Heart Transplantation

AUTHOR INFORMATION

Authored by Richard E Chinnock, MD, FAAP, Director of Pediatric Heart Transplant, Professor, Vice-Chair, Program Director, Department of Pediatrics, Loma Linda University School of Medicine and Children's Hospital

Richard E Chinnock, MD, FAAP, is a member of the following medical societies: American Heart Association, International Society for Heart and Lung Transplantation, and Society for Pediatric Research

Edited by Richard G Ohye, MD, Director, Pediatric Cardiac Transplantation, Fellowship Program Director, Pediatric Cardiac Surgery, Assistant Professor, Department of Surgery, Section of Cardiac Surgery, University of Michigan Medical Center; Robert Konop, PharmD, Clinical Assistant Professor, Department of Pharmacy, Section of Clinical Pharmacology, University of Minnesota; Steve Dunn, MD, Chief, Solid Organ Transplantation, Department of Surgery, Alfred I DuPont Hospital for Children at Wilmington; Gilbert Herzberg, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Cardiology, New York Medical College; and Steven Neish, MD, Director of Pediatric Cardiac Catheterization Services, Head of Pediatric Cardiology Division, Associate Professor, Department of Pediatrics, University of Wisconsin and Children's Hospital

eMedicine Journal, October 9 2001, Volume 2, Number 10

INTRODUCTION

The application of heart transplantation to infants and children has come of age. While many programs were outgrowths of adult heart transplant programs, most pediatric heart transplant programs have separate teams devoted to the care of infants and children. Most programs now have 5-year survival rates in excess of 70%. But, while an additional 5 years of life is important for all, the goal of pediatric heart transplantation is to provide as much of a normal life span for these children as possible. This chapter describes the unique aspects of heart transplantation as applied to infants and children.

History of the Procedure: The first pediatric heart transplant was performed in 1968 when the heart of an anencephalic infant was transplanted into an 18-day-old infant with Ebstein anomaly. This neonate died 5 hours after the procedure. Older children occasionally underwent transplants during the 1970s and early 1980s. Routine successful cardiac transplantation began after the introduction of cyclosporine and with the pioneering efforts of Bailey and his team at Loma Linda University Children's Hospital in 1985.

Problem: An estimated 10% of congenital heart disease cases have been deemed uncorrectable. One of the most common indications for infant heart transplantation is hypoplastic left heart syndrome (HLHS). This occurs in about 1 in 6,000 live births. Congenital cardiomyopathy occurs in approximately 1 in 10,000 live births.

Frequency: Worldwide, approximately 300-350 pediatric heart transplant procedures are performed each year, representing about 10% of the total number of heart transplants performed.

Etiology: The 4 etiologies leading to conditions that might require heart transplantation are errors in the formation of the heart, cardiac tumors, infections, and toxins (either endogenous or exogenous) leading to damage to the myocardium. Many of the congenital anomalies, including congenital cardiomyopathy, now are known to have specific chromosomal abnormalities associated with them. A good example is the "Catch-22" syndrome, a 22q11 band deletion associated with DiGeorge syndrome and interrupted aortic arch.

Conditions considered for pediatric heart transplantation include the following:

• Cardiomyopathy (dilated, hypertrophic, restrictive)
• Anatomically uncorrectable congenital heart disease (hypoplastic left heart syndrome, pulmonary atresia with intact ventricular septum plus sinusoids, congenitally corrected transposition of the great arteries with single ventricle and heart block, severely unbalanced atrioventricular septal defects)
• Congenital heart disease at high risk for repair (severe Shone complex, interrupted aortic arch and severe subaortic stenosis, critical aortic stenosis with severe endocardial fibroelastosis, Ebstein anomaly in a symptomatic newborn)
• Refractory heart failure after previous cardiac surgery
• Unresectable symptomatic cardiac neoplasms

Pathophysiology: The pathophysiology of conditions requiring heart transplantation is obviously as varied as the conditions themselves. Inherent in each condition, however, is the underlying principle of the inability of the pump to supply adequate perfusion for end-organ health and well being. Details of the pathophysiology of each condition should be obtained from the section in this text dedicated to that condition.

Clinical: Infants with serious congenital heart disease generally present in the newborn period with varying degrees of cyanosis, tachypnea, tachycardia, dysrhythmias, poor perfusion, feeding intolerance, and other symptoms of heart failure. Symptoms of heart failure, either of rapid or slow onset, are associated with the cardiomyopathies. Children with tumors may present with congestive heart failure (CHF) or with syncope or cardiac arrest from arrhythmias. Specific presentations for each of the diagnoses can be found in the appropriate sections of this text.

An increasing number of congenital lesions are diagnosable by fetal ultrasound. In the author's experience, almost half of all infants with hypoplastic left heart syndrome are diagnosed in utero.

INDICATIONS

Dilated cardiomyopathy

Guidelines about specific hemodynamic, echocardiographic, and clinical criteria that indicate the advisability of cardiac transplantation are not yet established. The risk of death is highest during the first 3 months after presentation, so decisions regarding transplantation should be made relatively soon after diagnosis. Risk factors for poor outcome include children older than 5 years at the time of presentation, familial cardiomyopathy and endocardial fibroelastosis, severe persistent depression of left ventricular systolic function (shortening fraction <0.12 and ejection fraction <0.20), severe mitral regurgitation, persistent left ventricular end-diastolic pressure >20 mm Hg, mural thrombus on echo, globular (rather than elliptical) left ventricular shape, and the presence of complex atrial and ventricular arrhythmias. Any child who presents with these risk factors should be considered for early referral for transplantation.

