Pediatric Heart Transplantation

 

Practice Essentials

Heart transplantation in infants and children is now accepted therapy. According to the registry of the International Society for Heart and Lung Transplantation, approximately 600-700 pediatric heart transplantation procedures are performed worldwide each year, representing about 12% of the total number of heart transplants performed. In 2016, 710 heart transplants were performed in children worldwide. [1In 2019, 507 of the 3551 heart transplants performed in the United States (14%) were in patients up to 17 years of age. [2The proportion of pediatric transplant patients by recipient age has remained relatively stable over the last decade. [1]

In infants, congenital malformations are still the most common indication for heart transplantation. Congenital cardiomyopathy occurs in approximately one 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.

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 one in 6000 live births. HLHS has diminished as an indication for heart transplantation because of the limited donor supply and the improvements that have been achieved in surgical palliation (ie, the Norwood procedure, with or without the Sano modification). See Surgical Treatment of Pediatric Hypoplastic Left Heart Syndrome. Over the past 3 decades, heart transplantation has evolved from a primary indication for treatment of neonates with unrepaired HLHS to the treatment of end-stage heart failure in adolescents and young adults with palliated congenital heart disease. [3]

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, of either rapid or slow onset, are associated with the cardiomyopathies. Children with cardiac tumors may present with congestive heart failure (CHF) or with syncope or cardiac arrest due to arrhythmias. An increasing number of congenital lesions are diagnosable by means of fetal ultrasonography.

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, although 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.

The donor supply remains 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.

For patient education information, see Heart Transplant.

Background

Human orthotopic heart transplantation began on December 3, 1967 when Drs. Chistiaan and Marius Barnard transplanted the heart of a 15-year-old trauma victim into a 55-year-old recipient in Capetown, South Africa. [4Three days later, on December 6, 1967, Dr. Adrian Kantrowitz performed the first orthotopic heart transplantation in a neonate in New York. [5The infant died of a cardiac arrest 6.5 hours after receiving the transplant.

The transplantation of infants would cease for 16 years before being attempted again. [6Over those 16 years, adult heart transplantation became routine and the lower age limit of recipients declined. By 1984, the medical field was again ready for infant transplantation.

At the same time, attempts at cardiac xenotransplantation in animal models was improving and on October 26, 1984, the first and only human cardiac xenotransplant took place, performed by Dr. Leonard L. Bailey at Loma Linda University in California. [7A baboon heart was transplanted into a 12-day old neonate with hypoplastic left heart syndrome. She died after 20 days.  

For the next 10 years, human-to-human orthotopic heart transplantation became an option for primary therapy in neonates with hypoplastic left heart syndrome. [8 A shift toward palliation of complex congenital heart disease took place at this time, due to the limited number of infant donors.

Indications

Generally, conditions that might necessitate heart transplantation may be divided into the following 4 categories:

  1. Errors in the formation of the heart (structural/anatomic defects and cardiomyopathies)
  2. Cardiac tumors
  3. Infections
  4. Toxins (endogenous or exogenous) that damage the myocardium

Many of the congenital anomalies, including congenital cardiomyopathy, have specific associated chromosomal abnormalities. An example is the so-called Catch-22 syndrome, a 22q11 band deletion associated with DiGeorge syndrome and interrupted aortic arch.

More specifically, the indications for pediatric heart transplantation include the following:

  • Cardiomyopathy (ie, dilatedhypertrophic, non-compaction, arrhythmogenic, or restrictive)

  • Anatomically uncorrectable congenital heart disease (eg, hypoplastic left heart sydrome, pulmonary atresia with intact ventricular septum with right ventricular–dependent coronary circulation, transposition of the great arteries with single ventricle and heart block, and severely unbalanced atrioventricular septal defects)

  • Potentially correctable congenital heart disease associated with greatly increased operative risk (eg, severe Shone complex, interrupted aortic arch and severe subaortic stenosis, critical aortic stenosis with severe endocardial fibroelastosis, and Ebstein anomaly in a symptomatic newborn)

  • Refractory heart failure after previous cardiac surgery due to ventricular dysfunction or valve disease
  • Complications of "failing Fontan" physiology (ie, protein-losing enteropathy, plastic bronchitis, liver cirrhosis/dysfunction, cyanosis due to pulmonary arteriovenous malformations)

  • Significant cardiac allograft vasculopathy or chronic graft dysfunction of a previous heart transplant

  • Unresectable symptomatic cardiac neoplasms

  • Refractory ventricular arrhythmias

The pathophysiology of conditions that necessitate heart transplantation is obviously as varied as the conditions themselves. However, the basic abnormality underlying each condition is the inability of the pump to supply adequate perfusion for end-organ health and well-being.

The severity of heart failure in pediatric heart disease is divided into 4 stages, as follows:

  • Stage A - At risk for developing heart failure

  • Stage B - Abnormal cardiac structure or function but no symptoms of heart failure

  • Stage C - Abnormal cardiac structure or function and past or present symptoms of heart failure

  • Stage D - Abnormal cardiac structure or function, requiring continuous intravenous (IV) infusion of inotropes or prostaglandin E1 (to maintain patency of the patent ductus arteriosus) or requiring mechanical ventilatory or mechanical circulatory support

The American Heart Association has published recommended indications for cardiac transplantation in children with heart disease. [9]

Dilated cardiomyopathy

At present, there are no specific guidelines outlining hemodynamic, echocardiographic, and clinical criteria for the advisability of cardiac transplantation in children with dilated cardiomyopathy. Because the risk of death is highest during the first 3 months after presentation, decisions regarding transplantation should be made relatively soon after diagnosis. Risk factors for poor outcome include the following:

  • Age greater than 5 years at 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 higher than 20 mm Hg
  • Mural thrombus on echocardiography
  • Globular (rather than elliptical) left ventricular shape
  • Complex atrial and ventricular arrhythmias

Any child who presents with these risk factors should be considered for early referral for transplantation.

Hypertrophic cardiomyopathy

The clinical presentation of hypertrophic cardiomyopathy varies widely, as does the natural history. Risk factors for poor prognosis include the following:

  • Presentation in infancy
  • Syncopal symptoms
  • Family history of progressive hypertrophic cardiomyopathy
  • Sustained ventricular tachycardia
  • Mitral regurgitation
  • Development of atrial fibrillation

Heart 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 with restrictive cardiomyopathy, survival rates are generally poor, with a median time from diagnosis to death of about 1 year. [10A tendency for a progressive increase in pulmonary vascular resistance also exists. Early referral for cardiac transplantation is indicated. [11]

Arrhythmogenic cardiomyopathy (arrhythmogenic right ventricular dysplasia)

Progressive biventricular dysfunction can occur, leading to end-stage heart failure and refractory arrhythmia, and may require cardiac transplantation.

