use of imaging-measured cardiac volume could prove more useful in achieving an appropriate match.

Another option that has increased donor lung availability for small recipients is the use of lobar transplants from adult donors into children. This technique can be applied for both brain-dead and living-related donors. Living-related lobar transplantation is a relatively new technique that provides organs for transplantation for a limited population of children. In the majority of cases children receive a lower lobe from each parent for bilateral lung transplantation. Donors have generally done well after the procedure, and early to midterm outcomes for recipients have been comparable to cadaveric transplant recipients. There have been reports that recipients of living-related lobar transplants have better pulmonary function at 2 years and experience bronchiolitis obliterans less frequently when compared to cadaveric donation, and that these transplants may be a better option for patients in need of retransplantation.

Donor Organ Retrieval

Successful thoracic organ transplantation begins with precise anatomic dissection and preservation of the donor organ. The process is complex and involves coordination between multiple teams from different locations and coordination between the retrieval team and recipient facility. There are many opportunities within this interaction for misadventure, but the coordinated effort of the surgical teams during anatomic dissection allows the organ-specific needs of each team to be met. Identification of the donor by a United Network for Organ Sharing–specific ID is a critical first responsibility of the retrieval team along with confirmation of ABO compatibility. All donor clinical information should be reviewed, including documentation for confirmation of brain death. This includes echocardiograms, chest x-ray, and results of laboratory work (including serology). Fiberoptic bronchoscopy is usually performed by the lung retrieval team as an adjunct to determine suitability for proceeding with transplantation.

Accurate hemodynamic monitoring should be guided by central venous pressure and an arterial catheter. Maintenance of a normal mean arterial blood pressure for the patient’s age is the goal along with avoidance of fluid overload and dehydration. The central venous pressure should be kept less than 10 mm Hg. For management of the donor lungs, the tidal volume is maintained at 10 mL/kg or less. The fraction of inspired oxygen is kept at less than 50%. Airway heaters and heating blankets should be avoided. Vasoactive infusions may be necessary. This should be coordinated with the abdominal organ retrieval team. Interventions, special protocols, and any specific donor medications should be coordinated between the retrieval teams. If the lungs are to be retrieved, it is also critical to communicate to the anesthesiologist to maintain ventilation of the lungs after the heart is explanted.

A generous median sternotomy is made and usually will be in continuity inferiorly with the abdominal incision ( Fig. 73.2 ). A double-bladed sternal retractor is ideal for exposure of the heart and access to both pleural spaces. The thymus should be excised completely. This will allow access to the trachea above the innominate vein and enhances exposure of the great vessels. The pericardium is incised, and pericardial sutures are secured to hemostats, which allows easy access to the pleural spaces if the lungs are to be harvested ( Fig. 73.3 ). The heart is inspected to assess function and evidence of chamber distention, particularly the right ventricle. This initial visual assessment should be used to rule out undocumented injuries or evidence of congenital anomalies. The coronary vessels should be palpated as well for evidence of atherosclerosis. Palpation of the lungs should be carried out, if retrieval is planned, to assess for masses and to assess for air underneath the visceral pleura. Air underneath the visceral pleura can be a subtle sign of undiagnosed injury to the airway. If the organs are felt to be acceptable, the implantation team is informed, so the recipient operation can be timed appropriately.

Donor procedure: median sternotomy. A generous median sternotomy is created in continuity with the abdominal midline incision. Care should be taken at the inferior aspect to protect the liver.

(From Camp PC. Heart transplantation donor operation for heart and lung transplantation. Oper Tech Thorac Cardiovasc Surg. 2010;15[2]:125-137.)

Exposure of the heart for explant. The pericardium is opened vertically from the diaphragm to its inflection at the ascending aorta.

(From Camp PC. Heart transplantation donor operation for heart and lung transplantation. Oper Tech Thorac Cardiovasc Surg. 2010;15[2]:125-137.)

The heart is prepared for explant at this time. The preference is to complete all necessary cardiac dissection as the abdominal dissection proceeds. The needs of the implanting team to achieve a successful recipient reconstruction should have been communicated. This may require additional segments of the aortic arch, descending aorta, and possibly the branch pulmonary arteries, particularly in patients with complex congenital heart disease. The innominate vein is mobilized from the anterior wall of the aortic arch. The aorta is dissected free of the main pulmonary artery with exposure of the proximal right pulmonary artery. The ascending aorta is dissected free from the main pulmonary artery to allow cross-clamp application. The superior vena cava (SVC) is circumferentially mobilized from surrounding tissues, exposing the azygous vein and the junction of the innominate and jugular veins. The azygous vein is ligated and divided. Next, the inferior vena cava (IVC) is dissected free from the diaphragm. For lung retrievals the trachea is circumferentially dissected free of surrounding structures above the innominate vein ( Fig. 73.4 ). Another critical maneuver when the lungs are retrieved is the development of the interatrial groove ( Fig. 73.5 ). Having this plane exposed before application of the aortic cross-clamp will allow accurate division of the atrial cuff for equal distribution to the heart and lung teams.

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