Hypertrophic cardiomyopathy

Clinical presentation is quite varied as is the natural history. Risk factors for poor prognosis include a presentation in infancy, syncopal symptoms, family history of progressive hypertrophic cardiomyopathy, sustained ventricular tachycardia, mitral regurgitation, and development of atrial fibrillation. Cardiac transplantation generally is reserved for patients who are symptomatic and who have either multiple risk factors for poor survival or impaired systolic function marking the onset of advanced stages of disease.

Restrictive cardiomyopathy

In children, survival rates are generally poor with a median time from diagnosis to death of about 1 year. A tendency for a progressive increase in pulmonary vascular resistance also exists. Early referral for cardiac transplantation is indicated.

Anatomically uncorrectable congenital heart disease

These lesions include any cardiac malformation for which a two-ventricle repair is not possible or advisable. Cardiac transplantation is recommended for certain subsets with poor short-term or intermediate survival rates.

A special case is the infant with HLHS. The current recommended options include a series of palliative operations leading to a later Fontan procedure (also called the Norwood operation) and cardiac transplantation. Each has pros and cons. The staged surgical repair requires multiple operative procedures and ends with single ventricle physiology. Transplantation requires life-long immunosuppression. Both options are palliative. Both options, in all likelihood, will eventually lead to transplantation or retransplantation in the child's future.

For all patients considered for the Fontan pathway, cardiac transplantation should be considered a more appropriate therapy if the Fontan mortality rate is expected to be 20% or greater. Factors that increase Fontan mortality include significant systemic atrioventricular (A-V) valve insufficiency, moderate (but not severe) elevation of pulmonary vascular resistance, and depressed systemic ventricular function.

Conditions at high risk for corrective operation

Patients with potentially correctable congenital heart disease but at greatly increased operative risk also should be considered for transplantation. This decision is somewhat dependent on the surgical results at specific institutions. Lesions that should be considered include complex truncus arteriosus (with severe truncal valve insufficiency, interrupted aortic arch, or coronary artery anomalies), some severe forms of Shone complex, and complex interrupted aortic arch.

Cardiac tumors

Primary cardiac tumors rarely metastasize, and therefore transplantation is not contraindicated. Transplantation is indicated if the tumor is unresectable, is confined to the portion of the heart removed at transplantation, and there are no major associated congenital anomalies. In children with tumors associated with tuberous sclerosis, spontaneous regression is common. Transplantation should be considered if severe left ventricular outflow obstruction, hemodynamic compromise, or life-threatening arrhythmias are present.

RELEVANT ANATOMY AND CONTRAINDICATIONS

Relevant Anatomy: Anatomic considerations are diverse and should be reviewed depending on the particular condition.

Abnormalities of situs, systemic venous return, and malpositions of the great vessels can be managed surgically at the time of cardiac transplantation.

Contraindications: Some anatomic considerations specifically referable to transplantation exist. The major anatomic contraindication is small pulmonary arteries that cannot be satisfactorily enlarged surgically. Other features that could preclude safe heart transplantation include subsets of anomalous pulmonary venous connection without a suitable pulmonary venous confluence for direct anastomosis to the donor left atrium.

Few absolute contraindications to pediatric heart transplantation exist. Many children who are quite ill can make a remarkable recovery once a new heart restores adequate perfusion. The following, however, are considered incompatible with successful transplantation:

• Irreversible elevated pulmonary vascular resistance (> or =5 Wood units M²)
• Diffuse hypoplasia of right and left pulmonary arteries
• Total anomalous pulmonary venous connection without pulmonary venous confluence
• Ectopia cordis
• Active systemic infection
• Infection with HIV or chronic active hepatitis B or C
• Malignancy without cure or of recent onset
• Severe primary renal or hepatic dysfunction
• Multiorgan system failure
• Major central nervous system abnormality
• Severe dysmorphism
• Marked prematurity (<36 wk)
• Low birth weight (<2 kg)
• Positive drug screen
• Lack of family support

WORKUP

Lab Studies:

• Blood type - To be used to list for an appropriate organ

• Infection screening - CBC with differential, urine and blood cultures, cytomegalovirus (CMV) titer, hepatitis B surface antigen (HBsAg), HIV test, rapid plasma reagin (RPR) test, endotracheal tube (ETT) aspirate (if applicable)

• Assess renal and liver function - Electrolytes, BUN, creatinine, and liver profile

• Assess pretransplant sensitization - Panel reactive antibody

Imaging Studies:

• Head ultrasound, CT scan, MRI, EEG as appropriate to assess neurological status

• Chest x-ray

• Renal ultrasound

Diagnostic Procedures:

• Echocardiogram to assess anatomy and function

• Cardiac catheterization

• May be needed to assess anatomy, rule out pulmonary venous drainage abnormalities, assess pulmonary artery adequacy, and assess pulmonary vascular resistance

• Recipients with elevated pulmonary vascular resistance (PVR) are at increased risk for acute right heart failure in the early posttransplant period.

• In the first few months of life, if the main and branch pulmonary arteries are of normal caliber and distribution, the elevated PVR of the newborn period usually rapidly normalizes shortly after transplantation. If there is pulmonary venous obstruction, pulmonary artery pressures may not normalize as quickly.