Left ventricular non-compaction cardiomyopathy

 Progressive left ventricular dysfunction and dilation occur, leading to end-stage heart failure, and may require cardiac transplantation.

Anatomically uncorrectable congenital heart disease

Anatomically uncorrectable congenital heart disease is understood to include any cardiac malformation for which a 2-ventricle repair is not possible or advisable. Cardiac transplantation is recommended for certain patient subsets with poor short-term or intermediate survival rates.

A special case is the infant with HLHS. [12There are 2 currently recommended options:

  • A series of palliative operations that lead to a later Fontan procedure (also known as the Norwood operation)
  • Cardiac transplantation

Each option has pros and cons. The staged surgical repair requires multiple operative procedures and ends with single-ventricle physiology; transplantation requires lifelong immunosuppression. Both options are palliative. With both options, the child is likely to require transplantation or retransplantation at some point in the future.

For infants with HLHS, cardiac transplantation should be considered more appropriate if the mortality with the Fontan procedure is expected to be 20% or higher. Factors that increase the Fontan mortality include the following:

  • Significant systemic atrioventricular (AV) valve insufficiency
  • Moderate (but not severe) elevation of pulmonary vascular resistance
  • Depressed systemic ventricular function

Complications of "failing Fontan" physiology

Several complications of single ventricular Fontan physiology may occur, necessitating cardiac transplantation

  • End-stage heart failure due to ventricular dysfunction and/or AV valve regurgitation
  • Protein-losing enteropathy
  • Plastic bronchitis
  • Liver cirrhosis/dysfunction
  • Cyanosis due to pulmonary arteriovenous malformations

Correctable conditions associated with high operative risk

Patients with potentially correctable congenital heart disease who are at greatly increased operative risk should also be considered for transplantation. This decision depends to some extent on the surgical results at specific institutions. Lesions that may fall into this category include the following:

  • Complex truncus arteriosus (with severe truncal valve insufficiency, interrupted aortic arch, or coronary artery anomalies)
  • Some severe forms of Shone complex
  • Complex interrupted aortic arch

Cardiac tumors

Because primary cardiac tumors rarely metastasize, they do not constitute a contraindication for transplantation. 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.

Intractable arrhythmia

Intractable arrhythmia, typically ventricular, can lead to ventricular dysfunction and end-stage heart failure necessitating transplantation.

Contraindications

The major anatomic contraindication for heart transplantation in pediatric patients is the presence of 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 (> 6 Wood units/m 2 or a transpulmonary gradient > 15 mm Hg)
  • Diffuse hypoplasia of the central branch 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 that is not cured or is of recent onset
  • Severe primary kidney or liver dysfunction
  • Multiorgan system failure
  • Major central nervous system (CNS) abnormality
  • Severe dysmorphisMarked prematurity (< 36 wk)
  • Small size (< 1800 g)
  • Positive finding on drug screen
  • Lack of family support systems

Outcomes

In the current era of heart transplantation, 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. [13Beyond 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.

Overall 15-year survival of 41% after initial heart transplantation was reported in a single-institution analysis of outcomes in children with congenital heart disease. [14 

Godown and colleagues examined the effects of body mass index (BMI) on waitlist mortality in a study of 2,712 children waitlisted for heart transplantation between 1997 and 2011. BMI percentile > 95% or < 1% was an independent risk factor for waitlist mortality in children with cardiomyopathy, but not in those with congenital heart disease. BMI did not affect post-transplant outcomes, regardless of the indication for transplantation. [15]

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.

Twenty-year median survival in the infant and older child has been achieved, with some children surviving greater than 30 years with their first graft. Longer-term prognosis is unknown. Significant numbers of children are now entering the second decade after their transplantation and are generally in good health.

Historically, patients with a prior Fontan procedure for complex congenital heart disease have been considered at higher risk for death after heart transplant. However, more recently, Fontan patient survival has significantly improved, with 1-year survival comparable to non-Fontan  patients with congenital heart disease (89% vs 92%, respectively). [16]

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 do, with about a 10-point decrement in standardized testing scores. These results are similar to those seen in infants undergoing comparable procedures for congenital heart disease.

In the absence of long-term higher-dose steroid therapy, children grow appropriately after heart transplantation. [17Data 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.

The biggest challenge is the long-term prevention or treatment of graft vasculopathy. Retransplantation at some later date 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 their primary transplant.  However, retransplantation in general, especially when required early after primary transplantation, leads to inferior survival with the second graft and earlier development of post-transplant co-morbidities (eg, cardiac allograft vasculopathy, rejection, renal dysfunction). [18]

The role of calcium channel blockers, statins, anti-platelet agents, and newer immunosuppressive agents (eg, mycophenolate mofetil, sirolimus, everolimus) in the prevention or treatment of vasculopathy remains to be determined.

Technical Considerations

In children with cardiomyopathy who have structurally normal extracardiac circulatory systems, the transplantation procedure is similar to adult heart transplantation. In children with structural congenital heart disease, the arterial and venous malformations can pose a challenge to the success of the transplant procedure itself. Additional donor structures, such as the aortic arch and branch pulmonary arteries, may be needed to enable transplantation in a child with hypoplasia of the aortic arch or branch pulmonary arteries. Venous anomalies, such as a left-sided superior or inferior vena cava, may necesitate routing of venous blood to the appropriate location in the chest to complete the required anastamoses.


Pediatric Heart Transplantation Periprocedural Care


Patient Education and Consent

Consent for cardiac transplantation should be obtained at the time of listing. The consent discussion should cover the potential benefits and risks of the procedure, as well as long-term morbidities and outcomes. In addition to the program and national outcome statistics, common co-morbidities such as rejection, infection, cancer, renal disease, coronary disease, and medication side effects are often discussed.

Patient and parental education should begin immediately after the decision to start a transplant evaluation is made. Verbal and written education about the transplant waiting period, peri-transplant care, post-transplant immunosuppressive and other medications, long-term care after cardiac transplant, and outcomes after cardiac transplant should be given. Due to the great amount of new information and tremendous stress that the family is under at this time, frequent reinforcement of the information should be made. Some transplant programs require a written test and/or an inpatient stay with the patient prior to discharge after transplantation.

 

 

Preprocedural Evaluation

The evaluation of potential patients for heart transplantation occurs in two phases. First, a comprehensive assessment of the patient is made to assure candidacy for transplantation. Following listing, continued, frequent patient assessment is required to ensure that the candidate is in the best medical condition possible when a donor heart becomes available.

Pre-transplant listing evaluation

The pre-listing evaluation should have a multi-disciplinary approach. Alternative therapies should be assessed and pursued if transplant deferral is possible. Medical, laboratory, and psycho-social evaluations should be undertaken prior to transplant listing.

