AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

Heart transplantation in infants and children is now accepted therapy. Survival in excess of 20 years after pediatric heart transplantation has been achieved. Most programs now report that more than 70% of their recipients survive at least 5 years. However, 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 article describes the unique aspects of heart transplantation as applied to infants and children.

History of the Procedure

The first pediatric heart transplantation was performed in 1968 when the heart of an infant with anencephaly 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 at Stanford University. Successful routine cardiac transplantation began after the introduction of cyclosporine. Its successful application to infant recipients began 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 had been hypoplastic left heart syndrome (HLHS), which occurs in about 1 in 6,000 live births. HLHS has diminished as an indication for heart transplantation because of inadequate donor supply and improvement in the surgical palliative approach (ie, the Norwood procedure, with or without the Sano modification). Congenital malformations are still the most common indication for infant heart transplantation. Congenital cardiomyopathy occurs in approximately 1 in 10,000 live births.

The most common indication for heart transplantation in older children is cardiomyopathy. The number of children who have failing cardiac function late after palliative surgery for congenital heart disease is increasing. An important example is the so-called failed Fontan.

Frequency

According to the registry of the International Society for Heart and Lung Transplantation, approximately 300-350 pediatric heart transplantation procedures are performed worldwide each year, representing about 10% of the total number of heart transplants performed.

Etiology

The 4 etiologies that lead to conditions that might require heart transplantation are errors in the formation of the heart, cardiac tumors, infections, and toxins (either endogenous or exogenous) that lead to damage to the myocardium. Many of the congenital anomalies, including congenital cardiomyopathy, are now known to have specific associated chromosomal abnormalities. An 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 (ie, dilated, hypertrophic, restrictive)
• Anatomically uncorrectable congenital heart disease (eg, HLHS, 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 (eg, 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 that require heart transplantation is obviously as varied as the conditions themselves. However, the underlying principle of the inability of the pump to supply adequate perfusion for end-organ health and well-being is inherent in each condition. Details of the pathophysiology of each condition can be obtained from the appropriate eMedicine articles.

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 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 due to arrhythmias. Specific presentations for each of the diagnoses can be found in the appropriate eMedicine articles.

An increasing number of congenital lesions are diagnosable based on fetal ultrasonography findings.

INDICATIONS

Section 3 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

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 greater than 20 mm Hg, mural thrombus on echocardiogram, 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 is generally 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 2-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 that lead to a later Fontan procedure (also called the Norwood operation) and cardiac transplantation. Each operation 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, 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 the Fontan mortality rate include significant systemic atrioventricular (AV) 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 who are at greatly increased operative risk should also be considered for transplantation. This decision somewhat depends 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; therefore, transplantation is not contraindicated. Transplantation is indicated if the tumor is unresectable and is confined to the portion of the heart removed at transplantation; major associated congenital anomalies must not be present. 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

Section 4 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

Anatomic considerations are diverse and should be reviewed according to the particular condition.

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

CONTRAINDICATIONS

Section 5 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

Some anatomic considerations specifically referable to transplantation exist. The major anatomic contraindication is small pulmonary arteries that cannot be satisfactorily surgically enlarged. 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.

Pediatric heart transplantation has few absolute contraindications. Many children who are quite ill can make a remarkable recovery once a new heart restores adequate perfusion. However, the following are considered incompatible with successful transplantation:

• Irreversible elevated pulmonary vascular resistance (>5 Wood units per 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 human immunodeficiency virus (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)
• Small size ( <1800 g)
• Positive finding on drug screen
• Lack of family support systems

WORKUP

Section 6 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

Lab Studies

• Blood type - To be used to list for an appropriate organ (Knowing the infant recipient's blood type is important, but successful transplantation across ABO-incompatible blood types has been successfully performed in >50 infants.)
• Infection screening - CBC count with differential, urine and blood cultures, cytomegalovirus (CMV) titer and/or CMV polymerase chain reaction (PCR), hepatitis B surface antigen (HBsAg), HIV test, rapid plasma reagin (RPR) test, Toxoplasma titer, Epstein-Barr virus (EBV) PCR, and 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 ultrasonography, CT imaging, MRI, EEG as appropriate to assess neurological status
• Chest radiography
• Renal ultrasonography