• Estimation of pulmonary artery pressures may be possible by echocardiography but usually requires cardiac catheterization for a more formal analysis. Elevated PVR that is reactive (ie, responds to vasodilator therapy) usually can be managed with oxygen and/or intravenous vasodilator therapy in the pretransplant period. This can lead to a decrease in the PVR, simplifying the posttransplant management. Elevated PVR that is fixed is an indicator of significant risk for acute graft failure.

TREATMENT

Medical therapy: The management of children with serious heart disease is diagnosis specific and discussed in those sections of this text dealing with each diagnosis. Issues specifically referable to transplantation are discussed here.

Most pediatric patients awaiting heart transplantation can be managed out of the hospital. They should be evaluated on a frequent basis (at least monthly). Particular attention should be paid to any febrile illness because transplantation in the face of acute infection can be dangerous. Aggressive infection surveillance and treatment is warranted. Vaccinations should be avoided while waiting to avoid stimulating the immune system when a donor may become available at any time.

Surgical therapy:
Donor operation: Attention to detail during the procurement of the donor organ and gentle handling of the donor organ is as important as the implantation of the organ. The donor operation must be tailored to the anatomic needs of the recipient. Recipient anomalies of pulmonary venous connection often require complete resection of the donor left atrium, dividing each donor pulmonary vein separately. In the case of anomalies of systemic venous return, extended removal of the superior vena cava, left innominate vein, and inferior vena cava may be required.

The pediatric cardioplegia solution usually is either the University of Wisconsin solution or Roe solution.

Preoperative details: Meticulous care of the child awaiting transplant is essential to ensure the best possible outcome. The management of children with advanced heart failure is outlined in the appropriate section of this text (see Heart Failure, Congestive). For patients with ductal dependent physiology, the lowest dose possible of prostaglandin (0.1-0.2 mcg/kg/min) should be used. The authors usually use a peripherally inserted central catheter (PICC) line, with a second heparin lock in place in the advent of sudden loss of the primary intravenous site. Oxygenation must be managed to balance the pulmonary and systemic blood flows. This may require adding nitrogen to the inspired gas mixture to render delivered oxygen at less than a fractional inspired oxygen (FiO₂) of 0.21. An important complication is a significantly restricted interatrial communication. Balloon atrial septostomy or surgical septectomy may be necessary.

Among all children waiting for heart transplantation, the mortality prior to transplantation is approximately 15-20%. Mortality during the waiting period for infants with HLHS is significant when the infant has to wait longer than about 3 months, with infants only occasionally surviving until aged 6 months. In the group of less critically ill children (United Network for Organ Sharing [UNOS] status II), pretransplant mortality by 12 months is about 10%.

Intraoperative details: The operative method of transplantation in children with cardiomyopathy is the same as for adults. A median sternotomy is utilized to perform thymectomy and expose the recipient’s native heart. If the donor heart is significantly larger than the native heart, the entire left pericardium anterior to the phrenic nerve is removed. Single venous and arterial cannulation generally is employed. A standard orthotopic technique utilizing biatrial or bicaval connection is used. Modifications for anatomy specific to congenital heart disease are as follows:

• For the infant with hypoplastic left heart syndrome, the ductus arteriosus is isolated and cannulated for arterial perfusion through a stab wound in the distal main pulmonary artery. All aortic arch vessels are isolated with loose tourniquets during the initial cooling phase in preparation for reconstruction. Implantation of the allograft is accomplished with systemic hypothermia, performing the atrial anastomoses under low-flow perfusion, with the pulmonary artery clamped and systemic perfusion maintained by means of the arterial cannula positioned in the ductus arteriosus. The aortic arch is then reconstructed under circulatory arrest with the arch vessel tourniquets tightened. The excision of ductal tissue at its entrance into the distal arch is important in providing secure aortic tissue for the anastomosis and to minimize the likelihood of a posttransplant stenosis in this area. The pulmonary artery anastomosis is completed while rewarming the patient.
• Other complex congenital heart anomalies, such as transposition of the great arteries, often can be managed by direct anastomosis if sufficient lengths of donor arterial and venous connections are procured.

Postoperative details: Management of the child who has undergone heart transplantation is similar to management for any pediatric cardiac surgery. Those details specifically referable to heart transplantation include the following:

• Prostaglandin therapy: For those patients on prostaglandin E (PGE) prior to transplantation, continuing for at least 1-2 days and then gradually weaning over 2-3 days to prevent rebound pulmonary hypertension is advisable.
• Pulmonary hypertension: The donor right ventricle is not tolerant of significant pulmonary hypertension and, for this reason, acute graft failure is one of the largest contributors to early mortality. Optimal therapy includes sedation, vasodilator therapy, alkalinization through hyperventilation, inotropic agents with minimal pulmonary vasoconstrictive effects, and inhaled nitric oxide when available.
• Pulmonary management: Many children receive donor organs that are larger than their native hearts. This leads to compression of lung parenchyma. Aggressive pulmonary toilet is indicated and close observation for respiratory compromise is required, especially after the initial extubation.
• Perioperative immunosuppression: A number of protocols exist for immunosuppression in the perioperative and postoperative period. The following protocol is used at Loma Linda University Children's Hospital. Cyclosporine (CSA) is begun at 0.1 mg/kg/h IV when the donor is identified, stopped during surgery, and restarted after transplantation. This is switched to oral dosing when possible with a target trough CSA level of 250-300 ng/mL. Methylprednisolone is given IV at a dose of 20 mg/kg every 12 hours for 4 doses. Antithymocyte induction therapy (Thymoglobulin) is given for recipients older than 30 days at a dose of 1.5 mg/kg/d once daily for the first 5 days. Azathioprine is started at 3 mg/kg/d IV or PO given once daily and adjusted downward as necessary to maintain a white blood cell count of at least 4 X 10⁹/L.