Medical evaluation should include a thorough multi-system review and spec ialty consultation (ie, neurology, nephrology, gastroenterology, hepatology, infectious disease, genetics/metabolics, psychiatry/psychology) should be obtained if concerns are present. A nutritional assessment should be made and nutrition should be optimized.

Laboratory evaluation is undertaken to assess for end-organ dysfunction and factors that may adversely affect post-transplant outcomes (ie, infection, immune status, metabolic disease).

Psycho-social evaluation is made by a qualified social worker and should confirm a stable means of ensuring quality post-transplant care. Family dynamics, finances, and prior compliance to therapies are all indicators of a family's ability to provide adequate post-transplant medical care. In rare instances, temporary or permanent removal from the biological family is required due to the inability to provide adequate care.

Laboratory studies

The blood type is determined so that the patient can be listed for an appropriate organ. Knowing the infant recipient’s blood type is important, but successful transplantation across ABO-incompatible blood types has been performed in infants and is becoming increasingly common, with acceptable outcomes.

Infection screening is carried out, including the following:

  • Complete blood count (CBC) with differential
  • Urine and blood cultures
  • Cytomegalovirus (CMV) titer or CMV polymerase chain reaction (PCR)
  • Hepatitis B surface antigen (HBsAg) test
  • HIV test
  • Rapid plasma reagin (RPR) test
  • Toxoplasma titer
  • Epstein-Barr virus (EBV) PCR
  • Endotracheal tube (ETT) aspirate (if applicable)

Kidney function and liver function are assessed by measuring electrolyte, blood urea nitrogen (BUN), and creatinine levels and obtaining a liver profile. Pretransplant sensitization is evaluated by measuring panel-reactive antibody (PRA) levels.

Imaging studies

Head ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI) or magnetic resonance spectroscopy (MRS), and electroencephalography (EEG) are performed as appropriate to assess neurologic status. Chest radiography and renal ultrasonography are also helpful. Echocardiography is performed to assess cardiac 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 (PVR). Pulmonary artery pressure may be estimated by means of echocardiography, but a more formal analysis usually requires cardiac catheterization.

Recipients with elevated 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 normalizes rapidly soon after transplantation. If pulmonary venous obstruction is present, pulmonary artery pressures may not normalize as quickly.

Elevated PVR that is reactive (ie, responsive to vasodilator therapy) can usually be managed with oxygen or intravenous vasodilator therapy in the pretransplant period. This can reduce the PVR, which simplifies posttransplant management. Elevated PVR that is fixed is an indicator of significant risk for acute graft failure.

Monitoring while listed for transplant

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.

Extracorporeal membrane oxygenation (ECMO) is the standard of care for children who require short-term mechanical circulatory support (MCS). Although ECMO is frequently life-saving, approximately one-half of all children supported with ECMO fail to survive to hospital discharge. The use of a new generation of short-term circulatory support devices, known as temporary circulatory support (TCS) devices, as a bridge to transplant has risen rapidly in recent years, led by the growth of magnetically levitated centrifugal flow pumps. Studies have reported that TCS offers a significant survival advantage compared with conventional ECMO. [19]

The issue of vaccination may arise in this setting. Generally, vaccinations (especially live virus vaccines) are not given during the pretransplant waiting period; stimulation of the immune system should be avoided, given that a donor may become available at any time. However, if the child is believed capable of safely waiting at least 6 weeks for the transplant, administration of live virus vaccines (if age appropriate) before the procedure is probably better because live virus vaccines are commonly avoided entirely after transplantation.

Monitoring and Follow-up

Close outpatient follow-up is essential to ensure long-term success. The highest risk of complications occurs in the first few months after transplantation, so the child should remain near the transplantation center for the initial follow-up. The following is an outline of the outpatient testing schedule at the author’s institution (Loma Linda University Children’s Hospital).

  • Physician visits take place twice weekly for 6 weeks, then less frequently as the rejection-free interval increases. The minimum visit frequency is monthly for the first year and every 3 months thereafter.
  • Echocardiography is performed twice weekly for 4 weeks, then less often as the rejection-free interval increases; after the initial period, it should be performed at the same time as the routine physician visits. In patients who have undergone arch reconstruction, full-study echocardiography is performed at 1 month, 3 months, and 12 months to evaluate the aortic arch.
  • Brain natriuretic peptide (BNP)  or N-terminal pro b–type natriuretic peptide (NT-proBNP) levels are measured with each echocardiogram.
  • Electrocardiography (ECG) is performed monthly until 1 year after transplantation, and then every 3 months thereafter.
  • Chest radiography is performed monthly for 3 months, at 12 months, and then annually.

Calcineurin inhibitor (cyclosporine or tacrolimus) trough levels are assessed on the following schedule:

  • Twice weekly for 2 weeks after discharge
  • Weekly for 4 weeks
  • Monthly for the first year
  • Every 3 months thereafter

Target cyclosporine levels (with a favorable rejection history) are 200-250 ng/mL for 4 months and are gradually reduced of the first post-transplant year to a goal of 50-75 ng/mL thereafter (depending on the secondary immunosuppression agent). Tacrolimus trough levels are maintained at 12-15 ng/mL for 4 months, then gradually reduced during the first post-transplant year to a goal of 4-5 ng/mL (depending of the secondary immunosuppression agent), if rejection history is favorable.

Mycophenolate mofetil (MMF) levels are checked concurrently with calcineurin inhibitor levels. Mycophenolic acid levels are maintained at 2-5 µg/mL (not to exceed 30 mg/kg/dose). Note that immunosuppression blood level targets are only starting points. Adjustments may be needed in the individual child because of rejection history and side effect profile.

Mammalian target of rapamycin (mTOR) inhibitors (sirolimus or everolimus) are rapidly gaining acceptance as secondary immunosuppressive agents, as a result of adult transplant studies showing improvement in cardiac allograft vasculopathy and renal dysfunction (due to lower calcineurin inhibitor requirements). Because of concerns about impaired wound healing, mTOR inhibitors are typically not initiated until at least several months after transplant. mTOR inhibitor leves are routinely checked with calcineurin inhibitor levels, with initial sirolimus targets of 8-10 ng/mL and everolimus targets of 5-8 ng/mL; those decrease to 4-5 ng/mL and 3-5 ng/mL, respectively, over the first post-transplant year. Infants frequently require reduced dosing intervals (ie, more doses per day).

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 of individually assessing the degree of immunosuppression and, thus, the risk of rejection and infection. [20]

A CBC 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 a complete metabolic profile (including magnesium levels) obtained every 3 months.

The 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.

Renal function is assessed via a BMP every 2 weeks for 2 months, then monthly for the first year, and every 3 months thereafter. Standard calculations to assess glomerular filtration rate (GFR) based on creatinine in individuals receiving calcineurin inhibition may not be accurate and alternative methods or calcuations should be used. [21]

Renal ultrasonography is performed as needed.

