The quest for clinical cardiac transplantation (CT) originated in research laboratories of the 1960s. Principal North American investigators included Norman Shumway and Richard Lower at Stanford University in California and Adrian Kantrowitz at Albert Einstein College of Medicine in New York, among others. While Shumway and Lower were focused on the potential for CT among adults, Kantrowitz’ studies were aimed at young infant recipients. At Stanford, investigators were learning the difficult balance between control of the host immune response and lethal opportunistic infections. Utilizing immunosuppressants of that era, adult laboratory animals were beginning to achieve survival of more than a year following orthotopic CT. In New York City, Kantrowitz observed that transplanted puppies experienced prolonged survival, even without immunosuppression. Then, unexpectedly, came news from Capetown, South Africa, that Christiaan Barnard and his team had accomplished the first clinical human CT.¹ On December 3, 1967, 55-year-old Louis Washkansky underwent orthotopic CT. He died of pneumonia 18 days later, but the celebrated transplant stimulated global interest, and a bevy of similar transplants. The vast majority of these early recipients experienced abbreviated survival, dying of rejection, infection, or both.

Just 3 days after the South African transplant, the first infant (neonatal) CT was attempted by Kantrowitz. The heart of an anencephalic infant was transplanted “off-pump” (i.e., with surface-induced hypothermia alone), into a neonate with severe Ebstein anomaly. The baby appeared to have a satisfactory operative procedure, but died suddenly and without clear explanation 6.5 h later. Kantrowitz did not pursue pediatric CT, and it would be 16 years before neonatal CT was to be attempted again. With the advent of cyclosporine for selective control of the cellular immune response,² clinical pediatric CT was successfully performed in the summer of 1984. Eric Rose, of Columbia University, transplanted a 4.5-year-old boy. Then, Douglas Behrendt performed CT in a 2-year-old girl at the University of Michigan. Neonatal CT was once again attempted on July 30, 1984 by Magdi Yacoub in London. The infant, who had hypoplastic left heart syndrome (HLHS), lived 18 days with an allograft from a Dutch infant donor.

On October 26, 1984, one of the authors (Leonard L. Bailey) performed CT on a premature human newborn with HLHS using the heart of a 9-month-old female baboon. The infant recipient became known as Baby Fae. She lived 3 weeks, dying of incompletely understood mechanisms. Her experience raised social and professional consciousness about the potential for infant CT. This new awareness led to the first successful neonatal CT, which occurred at Loma Linda University (LLU) on November 15, 1985.³ The recipient was near death from HLHS at 4 days of age, when a distant neonatal donor was identified and transferred to LLU. The newborn recipient, now fully grown and gainfully employed, turned 27 years old in the fall of 2012. Additional infant allograft CTs were accomplished as procurement agencies began to take note of this donor organ resource. Throughout the decade of the 1990s, pediatric recipients produced major growth in the number of CTs performed worldwide.

Since 1982, CT has been recorded by the Registry of the International Society for Heart and Lung Transplantation (ISHLT) in over 8000 pediatric recipients. The incidence of pediatric CT has plateaued, with about 450 infant and childhood recipients reported annually to the ISHLT Registry. Today, infants and children (0–18 years old) constitute 12.5 percent of all reported recipients of CT.⁴

This chapter reviews indications for and contraindications to pediatric CT, timing for surgery, surgical techniques, immunosuppression regimens, rejection surveillance, complications, outcomes (highlighting the LLU experience), and future trends.

CT provides the most effective treatment for end-stage heart disease, whether myopathic or congenital. Complex congenital heart disease remains the primary indication for CT among patients in the first year of life. Over the past decade, however, increasing numbers of CTs have been performed in infants for both primary and secondary cardiomyopathy, or for failure of single ventricle physiology. End-stage primary cardiomyopathy (including “burned-out” congenital heart disease) is the predominant indication for transplantation among recipients who are beyond the first year of life. Retransplantation accounts for 5 percent of all pediatric CT (Table 89-1).⁴ The various cardiac diagnoses (myopathic and congenital) that may be considered for orthotopic pediatric CT are shown in Tables 89-2 and 89-3.