Adjunctive therapy includes intravenous immune globulin at a dose of 2 g/kg given over 24 hours beginning right after the transplant. Ranitidine is given while on methylprednisolone. Ganciclovir is given IV for 2 weeks for those recipients who are CMV positive or who receive a CMV positive donor. Aspirin at 3-5 mg/kg/d is given if the platelet count is chronically over 500 X 10⁹/L.

Follow-up care: Close outpatient follow-up is essential to ensure long-term success. The highest risk for complications occurs in the first few months after transplantation, and, for this reason, the child should remain near the transplant center for the initial follow-up. The outpatient-testing schedule at Loma Linda University Children's Hospital is as follows:

• Physician visits are twice weekly for 6 weeks, then less frequently as rejection free interval increases. Minimum visit frequency is monthly for the first year and every 3 months thereafter.
• Echocardiogram/ECG is obtained twice weekly for 4 weeks, then less often as the rejection free interval increases and should be performed at the same time as the routine physician visits thereafter. Full-study echocardiogram is obtained at 1 month, 3 months, and 12 months to evaluate the aortic arch in patients with arch reconstruction.
• Chest x-ray is taken monthly for 3 months, at 6 and 12 months, then annually.
• Cyclosporine trough level is assessed twice weekly for 2 weeks after discharge, weekly for 4 weeks, monthly for the first year, and then every 3 months thereafter. Target CSA levels (with favorable rejection history) are 250-300 ng/mL for 6 months, 200-250 ng/mL for 6-12 months, and then 125-150 ng/mL thereafter.
• CBC with platelets is obtained every 2 weeks for 2 months, then monthly for the first year and every 3 months thereafter.
• Basic electrolytes are obtained at the same time as the CBC for the first year with complete metabolic profile every 3 months.
• CMV immunoglobulin G (IgG) titer and Epstein-Barr virus (EBV) titers are assessed at 6 months, 12 months, and then annually until conversion. (Antigen load by PCR may replace/supplement these values.)
• HIV and HBsAg tests are obtained at 6 months.
• Developmental assessment is conducted at age 4 months and 18 months for infant recipients.
• Speech and language evaluation is conducted at age 3 years for infant recipients.
• Standard psychometric testing is conducted at age 5 years for those transplanted during infancy.
• Isotopic glomerular filtration rate (GFR) is assessed at 3 months, 12 months, and every year thereafter for those transplanted during infancy. Isotopic GFR is assessed every 2 years for those transplanted after the first year and for those children who are older than 2 years and whose most recent GFR is more than 100 mL/min/1.73 m².
• Renal ultrasound is performed at 3 months, 12 months, and then every other year.
• Metabolic exercise stress testing is started at age 6 years for those transplanted while younger than 6 years; test annually for all children older than 6 years.
• Endomyocardial biopsy is obtained annually for those who are newborn to aged 2 years at transplant; at 1 month, 3 months, 12 months, and annually thereafter for children aged 2-8 years at transplant; and prior to discharge, at 1 month, 2 months, 3 months, 6 months, 12 months, and annually thereafter for patients aged 9 years or older at transplant.
• Coronary angiography is performed annually, starting at the first anniversary of transplant. (Consider intravascular ultrasound for children aged 6 years or older.)
• All routine vaccinations, except live virus vaccines (eg, oral polio, varicella vaccine, measles-mumps-rubella [MMR]) should be given, starting as early as 6 weeks after transplantation.

COMPLICATIONS

The most significant causes of death after transplantation include early graft failure (either primary graft failure or secondary to pulmonary hypertension), allograft rejection, infection, allograft vasculopathy, and malignancy.

• Allograft rejection: The diagnosis of rejection is made based on clinical signs and symptoms, echocardiographic changes, and endomyocardial biopsy.

Clinical clues to rejection include a decrease in the child’s activity or feeding, low-grade fever, persistent resting tachycardia, ventricular ectopy, S₃ gallop, tachypnea/dyspnea, hepatic congestion, ileus, and other signs and/or symptoms of low cardiac output. Echocardiographic criteria for rejection are somewhat controversial, but include findings reflective of an increase in left ventricular mass, impairment of systolic and diastolic function, new pericardial effusion, and new mitral insufficiency. Endomyocardial biopsies are graded according to the criteria of the International Society for Heart and Lung Transplantation, with most centers only treating biopsies with a 3A (ie, lymphocytic infiltration with myocyte degeneration) or greater histology.

Rejection is treated with bolus steroid therapy. The authors use methylprednisolone IV at a dose of 20 mg/kg/dose every 12 hours for 8 doses. For recurrent rejection or rejection accompanied by hemodynamic compromise, antithymocyte therapy is added. Various agents are available, such as Orthoclone OKT3 (monoclonal mouse derived), antithymocyte gamma globulin (ATGAM) (polyclonal equine derived), and Thymoglobulin (polyclonal rabbit derived). The authors use Thymoglobulin at a dose of 1.5 mg/kg/dose given over 6 hours daily for 10 days. The target T-cell count (CD3 by flow cytometry) is 150/mL or less.