The endomyocardial biopsy follow-up schedule varies according to age at transplantation, as follows:

  • Up to 2 years of age – Annually
  • Age 2-8 years – At 1 month, 3 months, 12 months, and annually thereafter
  • Age 9 years and older – Before discharge, at 1 month, 2 months, 3 months, 6 months, 12 months, and annually thereafter

Some programs have reduced the frequency of biopsy in younger children to less than one per year (eg, every 2 or 5 years) after the first post-transplant year. Donor-specific antibody (DSA) monitoring is obtained with each biopsy.

Coronary angiography is performed annually, starting at the first anniversary of transplantation. Intravascular ultrasonography is performed at age 6 years and every other year thereafter unless previous intravascular ultrasonography demonstrated Stanford class 4 findings.

All routine vaccinations, except for live virus vaccines (eg, oral polio, varicella, and measles-mumps-rubella [MMR] vaccines), should be administered, starting as early as 6 weeks after transplantation.

Patient Preparation

Standard preoperative precautions are made prior to transplantation. Patients should be made NPO prior to the procedure and preoperative laboratories are obtained (ie, blood type/crossmatch, CBC, comprehensive metabolic profile, prothrombin time with international normalized ratio [INR], activated partial thromboplastin time [aPTT]).

Blood products should be ordered and made available in the operating room. Central arterial and venous catheters should be placed in the operating room and the patient is intubated for the procedure.

Some individuals with significant pre-transplant HLA sensitization will undergo desensitization therapy prior to transplantation, which may include anti-B cell antibodies, intravenous immunoglobulins, plasmapheresis, or plasma exchange in the operating room.

Isohemagglutinin titers are followed closely for infants and young children undergoing ABO-incompatible heart transplantation.


Pediatric Heart Transplantation Technique


Approach Considerations

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. Anatomic considerations in heart transplantation are diverse and should be reviewed according to the particular condition present in the recipient.

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, with each donor pulmonary vein divided 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. For individuals with branch pulmonary artery or aortic hypoplasia, the donor branch pulmonary arteries and aortic arch may be required.

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

Meticulous care of the child awaiting transplant is essential to ensure the best possible outcome. For patients with ductal-dependent physiology, the lowest dose possible of prostaglandin (0.1-0.2 µg/kg/min) should be used. The authors usually use a peripherally inserted central catheter (PICC) line, with a second heparin lock in place in case the primary intravenous (IV) site is suddenly lost.

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 a fractional inspired oxygen (FI O2) of less than 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 multiple centers to allow children with hypoplastic left heart syndrome (HLHS) to wait without prostaglandin E (PGE) infusion, even outside the hospital.

Among all children waiting for heart transplantation, the death rate before transplantation is approximately 15-20%. For infants with hypoplastic left heart syndrome (HLHS), mortality during the waiting period is significant when the wait is longer than about 3 months; these infants only occasionally survive until age 6 months. Among less critically ill children (United Network for Organ Sharing [UNOS] status II), pretransplant mortality by 12 months is about 10%.

Transplantation of Heart

In children with cardiomyopathy, the operative method of transplantation is the same as it is in adults (see Heart Transplantation). A median sternotomy is made, a thymectomy is performed, and the recipient’s native heart is exposed. 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.

See the image below.

View of the recipient's chest after the heart is rView of the recipient's chest after the heart is removed, with the patient on cardiopulmonary bypass.

A standard orthotopic technique using biatrial or bicaval connection is used. If necessary, modifications are made for anatomy specific to congenital heart disease, as follows.

In children 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 initial cooling in preparation for reconstruction. Implantation of the allograft is accomplished with systemic hypothermia; the atrial anastomoses are performed 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 the duct’s entrance into the distal arch is important for providing secure aortic tissue for the anastomosis and for minimizing the likelihood of a post-transplant 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 by means of direct anastomosis if sufficient lengths of donor arterial and venous connections are procured.

Systemic venous anomalies (ie, left-sided inferior or superior vena cava) require redirecting venous blood flow to opposite side of the body via a combination of donor and recipient tissues. These low-pressure anastomoses are at risk of stenosis after transplantation.

Following all anastomoses and rewarming, the donor heart will frequently fibrillate, and defibrillation is required to restore sinus rhythm.  The patient is kept on cardiopulmonary bypass until adequate re-perfusion has occurred. Weaning from bypass is typically made with the addition of inotropic support, such as milrinone and epinephrine. Atrioventricular or ventricular pacing is frequently employed in the early post-transplant period.  Inhaled nitric oxide is given to those with an increased risk of elevated pulmonary vascular resistance.

After control of bleeding is obtained, chest tubes are placed and the chest is closed in most instances.

Postoperative Management

In general, management of the child who has undergone heart transplantation is similar to postoperative management for any pediatric cardiac procedure. There are, however, certain considerations that are specific to heart transplantation, as summarized below.

Post-transplant cardiac support

Inotropic support with a combination of milrinone, epinephrine, and dopamine is generally employed in the early post-transplant period (24-48 hours), due to the low cardiac output state seen after prolonged cardiopulmonary bypass and to aid in recovery of the donor heart.  If hypertension is present, additional afterload reducers and vasodilators may be needed.

Diuretics are generally started in the first 12-24 hours after transplant and continued for several weeks to months after transplant.

Post-transplant hypertension is common after weaning of inotropic support and intravenous vasodilators, and may require medical therapy.  Dihydropyridine calcium channel blockers (eg, amlodipine, nifedipine, nicardipine) are commonly employed due to their lack of nephrotoxic and cardiac side effects. Angiotensin-converting enzyme (ACE) inhibitors may not be the best option early, given the need for high-dose calcineurin inhibition, which compounds the nephrotoxic effects of ACE inhibitors.

In patients receiving prostaglandn E before transplantation, it is advisable to continue prostaglandin therapy for at least 1-2 days, then gradually taper it over 2-3 days so as to prevent rebound 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 the following:

  • Sedation
  • Vasodilator therapy
  • Alkalization through hyperventilation
  • Inotropic agents with minimal or reductive pulmonary vasoconstrictive effects
  • Inhaled nitric oxide, when available
  • Sildenafil has also been used

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.

Post-transplant immunosuppression

Numerous immunosuppression protocols exist for the perioperative and postoperative period, but most follow similar general principles. Immunosuppression can be broken down into two phases: induction and maintenance.