The main contraindication to CT is elevated pulmonary vascular resistance (more than 5 Woods units) that is unresponsive to oxygen, intravenous vasodilators, and inhaled nitric oxide. Children with a transpulmonary gradient greater than 15 mm Hg are largely unsuitable for isolated CT.⁵ Pulmonary vascular resistance is seldom an issue during early infancy, but it can become an important contraindication in older children and adolescents. Other contraindications are listed in Table 89-4. They include multisystem organ failure, active neoplasia, profound neurologic dysfunction, untreated clinical infection, and severe chromosomal abnormalities that limit survival, among others.

Proceeding with CT is a team decision and is multifactorial. Pretransplant evaluation of potential recipients should be expeditious, leading to early registration with the national organ procurement and distribution center. Delay leads to unnecessary morbidity and mortality. Even when registered, a potential recipient’s waiting time is entirely unpredictable. A waiting recipient may encounter major morbidities, such as overwhelming sepsis, cerebral hemorrhage, necrotizing enterocolitis, cardiac arrest, and hepatorenal failure, among others. Such morbidities may become contraindications to CT.

Recipients with complex congenital heart disease who are not candidates for surgical repair or palliation are listed early for primary CT. An occasional infant with unmanageable primary cardiac tumor or those with severe familial cardiomyopathy are also registered early for CT. Older pediatric recipients are typically listed for CT when they become resistant to medical management for congestive heart failure (CHF) and/or malignant arrhythmias, or when they fail to respond favorably to palliated single-ventricle physiology. Progressive deterioration, failure to thrive, and poor quality of life, even with optimal medical care indicate the need to list for CT. Also, patients with progressive pulmonary hypertension that might preclude transplantation at a later date are being listed more expeditiously.⁶ As indications for CT have expanded, and as organ supply has remained constant, recipient waiting time and morbidity have increased. Mortality while waiting for a donor heart graft ranges between 12 and 40 percent.

Mechanical circulatory support as a bridge to pediatric CT has become increasingly important. Extracorporeal membrane oxygenation (ECMO, Chapter 87) is useful only for relatively short periods, but may bridge to a more durable device.⁷ Utilization of infant-sized ventricular assist devices (VADs, Chapter 88) has proved to be a viable option for bridging to CT, similar to their use in older children and adolescents. VADs have been shown to improve waiting time survival without negatively affecting CT outcome.⁸ Early listing for CT optimizes recipient survival and reduces the need for intermediate mechanical circulatory support.

Donor heart recovery is tailored to the individual anatomic demands of the recipient. En bloc excision of the heart, the central pulmonary arterial tree, the superior vena cava (SVC) in continuity with the brachiocephalic vein and the origin of the internal jugular veins, and some or all of the aortic arch may be required to simplify recipient reconstruction. Concomitant lung donation may not be suitable when replacement of the main and branch pulmonary arteries is anticipated in a recipient, or when a recipient has situs inversus or anomalous pulmonary venous connections. A general rule of thumb is to obtain more, rather than less, of what the recipient will require. Aggressive trimming of the donor heart is postponed until its implantation into the recipient.