Many options for adjusting immunosuppression protocols exist, depending on rejection history. Several programs now use tacrolimus and/or mycophenolic acid as primary immunosuppression therapy. These can also be used as "rescue" therapy for recalcitrant rejection. Total lymphoid irradiation also can be used for cases of rejection particularly difficult to treat.

• Infection is an expected complication, with a significant number of recipients experiencing one or more potentially serious infections in the first few months after transplantation. These infections in the early postoperative period usually are bacterial and include wound infections, pneumonia, bacteremia, and urinary tract infections. CMV is a significant complication. Pneumocystis carinii occurs but is less frequent. Other opportunistic infections should be anticipated and aggressively treated when present.
• Malignancy, usually posttransplant lymphoproliferative disease associated with EBV infection, occurs in 2-10% of children. When the histology is low-grade (polymorphous hyperplasia), it usually responds to short-term cessation of immunosuppression. Higher-grade lymphomas also may respond to this therapy, with chemotherapy reserved for rapidly progressive or persistent disease. A more recent development is the ability to use anti-CD20 monoclonal antibody (rituximab) to treat those tumors that express CD20.
• Allograft vasculopathy has emerged as the most important limiting factor for long-term survival. At 10 years after transplantation, as many as 20% of recipients will have developed significant allograft vasculopathy. Since the donor heart is denervated, children with graft vasculopathy rarely present with angina. They may have atypical angina such as shoulder or back pain, or, more frequently, abdominal pain. They also may present with syncope or sudden death. Significant vasculopathy that is diagnosed by coronary angiography probably is best treated with retransplantation.

Other modalities that have been useful in diagnosis are treadmill testing and dobutamine stress echocardiography. Data in adult heart transplantation suggest that calcium channel blockers and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) inhibitors may help prevent allograft vasculopathy, but data in children are lacking. Some transplant centers treat all children with these agents while others use them only in high-risk patients.

• Nephrotoxicity is the most import nonlethal complication. Hypertension, metabolic acidosis, and other metabolic abnormalities may be observed with varying frequency. Adjusting the calcineurin inhibitor to the lowest level possible helps ameliorate these problems. Minimizing steroid dosing also helps significantly with hypertension and with issues relating to growth and bone density.

OUTCOME AND PROGNOSIS

In the current era in experienced centers, expected 1-year survival is 80-90%, 2-year survival is 80-85%, and 5-year survival is approximately 70-80%. Mortality while waiting for a donor organ is additive to these survival figures. A survival advantage appears to exist for infants transplanted in the first month of life compared to infants transplanted during the remainder of the first year of life. This likely is related to immunologic and nonimmunologic factors.

The condition of the children who have survived beyond 10 years after transplant is good. Two thirds of infant recipients who are older than 10 years are described as developmentally normal by their parents. More formal psychometric testing shows that infant heart transplant recipients score lower on IQ testing than normal controls, with about a 10-point decrement in standardized testing. This is similar to infants undergoing other similar congenital heart surgery. In the absence of long-term higher-dose steroids, children grow appropriately after heart transplantation. Recent data indicate that they progress through puberty in a normal fashion. In the absence of repeated graft rejection or graft vasculopathy, cardiac function and exercise tolerance are normal.

FUTURE AND CONTROVERSIES

The oldest newborn recipient of a heart transplant reached age 15 years in 2000. Longer-term prognosis is unknown. Significant numbers of children are now entering the second decade after their transplantation and are generally in good health. The biggest challenge in the long-term is preventing or treating graft vasculopathy. Retransplantation, at some point in time, probably is inevitable for most, if not all, children who have undergone heart transplantation. If the vasculopathy is diagnosed in a timely manner, these children tolerate the second transplant well, with better survival rates than for the primary transplant. The role of calcium channel blockers, HMG-CoA reductase inhibitors, and newer immunosuppressive agents (eg, mycophenolate, sirolimus) in the prevention of vasculopathy remains to be determined.

The most appropriate initial immunosuppression protocol is not known. Probably, a different protocol exists for nearly each transplant center. Clear data are difficult to obtain because of the small number of transplants performed each year and the need for centers to standardize practice across institutions. In addition, while early rejection and survival are important therapeutic end points for research design, graft vasculopathy is the most important outcome measure. Vasculopathy does not become a significant issue for at least 5 years after transplantation. Much work remains to be done on this front.

Finally, donor supply is inadequate. Improved public and physician awareness of donor issues is the most important factor in increasing donor supply because many potential donors are not identified as such. Other more innovative and controversial sources of donors include resuscitation of asystolic donors and the use of xenografts.