The goal of induction immunotherapy is to allow for the delay in initiation of maintenance immunosuppressants, which may adversely affect other organs recovering from pre-transplant and peri-transplant damage (ie, renal and hepatic dysfunction).The following are used for induction immunosuppression:

  • Anti-thymocyte antibodies (ie, antithymocyte globulin [ATG])
  • Anti–interleukin-2 (IL-2) antibodies (eg, basiliximab)
  • Corticosteroids (eg, methylprednisolone, prednisone)
  • Other immune modulators (eg, intravenous immunoglobulin [IVIg], rituximab)

After end-organ function has recovered sufficiently, maintanance immunosuppression is commenced. The following classes of immunosuppressive agents and combinations of agents are used:

  • Calcineurin inhibitors (ie, cyclosporine, tacrolimus)
  • Cell cycle inhibitors (ie, mycophenolate mofetil, azothiaprine)
  • mTOR inhibitors (ie, sirolimus, everolimus)
  • Corticosteroids (eg, prednisone)

At Loma Linda University, we use high-dose corticosteroids in the early peri-transplant periods (20 mg/kg intraoperatively and 20 mg/kg IV x 4 doses post-transplant) with ATG (1.5 mg/kg for 3-7 days, targeting a CD3 count of < 25 cells/mm3), and IVIg (2 g/kg total dose).  Maintenance immunosuppression consists of cyclosporine (target trough 200-250 ng/mL) or tacrolimus (target trough 12-15 ng/mL) with mycophenolate mofetil (target trough 2-5 ng/mL), which is started 2-3 days after transplantation (depending on renal function, PO status, white blood cell counts, and infection status). No maintenance corticosteroids are given.

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 lack of standardized practice across institutions.

In addition, whereas early rejection and survival are important therapeutic endpoints 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.

Adjunct therapies with nystatin and ganciclovir or valganciclovir are initiated for 3-6 months for infectious prophylaxis. Some centers utilize trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis, as well. Aspirin and statins are given by some programs for coronary prophylaxis. Magnesium and bicarbonate supplementation are frequently needed early after transplant, when calcineurin levels are kept high.

Complications

The most significant causes of death after heart transplantation are as follows [22:

  • Early graft failure (either primary or secondary to pulmonary hypertension)
  • Allograft rejection
  • Infection
  • Allograft vasculopathy
  • Malignancy

Allograft rejection

Preventing rejection while avoiding severe infections, renal failure, and cancer is the biggest challenge facing the transplant physician. [23Although an extensive discussion of important immunosuppressive agents is beyond the scope of this article, a brief review of immunosuppression strategies in pediatric heart transplantation is worthwhile. Broadly speaking, such strategies are built around the following 2 considerations:

  • Induction versus no induction
  • Dual-drug regimens versus triple-drug regimens

Note that none of these strategies have been studied in sufficiently large-scale, randomized, controlled studies. Rather, they have been extrapolated from adult thoracic and pediatric noncardiac solid-organ trials and adapted through application to and experience with pediatric heart transplantation.

Induction versus no induction

The use of monoclonal or polyclonal antibody T-cell–depleting agents (ie, induction therapy) has been controversial for years. Early in the history of transplantation, induction therapy was commonly used, but it fell out of favor because of concerns about overimmunosuppression with resultant infections and posttransplant lymphoproliferative disease (PTLD). However, there is now renewed interest in the use of induction therapy as a means of reducing or eliminating steroid use. Several studies have demonstrated the efficacy of this approach. [2425]

According to the heart-lung transplantation registry of the International Society for Heart and Lung Transplantation (ISHLT), the majority of pediatric patients who received a heart transplant were treated with induction strategies. Of those, about two-thirds received polyclonal antibody T-cell–depleting agents, and one-third received interleukin-2 receptor antagonist. At Loma Linda, rabbit-derived polyclonal antibody has been used in a steroid-avoidance regimen.

Dual versus triple therapy

Essentially, all regimens start with the foundation of a calcineurin inhibitor—either cyclosporine or tacrolimus. To date, only 1 small-scale trial has compared cyclosporine with tacrolimus in pediatric heart transplantation; it found the 2 agents to have essentially equivalent efficacy. [26]

Nevertheless, the pediatric heart transplant community has gradually shifted toward greater use of tacrolimus. According to the ISHLT, 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 milligram-for-milligram basis and is successfully used for patients with recurrent rejection.

Increased incidence of PTLD and greater frequency of posttransplant diabetes are concerns. Newer strategies that incorporate lower target levels have helped greatly with both of those concerns. Renal dysfunction is an adverse effect of both medications in this class.

Oral administration yields incomplete and variable results, with absolute bioavailability ranging from 17-22% in adults. In children, tacrolimus bioavailability is about 31%, though whole-blood concentrations in a study of 31 children younger than 12 years indicate that children require higher doses than adults to achieve similar 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. [27]

Tacrolimus is not commercially available as a liquid preparation; the solution must be compounded in a local pharmacy, and this carries a potential for formulation errors. In addition, it is recommended that tacrolimus be administered on an empty stomach; this complicates its use in school-age children, who may have little time available before school. Many centers seem to achieve good results without strictly adhering to this suggestion; it is unknown whether these results are obtained by increasing the dose to overcome bioavailability issues.

At the author’s institution, cyclosporine was the preferred calcineurin inhibitor, but tacrolimus is being more widely used at this time. Target trough levels (whole blood, monoclonal assay) for cyclosporine are 200-250 ng/mL for the first 4 months, with reduction to 50-75 ng/mL by 1 year post-transplant, if the rejection history is acceptable. Transition to tacrolimus occurs at 1 year post-transplant or earlier. Tacrolimus levels are kept at 12-15 ng/mL during the first 4 months post-transplant and are gradually reduced to 4-5 ng/mL after 1 year post-transplant, depending on rejection status and the secondary immunosuppressive agent used.

In this institution, tacrolimus is used primarily for certain select high-risk candidates (eg, patients with multiple previous cardiac operations, patients with high panel-reactive antibody [PRA] levels, and African-American recipients), as well as for patients who have experienced recurrent rejection. A significant number of children experience problematic cosmetic side effects, especially those who require orthodontia, in whom gingival hyperplasia is counterproductive.

Antiproliferative agents/cell-cycle toxins

Among the antiproliferative agents, azathioprine (AZA) had been the therapeutic mainstay. According to the ISHLT, however, mycophenolate mofetil (MMF) is now used in approximately 60% of pediatric patients who receive a heart transplant. Again, no prospective studies are available.

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. Like AZA, MMF can induce bone marrow suppression. [2829The biggest challenge is the significant risk of gastrointestinal (GI) side effects, which affect patient tolerance of pharmacotherapy. A significant advantage of MMF is that the drug can be dosed to a therapeutic level.

At Loma Linda, MMF is given as part of the primary immunosuppression regimen. Dosing begins at 300 mg/m2/day or 40 mg/kg/day divided into 2 doses and is increased as tolerated to maintain a mycophenolic acid level of 2-5 µg/mL. Infants may require dosing every 8 hours.