Heart recovery is usually accomplished in concert with the recovery of other organs (by other teams) through a long midline incision. The donor is given 25 mg/kg of cephalosporin antibiotic and 10 to 25 mg/kg of methylprednisolone. Fifty percent dextrose (0.5–1.0 mL/kg) is administered intravenously to the donor every 15 minutes until the organ is excised. The aorta is separated from the pulmonary artery, and the aortic arch vessels are doubly ligated and divided. The SVC and the innominate vein (as needed) are isolated. The azygous vein is ligated and divided. Its posterior location becomes a landmark for the future SVC anastomosis, or it can be used to enlarge the donor SVC if there is size discrepancy. Both pleural spaces are opened to accommodate drainage. When each team has completed their dissection, the donor receives intravenous heparin in a dose of 500 U/kg, and the heart is decompressed by transecting the inferior vena cava (IVC) and both of the left pulmonary veins. The aorta is cross-clamped, and 250 to 500 mL of antegrade cold crystalloid cardioplegia is administered by gravity infusion while the heart is being removed. The authors utilize cold Roe’s solution for myocardial protection. An infusion volume of 50 to 75 mL/kg is used in neonates and smaller children. The idea is to gently chill the heart, but not freeze it. Cardiectomy is completed by lifting the heart upward; the posterior attachments, including the right pulmonary veins, are divided. The SVC, the aorta and the pulmonary arteries are divided to include the amount of tissue needed. If the lungs are being recovered, the left heart is vented through a broad incision in the left atrium (anterior to the left pulmonary veins). This is done before the infusion of lung preservation solution. The pulmonary veins are, in this particular instance, not divided at the pericardial reflection. Instead, the left atrium is opened and carefully transected to preserve a posterior atrial cuff around the pulmonary veins, much as in the case for cardiectomy in the recipient. The main pulmonary artery is divided before the bifurcation. The remainder of the heart recovery is as described above. The heart is removed from the operative field to a back table, where it is examined while being immersed in ice-cold saline solution. If present, a patent foramen ovale is closed. The graft is packaged in a self-sealing plastic bag containing 5 percent dextrose in normal saline solution. The packaged graft is placed in a sterile, sealed container and immersed in ice in a chest for transport. Portions of donor thymus, spleen, and hilar or mesenteric lymph nodes are obtained and stored for immunologic evaluation. Frequent communication between the recovery team and the recipient team will minimize graft cold ischemia time. It is generally recommended that graft cold ischemic time be kept less than 4 h. However, successful CT with longer cold ischemic times (up to 10.5 h) have been reported by investigators at LLU.⁹

The biatrial technique (Fig. 89-1A) of graft implantation during CT was described by Lower and Shumway in 1967.¹⁰ This technique may create oversized atria and may distort right atrial geometry leading to atrioventricular valve insufficiency and/or arrhythmias. Bicaval anastomosis, described by Dreyfus and colleagues,¹¹ is now the most commonly employed technique (Fig. 89-1B). Bicaval CT preserves right atrial morphology and is applicable at any age. It is particularly useful during reoperative CT or when space is an issue. The recipient procedure is accomplished through a median sternotomy. The thymus is excised. At LLU, the recipient is placed on cardiopulmonary bypass using aortic and right atrial cannulation. Systemic cooling to a core temperature of 18 to 20°C is utilized routinely. The aorta is cross-clamped, and when target hypothermia is achieved, bypass flow is markedly reduced, and the passive venous cannula is replaced by flexible pump suckers. The aorta and pulmonary trunk are divided. Both the SVC and the IVC are divided, preserving a small atrial cuff on each cava to facilitate anastomoses. A left atriectomy is performed, leaving a posterior atrial cuff that contains the pulmonary veins. The native heart is removed from the chest. The donor heart is evaluated, and the left atrium is trimmed to match the recipient left atrial cuff. The left atrioatrial anastomosis is performed first. A small area of the anastomosis is kept incomplete so that cold saline can be flushed intermittently through the left-sided structures. The IVC anastomosis is then completed, followed by an end-to-end anastomosis of the SVC. The passive venous cannula for cardiopulmonary bypass is inserted into the donor right atrium, via the appendage. The aortic anastomosis is completed, and intracavitary air is displaced by flushing of the left heart with cold saline. The aortic clamp is removed, ending graft cold ischemia. The pulmonary arterial anastomosis is completed during reperfusion of the allograft. All anastomoses are performed with continuous polypropylene sutures. The graft and the patient are rewarmed and reperfused for at least an hour to permit full recovery of the allograft heart. As the recipient rewarms, nitroglycerin is infused intravenously. Drugs, such as dopamine and milrinone, are infused in low dosage intravenously when the recipient reaches 34 to 36°C. The recipient is then separated from extracorporeal circulation.