BIBLIOGRAPHY

• Armitage JM, Fricker FJ, del Nido P, et al: A decade (1982 to 1992) of pediatric cardiac transplantation and the impact of FK 506 immunosuppression. J Thorac Cardiovasc Surg 1993 Mar; 105(3): 464-72; discussion 472-3[Medline].
• Assaad A: Posttransplantation management of the newborn and the immunosuppressive role of prostaglandin E1. J Heart Lung Transplant 1993 Nov-Dec; 12(6 Pt 2): S191-4[Medline].
• Bailey LL: Heart transplantation techniques in complex congenital heart disease. J Heart Lung Transplant 1993 Nov-Dec; 12(6 Pt 2): S168-75[Medline].
• Bailey LL, Gundry SR, Razzouk AJ, et al: Bless the babies: one hundred fifteen late survivors of heart transplantation during the first year of life. The Loma Linda University Pediatric Heart Transplant Group. J Thorac Cardiovasc Surg 1993 May; 105(5): 805-14; discussion 814-5[Medline].
• Bailey LL, Zuppan CW, Chinnock RE, et al: Graft vasculopathy among recipients of heart transplantation during the first 12 years of life. The Pediatric Heart Transplant Group. Transplant Proc 1995 Jun; 27(3): 1921-5[Medline].
• Bauer J, Dapper F, Demirakca S, et al: Perioperative management of pulmonary hypertension after heart transplantation in childhood. J Heart Lung Transplant 1997 Dec; 16(12): 1238-47[Medline].
• Baum D, Bernstein D, Starnes VA, et al: Pediatric heart transplantation at Stanford: results of a 15-year experience. Pediatrics 1991 Aug; 88(2): 203-14[Medline].
• Baum M, Chinnock R, Ashwal S, et al: Growth and neurodevelopmental outcome of infants undergoing heart transplantation. J Heart Lung Transplant 1993 Nov-Dec; 12(6 Pt 2): S211-7[Medline].
• Baum M, Freier MC, Freeman KR: Developmental outcomes and cognitive functioning in infant and child heart transplant recipients. Progress in Pediatric Cardiology 2000; 11: 159-163.
• Berner M, Beghetti M, Spahr-Schopfer I, et al: Inhaled nitric oxide to test the vasodilator capacity of the pulmonary vascular bed in children with long-standing pulmonary hypertension and congenital heart disease. Am J Cardiol 1996 Mar 1; 77(7): 532-5[Medline].
• Bork J, Chinnock R, Ogata K, Baum M: Infectious complications in infant heart transplantation. J Heart Lung Transplant 1993 Nov-Dec; 12(6 Pt 2): S199-202[Medline].
• Boucek MM, Faro A, Novick RJ, et al: The Registry of the International Society of Heart and Lung Transplantation: Third Official Pediatric Report-1999. J Heart Lung Transplant 1999 Dec; 18(12): 1151-72[Medline].
• Boucek MM, Mathis CM, Kanakriyeh MS, et al: Donor shortage: use of the dysfunctional donor heart. J Heart Lung Transplant 1993 Nov-Dec; 12(6 Pt 2): S186-90[Medline].
• Boucek MM, Mathis CM, Boucek RJ Jr, et al: Prospective evaluation of echocardiography for primary rejection surveillance after infant heart transplantation: comparison with endomyocardial biopsy. J Heart Lung Transplant 1994 Jan-Feb; 13(1 Pt 1): 66-73[Medline].
• Boucek RJ Jr, Naftel D, Boucek MM, et al: Induction immunotherapy in pediatric heart transplant recipients: a multicenter study. J Heart Lung Transplant 1999 May; 18(5): 460-9[Medline].
• Burch M, Siddiqi SA, Celermajer DS, et al: Dilated cardiomyopathy in children: determinants of outcome. Br Heart J 1994 Sep; 72(3): 246-50[Medline].
• Canter C, Naftel D, Caldwell R, et al: Survival and risk factors for death after cardiac transplantation in infants. A multi-institutional study. The Pediatric Heart Transplant Study. Circulation 1997 Jul 1; 96(1): 227-31[Medline].
• Canter CE: Preoperative assessment and management of pediatric heart transplantation. Progress in Pediatric Cardiology 2000; 11: 91-97.
• Cetta F, O'Leary PW, Seward JB, Driscoll DJ: Idiopathic restrictive cardiomyopathy in childhood: diagnostic features and clinical course. Mayo Clin Proc 1995 Jul; 70(7): 634-40[Medline].
• Chartrand C, Guerin R, Kangah M, Stanley P: Pediatric heart transplantation: surgical considerations for congenital heart diseases. J Heart Transplant 1990 Nov-Dec; 9(6): 608-16; discussion 616-7[Medline].
• Chen JM, Levin HR, Michler RE, et al: Reevaluating the significance of pulmonary hypertension before cardiac transplantation: determination of optimal thresholds and quantification of the effect of reversibility on perioperative mortality. J Thorac Cardiovasc Surg 1997 Oct; 114(4): 627-34[Medline].
• Chiavarelli M, Gundry SR, Razzouk AJ, Bailey LL: Cardiac transplantation for infants with hypoplastic left-heart syndrome. JAMA 1993 Dec 22-29; 270(24): 2944-7[Medline].
• Chinnock R, Baum M: Somatic growth in infant heart transplant recipients. Pediatr Transplant 1998 Feb; 2(1): 30-4[Medline].
• Chinnock R, Emery J, Larsen R, et al: Methotrexate therapy for complex graft rejection in pediatric heart transplant recipients. The Pediatric Heart Transplant Team--Loma Linda. J Heart Lung Transplant 1995 Jul-Aug; 14(4): 726-33[Medline].
• Chinnock RE, Baum MF, Larsen R, Bailey L: Rejection management and long-term surveillance of the pediatric heart transplant recipient: the Loma Linda experience. J Heart Lung Transplant 1993 Nov-Dec; 12(6 Pt 2): S255-64[Medline].
• Chinnock RE: Pediatric heart transplantation at Loma Linda: 1985 to 1996. Clin Transpl 1996; 145-51[Medline].
• Chinnock RE, Torres VI, Jutzy RV, et al: Cardiac pacemakers in pediatric heart transplant recipients: incidence, indications, and associated factors. Pediatric Heart Transplant Group- Loma Linda. Pacing Clin Electrophysiol 1996 Jan; 19(1): 26-30[Medline].
• Chinnock RE, Cutler D, Baum M: Clinical outcome 10 years after infant heart transplantation. Progress in Pediatric Cardiology 2000; 11: 165-169.
• del Rio MJ: Transplantation in complex congenital heart disease. Progress in Pediatric Cardiology 2000; 11: 107-113.
• Denfield SW, Rosenthal G, Gajarski RJ, et al: Restrictive cardiomyopathies in childhood. Etiologies and natural history. Tex Heart Inst J 1997; 24(1): 38-44[Medline].
• Dent CL, Canter CE, Hirsch R, Balzer DT: Transplant coronary artery disease in pediatric heart transplant recipients. J Heart Lung Transplant 2000 Mar; 19(3): 240-8[Medline].
• Fricker FJ, Addonizio L, Bernstein D, et al: Heart transplantation in children: indications. Report of the Ad Hoc Subcommittee of the Pediatric Committee of the American Society of Transplantation (AST). Pediatr Transplant 1999 Nov; 3(4): 333-42[Medline].
• Fritzsche SD, McCabe JL, Chinnock RE: Rare combined heart and kidney transplant in a pediatric patient: a case study. J Transpl Coord 1999 Sep; 9(3): 145-8[Medline].
• Fukushima N, Gundry SR, Razzouk AJ, Bailey LL: Risk factors for graft failure associated with pulmonary hypertension after pediatric heart transplantation. J Thorac Cardiovasc Surg 1994 Apr; 107(4): 985-9[Medline].