Diagnostic Procedures

• Echocardiogram to assess anatomy and function
• Cardiac catheterization
• • Cardiac catheterization may be needed to assess anatomy, to rule out pulmonary venous drainage abnormalities, to assess pulmonary artery adequacy, and to 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 pulmonary venous obstruction is present, pulmonary artery pressures may not normalize as quickly.
  • Pulmonary artery pressure may be estimated with echocardiography but usually requires cardiac catheterization for a more formal analysis. Elevated PVR that is reactive (ie, responds to vasodilator therapy) can usually 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

Section 7 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

Medical therapy

The management of children with serious heart disease is specific to each diagnosis and is discussed in the appropriate eMedicine articles. Issues specifically referable to transplantation are discussed here.

Many pediatric patients awaiting heart transplantation can be managed out of the hospital. Evaluate patients on a frequent basis (at least monthly). Pay particular attention to any febrile illness because transplantation in the face of acute infection can be dangerous. Aggressive infection surveillance and treatment is warranted. The issue of vaccination may arise in this setting. Generally, vaccinations, especially live virus vaccines, should be avoided while waiting for transplantation to avoid stimulating the immune system when a donor may become available at any time. However, in a child believed to be capable of safely waiting at least 6 weeks for transplantation, administration of live virus vaccines (if appropriate for age) prior to transplantation is probably better, as live virus vaccines are commonly avoided entirely after transplantation.

Surgical therapy

Attention to detail during the procurement of the donor organ and gentle handling of the donor organ are 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 is usually either the University of Wisconsin solution or Roe solution.

Preoperative details

Meticulous care of child awaiting transplant is essential to ensure the best possible outcome. The management of children with advanced heart failure is outlined in 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. A protocol that incorporates stenting of the patent ductus arteriosus and pulmonary artery banding has been used in Denver to allow children with HLHS to wait without prostaglandin E (PGE)infusion, even outside the hospital.

Among all children waiting for heart transplantation, the mortality rate 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 age 6 months. In the group of less critically ill children (United Network for Organ Sharing [UNOS] status II), the pretransplant mortality rate by 12 months is about 10%.

Intraoperative details

The operative method of transplantation in children with cardiomyopathy is the same as that for adults. A median sternotomy is used to perform thymectomy and to 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 is generally used. A standard orthotopic technique using biatrial or bicaval connection is used. Modifications for anatomy specific to congenital heart disease are as follows:

• For the infant with HLHS, 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 the patient is rewarmed.
• Other complex congenital heart anomalies, such as transposition of the great arteries, can often be managed with 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 patients receiving 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; 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. Sildenafil has also been used in this setting.
• 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 is begun at 0.1 mg/kg/h intravenously when the donor is identified, stopped during surgery, and restarted after transplantation. This is switched to oral dosing when possible, with a target trough cyclosporine level of 250-300 ng/mL.
  • Methylprednisolone is intravenously administered at a dose of 20 mg/kg every 12 hours for 4 doses.
  • Antithymocyte induction therapy (Thymoglobulin) is administered in recipients older than 30 days at a dose of 1.5 mg/kg/d once daily for the first 5 days.
  • Mycophenolate mofetil (MMF) is intravenously or orally administered twice daily at 500 mg/m²/dose and adjusted as necessary to maintain an MMF level of 2.5-5 mcg/mL and a white blood cell count of at least 4 X 10⁹/L.
• Adjunctive therapy: Adjunctive therapy includes intravenous immune globulin at a dose of 2 g/kg administered at 500 mg/kg/d for 4 days, given over 12 hours, beginning right after the transplantation. Ranitidine is administered while the patient is receiving methylprednisolone. Ganciclovir is intravenously administered for 2 weeks in recipients who are CMV positive or who receive a CMV-positive donor. Aspirin at 3-5 mg/kg/d is administered if the platelet count is chronically more than 500 X 10⁹/L.