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, early weaning to zero, or both.

Steroid avoidance is believed to require induction therapy. The newer immunosuppressive agents have given more confidence to transplant physicians who wish to wean to zero. Programs that use steroids typically start with oral prednisone at a dosage of 2 mg/kg/day and then wean over the first 3 months to a maintenance regimen of 0.1-0.3 mg/kg once daily or once every other day.

At Loma Linda, steroid avoidance has been practiced from program inception, with oral prednisone used only to treat children who experience allograft rejection or in whom no other combination is effective or tolerated. This approach has received some validation from the immunology literature, which has demonstrated that long-term glucocorticoid therapy leads to downregulation of cytoplasmic glucocorticoid receptor expression, as evidenced in T cells.

Sirolimus

The mammalian target of rapamycin (mTOR) inhibitor sirolimus is a newer agent that works synergistically with calcineurin inhibitors. A retrospective study by the Pediatric Heart Transplant Study Group of 2,531 patients undergoing primary heart transplantation from 2004 to 2013 with at least 1 year of follow-up found that 44 patients (7%) were on sirolimus at 1 year post transplant. Rates of survival and major transplant adverse events in patients receiving sirolimus were similar to those in patients not treated with sirolimus. [30]

At Loma Linda, sirolimus has been used in the following settings:

  • For recurrent rejection
  • In children with renal insufficiency (to decrease the 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
  • In children who have coronary intravascular evidence of moderate-to-severe cardiac allograft vasculopathy

Nonpharmacologic measures

The following 3 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 before transplantation in patients who are highly sensitized or after transplantation in patients who experience acute antibody-mediated rejection (AMR) or in whom AMR is anticipated

  • Photophoresis involves extraction of lymphocytes from patients who were pretreated with psoralen, exposure of the lymphocytes to ultraviolet A light, and reinfusion [31; it has been helpful in the prevention and treatment of recurrent rejection, though no reports on its use in children have been published

Treatment of acute cellular rejection:

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

At Loma Linda, acute rejection is treated with IV methylprednisolone at 20 mg/kg (not to exceed a dose of 500 mg) twice daily for 8 doses. Uncomplicated rejection diagnosed on the basis of biopsy findings alone may be treated with oral prednisone at 2 mg/kg/day 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. At Loma Linda, antithymocyte globulin 1.5 mg/kg/day is administered by slow IV infusion over 6 hours. This dosage is continued 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 IV immunoglobulin in the treatment of graft rejection may be beneficial.

Treatment of the rejection episode must be accompanied by evaluation of the causative mechanisms. If immunosuppressive doses have been faithfully given and 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.

Treatment of antibody-mediated rejection:

Appropriate treatment of antibody-mediated rejection (AMR) is less clear, as is its diagnosis. AMR appears to play a signficant factor in allograft vasculopathy and in graft loss. Newer monoclonal antibodies targeting B-cells and terminal complement fixation are now being employed to treat preformed donor specific antibodies and AMR. Rituximab is an antibody targeting CD-20, which is present on memory B-cells.  Bortezomib is an antibody targeting plasma B-cells, while eculizumib targets complement binding and fixation.

Diagnosis of rejection

Rejection is diagnosed on the basis of clinical signs and symptoms, echocardiographic changes, and endomyocardial biopsy findings.

Clinical clues to rejection include the following:

  • A decrease in the child’s activity or feeding
  • Low-grade fever
  • Persistent resting tachycardia
  • Ventricular ectopy
  • 3 gallop
  • Tachypnea or dyspnea
  • Hepatic congestion
  • Ileus
  • 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, [32new pericardial effusion, and new mitral insufficiency. Some have advocated tissue Doppler imaging to improve the sensitivity of echocardiographic diagnosis of rejection. [33]

Electrocardiographic (ECG) analysis may be of some use, with significant lowering of voltage indicating a risk for rejection. Signal-averaged ECG may reveal an abnormal strain pattern with rejection. [34]

Cardiac functional biomarkers have been advocated for the diagnosis of rejection. B-type natriuretic peptides have been used, although the levels of these substances vary widely and demonstrate an overlap between normal and rejection. They may be most useful in the emergency department setting, where a normal value can provide reassurance that rejection is unlikely.

Gene expression profiling is also under investigation, but its applicability to pediatrics is controversial. Endomyocardial biopsies are the criterion standard and are graded according to the criteria of the ISHLT, with treatment generally initiated only when biopsy samples demonstrate a 2R (ie, 2 or more foci lymphocytic infiltration with associated myocyte damage) or greater histology. [35]

AMR is becoming increasingly recognized. Preformed antibodies have long been known to create the potential for hyperacute rejection in the early posttransplant period. [36Retrospective crossmatching should be performed, and consideration should be given to plasmapheresis in the setting of a positive crossmatch finding and graft dysfunction. Anti-CD20 monoclonal antibody has also been used in this setting, to reduce production of antidonor antibodies.

De novo development of anti–human leukocyte antigen (HLA) antibodies, particularly to class II, has been associated with an increased incidence of allograft vasculopathy. Many centers now test for the presence of C4d on endomyocardial biopsy specimens, especially in the face of graft dysfunction, as a marker of antibody-mediated rejection.

Infection

Infection is an expected complication: a significant number of recipients experience 1 or more potentially serious infections in the first few months after transplantation. These early postoperative infections are usually bacterial and include wound infections, pneumonia, bacteremia, and urinary tract infections. CMV infection is a significant complication. Pneumocystis jirovecii infections occur but are less frequent. Other opportunistic infections should be anticipated and aggressively treated when present.

A review of data from a multi-institutional registry of 1854 pediatric heart transplant recipients by Zaoutis et al noted 139 invasive fungal infections in 123 patients. The most common pathogens were yeasts (66.2%), molds (15.8%), and P jirovecii (13%). Candida species accounted for 90% of the yeast infections, and Aspergillus species accounted for 82% of the mold infections. Of patients with invasive fungal infections, 49% died within 6 months after transplantation, with risk and mortality being highest in those who required mechanical support and those with a history of previous surgery. [37]

Guidelines from the ISHLT recommend considering IV antifungal prophylaxis for infants (< 1 year of age) with an open chest and/or requiring extracorporeal membrane oxygenation (ECMO) support in the perioperative period (class IIb). The ISHLT recommends instituting prophylaxis for P jirovecii for a minimum of 3 months and up to a maximum of 24 months postoperatively. [38]

Malignancy

Malignancy, usually post-transplant lymphoproliferative disease (PTLD) associated with Epstein-Barr virus (EBV) infection, occurs in 2-10% of children. [3940When the histology is low grade (polymorphous hyperplasia), PTLD usually responds to short-term cessation of immunosuppression. Higher-grade PTLD (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 (see Posttransplant Lymphoproliferative Disease).