• Gajarski RJ, Towbin JA, Bricker JT, et al: Intermediate follow-up of pediatric heart transplant recipients with elevated pulmonary vascular resistance index. J Am Coll Cardiol 1994 Jun; 23(7): 1682-7[Medline].
• Hirsch R, Huddleston CB, Mendeloff EN, et al: Infant and donor organ growth after heart transplantation in neonates with hypoplastic left heart syndrome. J Heart Lung Transplant 1996 Nov; 15(11): 1093-100[Medline].
• Hsu DT, Garofano RP, Douglas JM, et al: Exercise performance after pediatric heart transplantation. Circulation 1993 Nov; 88(5 Pt 2): II238-42[Medline].
• Jacobs ML, Blackstone EH, Bailey LL: Intermediate survival in neonates with aortic atresia: a multi- institutional study. The Congenital Heart Surgeons Society. J Thorac Cardiovasc Surg 1998 Sep; 116(3): 417-31[Medline].
• Jenkins PC, Flanagan MF, Jenkins KJ, et al: Survival analysis and risk factors for mortality in transplantation and staged surgery for hypoplastic left heart syndrome. J Am Coll Cardiol 2000 Oct; 36(4): 1178-85[Medline].
• Kawauchi M, Gundry SR, de Begona JA, et al: Prolonged preservation of human pediatric hearts for transplantation: correlation of ischemic time and subsequent function. J Heart Lung Transplant 1993 Jan-Feb; 12(1 Pt 1): 55-8[Medline].
• Kirklin JK: Pediatric cardiac transplantation. Ann Thorac Surg 2000 May; 69(5): 1627-8[Medline].
• Kuhn MA, Jutzy KR, Deming DD, et al: The medium-term findings in coronary arteries by intravascular ultrasound in infants and children after heart transplantation. J Am Coll Cardiol 2000 Jul; 36(1): 250-4[Medline].
• Larsen RL, Applegate PM, Dyar DA, et al: Dobutamine stress echocardiography for assessing coronary artery disease after transplantation in children. J Am Coll Cardiol 1998 Aug; 32(2): 515-20[Medline].
• Loker J, Darragh R, Ensing G, Caldwell R: Echocardiographic analysis of rejection in the infant heart transplant recipient. J Heart Lung Transplant 1994 Nov-Dec; 13(6): 1014-8[Medline].
• Lynch BJ, Glauser TA, Canter C, Spray T: Neurologic complications of pediatric heart transplantation. Arch Pediatr Adolesc Med 1994 Sep; 148(9): 973-9[Medline].
• Moran AM, Lipshultz SE, Rifai N, et al: Non-invasive assessment of rejection in pediatric transplant patients: serologic and echocardiographic prediction of biopsy-proven myocardial rejection. J Heart Lung Transplant 2000 Aug; 19(8): 756-64[Medline].
• Morrow WR, Naftel D, Chinnock R, et al: Outcome of listing for heart transplantation in infants younger than six months: predictors of death and interval to transplantation. The Pediatric Heart Transplantation Study Group. J Heart Lung Transplant 1997 Dec; 16(12): 1255-66[Medline].
• Morrow WR, Frazier E, Naftel DC: Survival after listing for cardiac transplantation in children. Progress in Pediatric Cardiology 2000; 11: 99-105.
• Pahl E, Crawford SE, Swenson JM, et al: Dobutamine stress echocardiography: experience in pediatric heart transplant recipients. J Heart Lung Transplant 1999 Jul; 18(7): 725-32[Medline].
• Pahl E, Zales VR, Fricker FJ, Addonizio LJ: Posttransplant coronary artery disease in children. A multicenter national survey. Circulation 1994 Nov; 90(5 Pt 2): II56-60[Medline].
• Pahl E: Transplant coronary artery diseasein children. Progress in Pediatric Cardiology 2000; 11: 137-143.
• Pietra BA, Boucek MM: Immunosuppression for pediatric cardiac transplantation in the modern era. Progress in Pediatric Cardiology 2000; 11: 115-129.
• Razzouk AJ, Chinnock RE, Dearani JA, et al: Cardiac retransplantation for graft vasculopathy in children: should we continue to do it? Arch Surg 1998 Aug; 133(8): 881-5[Medline].
• Razzouk AJ, Chinnock RE, Gundry SR, et al: Transplantation as a primary treatment for hypoplastic left heart syndrome: intermediate-term results. Ann Thorac Surg 1996 Jul; 62(1): 1-7; discussion 8[Medline].
• Razzouk AJ, Gundry SR, Chinnock RE, et al: Orthotopic transplantation for total anomalous pulmonary venous connection associated with complex congenital heart disease. J Heart Lung Transplant 1995 Jul-Aug; 14(4): 713-7[Medline].
• Schowengerdt KO, Naftel DC, Seib PM, et al: Infection after pediatric heart transplantation: results of a multiinstitutional study. The Pediatric Heart Transplant Study Group. J Heart Lung Transplant 1997 Dec; 16(12): 1207-16[Medline].
• Schowengerdt KO, Fricker FJ, Bahjat KS, Kuntz ST: Increased expression of the lymphocyte early activation marker CD69 in peripheral blood correlates with histologic evidence of cardiac allograft rejection. Transplantation 2000 May 27; 69(10): 2102-7[Medline].
• Shaddy RE, Naftel DC, Kirklin JK, et al: Outcome of cardiac transplantation in children. Survival in a contemporary multi-institutional experience. Pediatric Heart Transplant Study. Circulation 1996 Nov 1; 94(9 Suppl): II69-73[Medline].
• Shaddy RE: Pulmonary hypertension in pediatric heart transplantation. Progress in Pediatric Cardiology 2000; 11: 131-136.
• Shaffer KM, Denfield SW, Schowengerdt KO, et al: Cardiac transplantation for pediatric patients. With inoperable congenital heart disease. Tex Heart Inst J 1998; 25(1): 57-63[Medline].
• Shirali GS, Cephus CE, Kuhn MA, et al: Posttransplant recoarctation of the aorta: a twelve year experience. J Am Coll Cardiol 1998 Aug; 32(2): 509-14[Medline].
• Sigfusson G, Fricker FJ, Bernstein D, et al: Long-term survivors of pediatric heart transplantation: a multicenter report of sixty-eight children who have survived longer than five years. J Pediatr 1997 Jun; 130(6): 862-71[Medline].
• Straatman LP, Coles JG: Pediatric utilization of rapamycin for severe cardiac allograft rejection. Transplantation 2000 Aug 15; 70(3): 541-3[Medline].
• Towbin JA: Pediatric myocardial disease. Pediatr Clin North Am 1999 Apr; 46(2): 289-312, ix[Medline].
• Tweddell JS, Canter CE, Bridges ND, et al: Predictors of operative mortality and morbidity after infant heart transplantation. Ann Thorac Surg 1994 Oct; 58(4): 972-7[Medline].
• Vricella LA, Razzouk AJ, del Rio M, et al: Heart transplantation for hypoplastic left heart syndrome: modified technique for reducing circulatory arrest time. J Heart Lung Transplant 1998 Dec; 17(12): 1167-71[Medline].
• Webber SA, Green M: Post-transplantation lymphoproliferative disorders: advances in diagnosis, prevention and management in children. Progress in Pediatric Cardiology 2000; 11: 145-157.
• Zales VR, Crawford S, Backer CL, et al: Role of endomyocardial biopsy in rejection surveillance after heart transplantation in neonates and children. J Am Coll Cardiol 1994 Mar 1; 23(3): 766-71[Medline].