Follow-up

Close outpatient follow-up is essential to ensure long-term success. The highest risk for complications occurs in the first few months after transplantation; for this reason, the child should remain near the transplantation 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 the rejection-free interval increases. Minimum visit frequency is monthly for the first year and every 3 months thereafter.
• Echocardiogram is obtained twice weekly for 4 weeks, then less often as the rejection-free interval increases, and it should be performed at the same time as the routine physician visits thereafter. A full-study echocardiogram is obtained at 1 month, 3 months, and 12 months to evaluate the aortic arch in patients with arch reconstruction. ECG is performed monthly for the first 3 months, then quarterly until 1 year after transplantation, and then every 6 months thereafter.
• A chest radiograph is taken monthly for 3 months, at 12 months, and then annually.
• Cyclosporine or tacrolimus 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 cyclosporine 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. Tacrolimus trough levels are maintained at 10-13 ng/mL for 6 months, 8-10 ng/mL from 6-12 months, and then 5-8 ng/mL thereafter if rejection history is favorable.
• MMF levels are checked concurrently with calcineurin inhibitor levels. Mycophenolic acid levels are maintained at 2.5-5 mcg/mL. Note that immunosuppression blood level targets are only starting points. Adjustments are needed in the individual child because of rejection history and side effect profile.
• CBC count with platelets is obtained every 2 weeks for 2 months, then monthly for the first year, and every 3 months thereafter.
• Levels of basic electrolytes are obtained at the same time as the CBC count for the first year, with complete metabolic profile (including magnesium levels) every 3 months.
• CMV immunoglobulin G (IgG) titer is assessed at 6 months, 12 months, and then annually until conversion. EBV PCR is assessed every 3 months.
• 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 patients who undergo transplantation during infancy.
• Isotopic glomerular filtration rate (GFR) is assessed at 3 months, 12 months, and every year thereafter for patients who undergo transplantation during infancy. Isotopic GFR is assessed every 2 years for patients who undergo transplantation after the first year and for 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 who undergo transplantation while younger than 6 years; tests are performed annually for all children older than 6 years.
• Endomyocardial biopsy is obtained annually for those who are newborn to aged 2 years at transplantation; at 1 month, 3 months, 12 months, and annually thereafter for children aged 2-8 years at transplantation; 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 transplantation.
• Coronary angiography is performed annually, starting at the first anniversary of transplantation. Intravascular ultrasound (IVUS) is performed starting at age 6 years and then every other year unless prior IVUS demonstrated Stanford class 4 findings.
• All routine vaccinations, except live virus vaccines (eg, oral polio, varicella vaccine, measles-mumps-rubella [MMR]) should be administered, starting as early as 6 weeks after transplantation.

For excellent patient education resources, visit eMedicine's Heart Center. Also, see eMedicine's patient education article Heart and Lung Transplant.

COMPLICATIONS

Section 8 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

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

Preventing rejection while avoiding severe infections, renal failure, and cancer is the biggest challenge facing the transplant physician. Immunosuppression strategies follow.

Introduction

In the earliest days of heart transplantation, the therapeutic options available to the clinician for the prevention of allograft rejection were limited. Initial protocols involved total body irradiation. This was shortly followed by the use of azathioprine (AZA), 6-mercaptopurine, and other myelotoxic agents. Steroids were used systematically beginning in the early 1960s. However, consistently successful immunosuppression did not arrive until the introduction of cyclosporine in the early 1980s. The clinician's armamentarium has now expanded to include agents from various categories.

Mechanisms of action

An extensive discussion of important immunosuppressive agents is beyond the scope of this article. Several recent reviews contain more information.

Immunosuppression strategies

Broadly speaking, immunosuppression strategies in pediatric heart transplantation are built around induction versus no induction and double versus triple drug regimens. Note that none of these strategies have been studied in sufficiently large-scale, randomized, controlled studies. Rather, their use has been adopted from adult thoracic and pediatric noncardiac solid organ trials and adapted through use and experience in pediatric heart transplantation.