Clinical protocols for prevention of PTLD are currently being explored. These include serial monitoring of EBV polymerase chain reaction (PCR) and intervening with ganciclovir or valganciclovir with or without serial infusions of IV immunoglobulin in an attempt to decrease the viral load while the patient’s immune system develops an adequate response to the infection. Rituximab has also been studied for PTLD prevention. [41]

In the face of acute EBV infection, the immunosuppression should be minimized as much as possible. However, rejection and graft vasculopathy have been suggested as important risks of excessively reducing immunosuppressive medications, especially in patients who have undergone heart transplantation.

Once the patient is 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, significant allograft vasculopathy has developed in as many as 20% of recipients.

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 changes in cardiac function and is confirmed by coronary angiography is probably best treated with retransplantation.

Other modalities that have been useful in the diagnosis of allograft vasculopathy include treadmill testing and dobutamine stress echocardiography. Adult heart transplantation data suggest that calcium channel blockers and statins may help prevent allograft vasculopathy. Some pediatric data suggest that the same effect is seen in children. Although some transplantation centers use these agents in all children, others use them only in high-risk patients.

Intravascular ultrasonography 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 detected with this modality have been shown to predict later development of significant cardiac events. Few reports have described the use of intravascular ultrasonography 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; in 1 report, the disease was reversed. [42The use of mTOR inhibitors in children is currently being explored.

Nephrotoxicity

Nephrotoxicity is the most import nonlethal complication of pediatric heart transplantation. 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 or everolimus to lower the calcineurin inhibitor dose. [43A combination of sirolimus and MMF has also been used as a non–calcineurin inhibitor immunosuppressive regimen.

Pulmonary complications

Chronic respiratory complications are being recognized with increased frequency. In 1 report, they occurred in 50% of patients. Bronchiectasis was reported in 17% of patients; obstructive sleep apnea was diagnosed in 7%. Sirolimus-associated pneumonitis has been described.

Metabolic abnormalities

Hyperlipidemia is found in a higher proportion of pediatric heart transplant recipients. It appears to be more common in patients receiving cyclosporine than in those receiving tacrolimus. It is also more common in children who are on long-term steroid therapy and those who are being treated with sirolimus. Posttransplant diabetes has also been described; it occurs more frequently in children treated with tacrolimus, steroids, or both.


Pediatric Heart Transplantation Medication


Medication Summary

The goals of pharmacotherapy are to prevent complications, to reduce morbidity, and to reduce the chances for organ rejection. Optimal therapy includes sedation, vasodilator therapy, alkalization through hyperventilation, inotropic agents with minimal pulmonary vasoconstrictive effects, and inhaled nitric oxide, when available. Sildenafil has also been used in this setting.

Vasodilators

Class Summary

These agents relax blood vessels and cause a decrease peripheral vascular resistance.

Sodium nitroprusside (Nitropress)

Sodium nitroprusside produces vasodilation and increases inotropic activity of the heart.

Nitroglycerin (Nitro-Bid, Nitro-Dur, Minitran)

Nitroglycerin causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate (cGMP) production, resulting in a decrease in blood pressure.

Amlodipine (Norvasc)

For post-transplant hypertension

Hydralazine

For post-transplant hypertension

Inotropic Agents

Class Summary

After the procedure, the patient is maintained on a combination of pressor agents while the donor heart regains energy stores. Once stabilized, the patient is rapidly weaned from the ventilator and the pressors. The chosen combination depends on the training and experience of the transplantation center.

Dopamine

Dopamine is a naturally occurring endogenous catecholamine that stimulates beta1-and alpha1-adrenergic and dopaminergic receptors in a dose-dependent fashion. It stimulates release of norepinephrine.

In low doses (2-5 μg/kg/min), dopamine acts on dopaminergic receptors in renal and splanchnic vascular beds, causing vasodilatation in these beds. In midrange doses (5-15 μg/kg/min), it acts on beta-adrenergic receptors to increase heart rate and contractility. In high doses (15-20 μg/kg/min), it acts on alpha-adrenergic receptors to increase systemic vascular resistance and raise blood pressure.

Dobutamine

Dobutamine is a sympathomimetic amine with stronger beta than alpha effects. It increases the inotropic state. Vasopressors augment the coronary and cerebral blood flow during the low-flow state associated with severe hypotension.

Dopamine and dobutamine are the drugs of choice to improve cardiac contractility, with dopamine the preferred agent in hypotensive patients. Higher dosages may cause an increase in heart rate, exacerbating myocardial ischemia.

Epinephrine (Adrenalin)

Its alpha-agonist effects include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Its beta2-agonist effects include bronchodilation, chronotropic cardiac activity, and positive inotropic effects.

Norepinephrine (Levophed)

Norepinephrine stimulates beta1- and alpha-adrenergic receptors, increasing cardiac muscle contractility and heart rate, as well as vasoconstriction; this results in systemic blood pressure and coronary blood flow increases. After obtaining a response, the rate of flow should be adjusted and maintained at a low-normal blood pressure, such as 80-100 mm Hg systolic, sufficient to perfuse vital organs.

Milrinone

Phosphodiesterase III Inhibitor, which lead to improved cardiac contractility and relaxation, along with reduction of systemic and pulmonary vascular resistances. It is used to treat post-operative low-cardiac output and ventricular dysfunction.

Pulmonary Vasodilators

Class Summary

Inhaled nitric oxide (NO) is a pulmonary vasodilator indicated for pulmonary hypertension. NO is also being studied for severe hypoxemia in acute respiratory distress syndrome (ARDS).

Nitric oxide, inhaled (INOmax)

NO is produced endogenously from the action of the enzyme NO synthetase on arginine. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine monophosphate (cGMP), which then leads to vasodilation. When inhaled, NO decreases pulmonary vascular resistance and improves lung blood flow.

Sildenafil (Revatio)

Sildenafil promotes selective smooth muscle relaxation in lung vasculature, possibly by inhibiting PDE5. This results in a subsequent reduction of blood pressure in pulmonary arteries and an increase in cardiac output.

Immunosuppressants

Class Summary

A number of protocols exist for immunosuppression in the perioperative and postoperative period. 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 transplantations performed each year and the need for centers to standardize practice across institutions. Below are the immunosuppressants used at Loma Linda University Children’s Hospital.

Cyclosporine (Neoral, Sandimmune, GENGRAF)

Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for various organs.

For children and adults, base dosing on ideal body weight. Maintaining appropriate levels of the drug in the bloodstream is crucial to the maintenance of the allograft. Foods can alter the level of the drug and time of administration. Medication must be taken at the same time every day.

Neoral is the capsular form of cyclosporine, available in 25- and 100-mg capsules. Sandimmune is the liquid form. GENGRAF is the branded generic form, available in 25- and 100-mg capsules.