eMedicine Journal, October 9 2001, Volume 2, Number 10

PICTURES

Caption: Picture 1. View of the recipient's chest after the heart is removed, with the patient on cardiopulmonary bypass.

Picture Type: Photo

Caption: Picture 2. Suturing of the donor heart. Note that the left atrial anastomosis is performed first.

Picture Type: Photo

Caption: Picture 3. The completed operation. Note the suture lines on the now implanted heart.

Picture Type: Photo

BIBLIOGRAPHY

• Caves PK, Stinson EB, Billingham M: Percutaneous transvenous endomyocardial biopsy in human heart recipients. Experience with a new technique. Ann Thorac Surg 1973 Oct; 16(4): 325-36[Medline].
• Copeland JG, Emery RW, Levinson MM: Selection of patients for cardiac transplantation. Circulation 1987 Jan; 75(1): 2-9[Medline].
• Griepp RB, Ergin MA: The history of experimental heart transplantation. J Heart Transplant 1984; 3: 145.
• Griffith BP, Hardesty RL, Deeb GM: Cardiac transplantation with cyclosporin A and prednisone. Ann Surg 1982 Sep; 196(3): 324-9[Medline].
• Hill JD: Bridging to cardiac transplantation. Ann Thorac Surg 1989 Jan; 47(1): 167-71[Medline].
• Hofflin JM, Potasman I, Baldwin JC: Infectious complications in heart transplant recipients receiving cyclosporine and corticosteroids. Ann Intern Med 1987 Feb; 106(2): 209-16[Medline].
• Kramer BL, Massie BM, Topic N: Controlled trial of captopril in chronic heart failure: a rest and exercise hemodynamic study. Circulation 1983 Apr; 67(4): 807-16[Medline].