Induction therapy

The use of monoclonal or polyclonal antibody T-cell–depleting agents (ie, induction therapy) has been a controversial subject for a number of years. Induction therapy was used early in transplantation and then fell out of favor because of concerns about overimmunosuppression with resultant infections and posttransplant lymphoproliferative disease (PTLD). However, interest has been renewed in their use as a means to reduce or eliminate steroid use. Several studies have demonstrated the efficacy of this approach. In the most recent report from the registry of the International Society for Heart and Lung Transplantation (ISHLT), 45% of pediatric patients who received a heart transplant were treated with induction strategies. Broken down by agent, about 28% used polyclonal antibody T-cell–depleting agents, 15% used interleukin-2 receptor antagonist, and 2% used muromonab-CD3 (Orthoclone OKT3). At Loma Linda, the authors have usedrabbit-derivedpolyclonal

antibody in a steroid-avoidance regimen.

Dual versus triple therapy

Essentially, all regimens start with the foundation of a calcineurin inhibitor—either cyclosporine or tacrolimus (Prograf, FK506). Only one small-scale trial has compared cyclosporine (Neoral, Sandimmune, Gengraf) with tacrolimus in pediatric heart transplantation, demonstrating essentially equivalent efficacy. Even so, the pediatric heart transplant community has gradually shifted toward greater use of tacrolimus. In the ISHLT registry report, the use of tacrolimus at 1 year after transplantation has now surpassed that of cyclosporine. The main advantage of tacrolimus is its lack of cosmetic side effects (hirsutism and gingival hyperplasia). It has greater potency than cyclosporine on a per-milligram basis and is successfully used for patients with recurrent rejection.

Increased incidence of PTLD and posttransplant diabetes is a concern. Newer strategies that incorporate lower target levels have helped greatly with both of these concerns. Oral administration is incomplete and variable, with absolute bioavailability ranging from 17-22% in adults. In children, bioavailability is about 31%, although whole blood concentrations in 31 children younger than 12 years showed that children required higher doses than adults to achieve similar tacrolimus trough concentrations. A high-fat meal reduces mean area under the curve (AUC) by 37%, whereas a high-carbohydrate meal decreases mean AUC by 28%. Peak concentrations are also reduced by 77% and 65%, respectively.

On a more practical note, tacrolimus is not commercially available as a liquid preparation; therefore, tacrolimus solution must be compounded in a local pharmacy, with potential for errors. In addition, tacrolimus is recommended to be administered on an empty stomach, complicating its use in school-aged children, who may have a limited amount of time in the morning before school. Many centers do not strictly adhere to this suggestion, with apparently good results. Whether the results reflect an increased dose to overcome issues with bioavailability is unknown.

At Loma Linda, the authors generally use cyclosporine as the preferred calcineurin inhibitor. Target trough levels (whole blood, monoclonal assay) are 250-300 ng/mL for the first 6 months, 200-250 ng/mL for the next 6 months, and 125-150 ng/mL thereafter if rejection history is acceptable. Tacrolimus is used primarily in certain select high-risk candidates (eg, patients with multiple prior cardiac surgeries, patients with high panel reactive antibody levels African American recipients). The authors also use tacrolimus for patients with recurrent rejection. A significant number of children experience problematic cosmetic side effects, especially children who require orthodontia, in whom gingival hyperplasia is counterproductive.

Antiproliferative agents

AZA (Imuran) has been the mainstay in this class of agents. However, in the ISHLT registry, MMF (CellCept) is now used in approximately 60% of pediatric patients who receive a heart transplant. Again, no prospective studies are available, but 2 retrospective studies in children have indicated potential benefits gained with AZA use.

Cardiac allograft vasculopathy significantly affects long-term graft and patient survival. In adult cardiac transplant trials, MMF has been shown to decrease the progression of coronary intimal thickness. MMF, like AZA, can induce bone marrow suppression effects. The biggest challenge is the significant risk of gastrointestinal side effects, which affect patient tolerability. A significant advantage is that the drug can be dosed to a therapeutic level.