Cyclosporine is begun at 0.1 mg/kg/h IV when the donor is identified, stopped during the procedure, and restarted after transplantation; this is switched to oral dosing when possible, with a target trough cyclosporine level of 200-250 ng/mL

Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol)

Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

At Loma Linda, acute rejection is treated with IV methylprednisolone at 20 mg/kg (not to exceed a dose of 500 mg) twice daily for 8 doses. Uncomplicated rejection diagnosed on the basis of biopsy findings alone may be treated with oral prednisone at 2 mg/kg/day for 3 days, with a taper to zero over 3 weeks.

Mycophenolate mofetil (CellCept, Myfortic)

Mycophenolate mofetil, a derivative of mycophenolic acid (MPA), blocks the de novo pathway of guanosine nucleotide synthesis by inhibiting the activity of inosine monophosphate dehydrogenase and thus inhibiting de novo purine synthesis. Both T and B lymphocytes are highly dependent on the de novo pathway, whereas other cells use the purine salvage pathway of nucleotide synthesis. As a result, MPA selectively inhibits lymphocyte activity. At Loma Linda, mycophenolate mofetil is given as part of the primary immunosuppression regimen. Dosing begins at 300 mg/m2/day or 40 mg/kg/day divided into 2 doses and is increased as tolerated to maintain a mycophenolic acid level of 2-5 µg/mL

Mycophenolate mofetil is administered IV or orally at 500 mg/m2 or 20 mg/kg twice daily; dosing is adjusted as necessary to maintain a mycophenolate mofetil level of 2-5 µg/mL and a white blood cell (WBC) count of at least 4 × 109/L

Prednisone

Prednisone is an immunosuppressant used for treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is an oral steroid with approximately 5 times the potency of endogenous steroids. Minimal to no oral prednisone should be given for the first 21 days after transplantation unless rejection occurs.

Programs that use steroids typically start with oral prednisone at a dosage of 2 mg/kg/day and then wean over the first 3 months to a maintenance regimen of 0.1-0.3 mg/kg once daily or once every other day.

Tacrolimus (Prograf)

Tacrolimus suppresses humoral immunity (T-cell activity). It is a calcineurin inhibitor with 2-3 times the potency of cyclosporine. Tacrolimus can be used at lower doses than cyclosporine, but it has severe adverse effects, including renal dysfunction, diabetes, and pancreatitis. Levels are adjusted according to renal function, hepatic function, and adverse effects.

In children, tacrolimus bioavailability is about 31%, though whole-blood concentrations in a study of 31 children younger than 12 years indicate that children require higher doses than adults to achieve similar trough concentrations. A high-fat meal reduces the mean area under the curve (AUC) by 37%, whereas a high-carbohydrate meal decreases the mean AUC by 28%. Peak concentrations are also reduced by 77% and 65%, respectively.

Tacrolimus is not commercially available as a liquid preparation; the solution must be compounded in a local pharmacy.

Azathioprine (Imuran, Azasan)

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells, which results in lower autoimmune activity. Antimetabolites are used to block the uptake of vital nutrients needed by the cells. As implied, these drugs affect not only the cells of the immune system but also other cells of the body. The potency of therapy is dose dependent. Azathioprine is not effective treatment for acute rejection episodes but remains an economical choice for long-term immunosuppression.

Among the antiproliferative agents, azathioprine has been the therapeutic mainstay. According to the ISHLT, however, mycophenolate mofetil is now used in approximately 60% of pediatric patients who receive a heart transplant. Again, no prospective studies are available.

Sirolimus (Rapamune)

Sirolimus, also known as rapamycin, is a macrocyclic lactone produced by Streptomyces hygroscopicus. It is a potent immunosuppressant that inhibits T-cell activation and proliferation by a mechanism that is distinct from that of all other immunosuppressants. This inhibition suppresses cytokine-driven T-cell proliferation by inhibiting progression from the G1 phase to the S phase in the cell cycle.

Sirolimus is a newer agent that works synergistically with calcineurin inhibitors. There is little published experience with this agent in pediatric heart transplantation, but what is available seems to indicate some usefulness in the management of rejection, renal dysfunction, and calcineurin adverse effects.

Everolimus (Afinitor, Afinitor Disperz, Zortress)

Everolimus is an mTOR inhibitor, which inhibits the mammalian target of Rapa.  Transition to an mTORi has been shown to reduce allograft vasculopathy and renal dysfunction, but has not yet been studied in children.

An initial dose of 0.25 - 1.5 mg is given twice daily and titrate to target a trough level of 5-8 ng/mL in the first year post-transplant and 3-5 ng/mL after the first post-transplant year.

Lymphocyte immune globulin, equine (Atgam)

This agent inhibits the cell-mediated immune response by altering T-cell function or by eliminating antigen-reactive cells.

There is little prospective, randomized data to suggest a single schedule that is superior, but experience suggests that a short infusion is best tolerated.

At Loma Linda, antithymocyte globulin 1.5 mg/kg/day is administered by slow IV administration over 6 hours. This dosage is continued 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 IV immunoglobulin in the treatment of graft rejection may be beneficial.

Immune Globulins

Class Summary

Intravenous immunoglobulin (IVIG) is the usual choice. It is derived from human plasma and is composed of all 4 immunoglobulin G (IgG) subclasses.

Intravenous immunoglobulin (IVIG; Carimune Gammagard S/D, Gamunex-C, Octagam)

IVIG uses anti-idiotypic antibodies to neutralize circulating myelin antibodies. IVIG down-regulates proinflammatory cytokines, including interferon-gamma. It blocks Fc receptors on macrophages, suppresses inducer T cells and B cells, and augments suppressor T cells. In addition, IVIG blocks the complement cascade, promotes remyelination, and may increase cerebrospinal fluid (CSF) IgG (10%).

Antifungals, Topical

Nystatin topical (Mycostatin topical, Pediaderm AF, PediDri)

To prevent post-transplant candidiasis.

Antivirals, CMV

Valganciclovir (Valcyte)

For prevention and treatment of post-transplant CMV and EBV infection.

Antibiotic

Trimethoprim/sulfamethoxazole (Bactrim, Bactrim DS, Cotrim)

Antiplatelet Agents, Cardiovascular

Aspirin (Acetylsalicylic acid, Adprin-B, Alka-Seltzer Extra Strength with Aspirin)

Lipid-Lowering Agents, Statins

Pravastatin (Pravachol)

Atorvastatin (Lipitor)

Alkalinizing Agents

Sodium citrate/citric acid (Bicitra, Albrights Solution, Cytra 2)

Sodium bicarbonate

Electrolytes

Magnesium oxide (Mag-Caps, Mag-Ox 400, Uro-Mag)

Magnesium hydroxide (Milk of Magnesia)


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