A biatrial anastomosis is usually employed in neonates and very small babies. The interatrial septum is anastomosed first, followed by the right atrium and then the left atrium. The recovery and trimming of the donor heart and the techniques of CT are modified to cope with various anatomic situations, examples of which are discussed below.

Infants Who Require Replacement/Reconstruction of the Aortic Arch

The technique of orthotopic CT and aortic arch reconstruction is exemplified by that used for HLHS or its equivalent (Fig. 89-2) and was first described in detail in 1986 and later modified to reduce the duration of circulatory arrest.¹² The chest is opened through a midsternal incision and thymectomy is accomplished. Cardiopulmonary bypass is initiated using a single venous drainage cannula in the right atrium, and an arterial perfusion cannula that is placed in the pulmonary trunk and directed into the arterial duct. The ductus containing the arterial cannula is snared to prevent flow into the lungs. Systemic cooling to a core temperature of 18 to 20°C is achieved within 12 to 15 minutes. During this period, branches of the aortic arch are dissected and surrounded individually with loose tourniquets. The perfusion rate (or volume) is reduced to approximately 20 cc/kg/min, and thereafter varies between 10 and 30 cc/kg/min until rewarming is begun. The diminutive ascending aorta is ligated and divided just proximal to the brachiocephalic artery. Traction on this ligature facilitates exposure of the proximal descending aorta. The passive atrial drainage cannula is replaced with a flexible pump sucker. The main pulmonary artery is transected at the level of the valve. The hypoplastic heart is excised, leaving in place posterior atrial wall cuffs and a rim of atrial septum.

After inspection of the recipient’s pulmonary veins, implantation of the donor heart begins with the atrial septum at its caudal aspect using a continuous monofilament suture, a portion of which is carried up the septum and around the top of the right atrium. The other portion of the same suture is used to anastomose the caudal portion of the right atrium, eventually meeting up with the segment of suture used to attach the upper portion of the atrium. A flexible suction catheter is repositioned into the right atrial appendage while the graft is retracted toward the operating surgeon and the left atrial anastomosis is initiated at its junction with the caudal septum. After half a dozen sutures, the heart graft is replaced into the remaining posterior pericardial well, and the dome of the left atrium is anastomosed toward the surgeon. Again, a small portion of the left atrial anastomosis is left incomplete so cold saline can be flushed through the left-sided structures. With the infant in Trendelenburg position, the aortic arch vessels are snared, the circulation is arrested, and the arterial perfusion cannula is withdrawn. The arterial duct is ligated and divided, and nearly all ductal tissue is excised. The undersurface of the aortic arch is incised from the level of the brachiocephalic trunk to about 1 cm down the descending aorta, beyond the ductus arteriosus. Special care is exercised to identify and avoid injury to the recurrent laryngeal and phrenic nerves. The neoaortic arch is reconstructed with the opened, long segment of donor aortic arch, starting at the descending aorta, beyond the amputated duct. Selective low-flow hypothermic cerebral perfusion may be employed here, but a period of 15 to 25 min of circulatory arrest provides an unencumbered, bloodless field for this part of the procedure, without additional neurological risk. The aorta is filled with cold saline by way of the donor brachiocephalic artery stump, which is also used for reinsertion of the arterial cannula. The passive venous cannula is placed through the appendage into the donor right atrium. Perfusion is resumed, the left atrial anastomosis is completed, and any residual air is evacuated through a vent site in the donor ascending aorta. The occluding tourniquets around the arch vessels are removed. The pulmonary arterial anastomosis is completed during the early warming phase of recirculation. The patient is gently rewarmed to 36°C, using a minimum of 60 minutes of extracorporeal reperfusion. In instances when cold graft ischemic time is markedly prolonged (as in very distant retrievals), reperfusion time may be extended to 80 or 90 minutes to achieve complete functional recovery of the heart.