At Loma Linda, the authors use MMF as part of the primary immunosuppression regimen. The authors start with a dose of 300 mg/m²/d divided twice daily and advance as tolerated to maintain a level of 2.5-5 mcg/mL (measuring mycophenolic acid levels).

Corticosteroids

Oral corticosteroids have been a mainstay of rejection prophylaxis since the early days of transplantation. However, in pediatric heart transplantation, reports from various centers over a number of years have documented effective rejection prophylaxis with steroid avoidance and/or early weaning to zero. Steroid avoidance is believed to require induction therapy. The newer immunosuppressive agents have given more confidence to those who wish to wean to zero. Programs that use steroids typically start with oral prednisone at a dose of 2 mg/kg/d and then wean over the first 3 months to a maintenance dose of 0.1-0.3 mg/kg/d once daily or once every other day.

At Loma Linda, the authors have practiced steroid avoidance from program inception, with oral prednisone only used in the treatment of rejection or in children in whom no other combination is effective or tolerated. This approach has received some validation from the immunology literature, which has demonstrated that chronic glucocorticoid therapy leads to downregulation of cytoplasmic glucocorticoid receptor expression, as evidenced in T lymphocytes.

mTOR inhibitors

The mTOR inhibitor sirolimus (Rapamune) is a newer agent that works synergistically with calcineurin inhibitors. Little published experience in pediatric heart transplantation has been reported, but what is available seems to indicate some usefulness in the management of rejection, renal dysfunction, and calcineurin side effects.

At Loma Linda, the authors have been using sirolimus for recurrent rejection, in children with renal insufficiency (to decrease calcineurin inhibitor dose or to eliminate the calcineurin inhibitor, used in conjunction with MMF), as solo therapy in the first few months after treatment for PTLD, and in children who have coronary intravascular evidence of moderate-to-severe cardiac allograft vasculopathy.

Nonpharmacologic measures

Three additional therapies are worth mentioning. Total lymphoid irradiation has been used in the treatment of recalcitrant rejection. It has become less necessary with the availability of newer immunosuppressive agents. Plasmapheresis has been used either pretransplantation in patients who are highly sensitized or posttransplantation in patients with acute antibody-mediated rejection (AMR) or in whom AMR is anticipated. Photophoresis involves the extraction of lymphocytes from patients who were pretreated with psoralen, treatment with ultraviolet A light, and reinfusion. It has been helpful in the prevention and treatment of recurrent rejection. No reports on its use with children have been published.

Treatment of acute rejection

The mainstay for the treatment of acute graft rejection is high-dose intravenous or oral corticosteroid administration. An oral steroid taper is often used after intravenous treatment. No controlled studies regarding the appropriate dose have been reported.

At Loma Linda, the authors treat acute rejection with intravenous methylprednisolone at a dose of 20 mg/kg/dose (not to exceed 500 mg/dose) twice daily for 8 doses. Uncomplicated rejection diagnosed based on biopsy findings alone may be treated with oral prednisone at a dose of 2 mg/kg/d for 3 days, with a taper to zero over 3 weeks. In patients with recurrent rejection or with acute rejection with hemodynamic compromise, anti–T-cell antibody preparations should be added. The authors use antithymocyte globulin (Thymoglobulin, Sangstat, rabbit-ATG) at a dose of 1.5 mg/kg/d, with slow intravenous administration over 6 hours. This is given daily for 7-10 days. A lymphocyte profile should be obtained on day 3, with a target absolute CD3 count of less than 200 cells/mL. The use of high-dose intravenous immunoglobulin in the treatment of graft rejection may be beneficial.

An evaluation of the causative mechanisms must accompany the treatment of the rejection episode. If immunosuppressive doses have been faithfully given and if the desired therapeutic levels have been maintained, either the desired level must be increased or the agent must be changed. Noncompliance must be suspected in any late rejection episode, especially with low drug levels and in the adolescent patient.

Diagnosis of rejection

Rejection is diagnosed based on clinical signs and symptoms, echocardiographic changes, and endomyocardial biopsy findings.

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 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 ISHLT, with treatment generally occurring only for biopsy samples that demonstrate a 2R (ie, 2 or more foci lymphocytic infiltration with associated myocyte damage) or greater histology (Stewart, 2005).

Infection

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 infections occur but are less frequent. Other opportunistic infections should be anticipated and aggressively treated when present.

Malignancy

Malignancy, usually PTLD 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 are treated with a modified chemotherapeutic regimen that consists of cyclophosphamide every 3-4 weeks for 4-6 months accompanied by anti-CD20 monoclonal antibody (rituximab) for tumors that express CD20. For more information, see Posttransplant Lymphoproliferative Disease.

Clinical protocols are currently being explored to prevent PTLD. These include serial monitoring of EBV PCR and intervening with ganciclovir (Cytovene) or valganciclovir (Valcyte) with or without serial infusions of intravenous immunoglobulin in an attempt to decrease the viral load while the patient's immune system develops an adequate response to the infection. In the face of acute EBV infection, the immunosuppression should be minimized as much as possible. However, rejection and graft vasculopathy have recently been suggested as important risks of excessively reducing immunosuppressive medications, especially in patients who have undergone heart transplantation.

Once infected, the EBV PCR viral load counts can widely vary. The development of PTLD is not always accompanied by high PCR counts.

Allograft Vasculopathy

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 have developed significant allograft vasculopathy. Because 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 may also present with syncope or sudden death. Significant vasculopathy that causes cardiac function changes and that is diagnosed using coronary angiography is probably best treated with retransplantation.

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

IVUS has been used extensively to assess coronary artery disease and especially to evaluate different immunosuppressive regimens in adult patients who have received a heart transplant. Abnormalities in IVUS findings have been shown to predict later development of significant cardiac events. Few reports have described the use of this technique in children, but it has been suggested as a more sensitive assessment of graft vasculopathy.

mTOR inhibitors have been shown to decrease the incidence of graft vasculopathy in adults who have received a heart transplant, and one reported noted the reversal of disease. mTOR inhibitor use is currently being explored in children.

Nephrotoxicity

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.

Newer immunosuppressive strategies to minimize nephrotoxicity have used the synergistic properties between calcineurin inhibitors and sirolimus to lower the calcineurin inhibitor dose. A combination of sirolimus and MMF has also been used as a non–calcineurin inhibitor immunosuppressive regimen.

OUTCOME AND PROGNOSIS

Section 9 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

In the current era, the expected 1-year survival rate is 80-90%, the 2-year survival rate is 80-85%, and the 5-year survival rate is approximately 70-80% in experienced centers. Beyond 10 years, a slow attrition rate continues, and a number of children require an additional transplant procedure, usually because of graft vasculopathy. Mortality while waiting for a donor organ is additive to these survival figures. Infants who undergo transplantation in the first month of life appear to have a survival advantage over infants who undergo transplantation during the remainder of the first year of life. This is likely related to immunologic and nonimmunologic factors.

The condition of children who have survived longer than 10 years after transplantation is good. Two thirds of infant recipients 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 intelligence quotient (IQ) testing than healthy controls, with about a 10-point decrement in standardized testing scores. 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.

Twenty-year survival in the infant and older child has been achieved.

FUTURE AND CONTROVERSIES

Section 10 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

The oldest newborn recipient of a heart transplant reached age 20 years in 2005. 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, is probably 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 or treatment of vasculopathy remains to be determined.

The most appropriate initial immunosuppression protocol is not known. Every transplantation center likely has a different protocol. 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 conducted on this front.

The use of genomics to evaluate the response to immunosuppressive medication and to assess the risk of rejection and graft vasculopathy is being studied; this is interesting and potentially treatment-shifting work. Gene array techniques that measure up-regulation and down-regulation of peripheral blood gene markers are also being studied as a means to individually assess the degree of immunosuppression and, therefore, risk for rejection and infection.

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.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

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