Pediatric cardiac transplantation

Pediatric Cardiac Transplantation Cynthia S. Herrington, MD, and Anna E. Tsirka, MD Pediatric cardiac transplant patients present many challenges to the medical community. These include such things as complex evaluations, preoperative heart failure support, complex operative interventions, and postoperative challenges in management. In spite of these challenges, survival outcomes for children undergoing a heart transplant have improved dramatically over the last two decades. Semin Thorac Cardiovasc Surg 16:404-409 © 2004 Elsevier Inc. All rights reserved. KEYWORDS pediatric cardiac transplant, secondary pulmonary hypertension, cardiomyopathy, UNOS listing criteria, pediatric heart failure, pediatric mechanical support, post-transplant lymphoproliferative disease

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he field of cardiac transplantation has evolved rapidly since its clinical emergence in the late 1960s. Pediatric cardiac transplantation had a much slower start, but rose to acceptance by the late 1980s. Heart transplants are now widely available for both children and adults with end-stage heart disease. Still, the expansion into the pediatric realm has exposed physicians to new challenges not frequently encountered in adults patients. Many unique issues face pediatric heart transplant surgeons and cardiologists. Pediatric heart transplants differ from adult heart transplants in many respects, including the multiple anatomic cardiac configurations seen in congenital heart disease, the small size of the organs, the limitations on the use of pediatric assist devices, the peculiarities of the immature immune system, and the intense involvement of parents in the decision making process. Internationally, from 1992 through 2001, a total of 3,529 infants and children underwent heart transplants. During this same time period, fewer than 250 pediatric patients underwent heart-lung transplants.1 During the last 10 years, about 260 to 280 pediatric heart transplants were performed annually in the United States, with only about 5 to 10 heartlung transplants performed in the pediatric population during the same period.

Indications for a Transplant A heart transplant is considered a palliative procedure, so it is offered only when no other medical or surgical options re-

University of Minnesota, Minneapolis, MN 55455. Address reprint requests to Cynthia S. Herrington MD, MMC 495, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail: [email protected]

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1043-0679/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.semtcvs.2004.09.008

main for the child. Our selection criteria for pediatric heart transplant recipients include the following: complex congenital heart disease not amenable to surgical intervention with a chance for acceptable outcome or survival; end-stage cardiomyopathy despite maximal medical therapy; a conceptual age greater than 36 weeks and a current weight greater than 2 kg; failure to thrive or growth retardation due to heart failure; malignant arrhythmias unresponsive to therapy or defibrillator placement; documentation of progressive rise in pulmonary vascular resistance that would prevent a later successful heart transplant; and unacceptably poor quality of life due to heart failure. The indications for a pediatric heart transplant include congenital cardiac anomalies, cardiomyopathies, and retransplant, but these indications vary significantly by age group. For example, the primary indication for children under 1 year of age who undergo a transplant is congenital anomalies (75%), whereas for children 11 to 17 years of age, the primary indication is cardiomyopathy (63%).1 Transplants for congenital heart disease are typically reserved for children with previous palliative procedures who are having progressive heart failure, children with univentricular hearts who are not candidates for systemic venousto-pulmonary artery anastomoses, and for children whose anatomy makes surgical palliation excessively risky. As more patients with repaired congenital heart disease survive long-term, ventricular dysfunction is seen with increasing frequency: the late survival rate after repair of transposition of the great vessels approaches 83% at 10 years,2 while 70% of patients with tricuspid atresia survive 10 years after the Fontan operation.3 Such patients may have had multiple operative procedures, may be very debilitated, and may suffer from protein-losing enteropathy, lung disease, or renal

Pediatric cardiac transplantation disease. Typically, they have also been exposed to multiple transfusions that could lead to a high level of preformed antibodies. Accurately calculating pulmonary vascular resistance may be challenging, especially in the setting of systemic-to-pulmonary artery shunts.

Congenital Heart Disease Several transplant centers consider pulmonary venous anomalies to preclude heart transplants, but we (along with other centers) advocate that every anatomic configuration is amenable to a successful transplant in the pediatric population. Once the recipient’s heart is removed, pulmonary arteries can be opened quite easily to alleviate stenoses and distortion, and baffles can be placed to move pulmonary veins to the midline or to divert venae cavae to their appropriate location. Doing so adds some additional time to the procedure, but it is not prohibitive, as long as donor organ retrieval includes generous portions of the aorta, pulmonary arteries, and venous connections. A great deal of dispute persists regarding children who are born with hypoplastic left heart syndrome. The great majority of pediatric cardiac surgery centers will offer the Norwood procedure and further staged procedures for palliation, reserving a heart transplant for those situations where the patient’s heart function is impaired, and he/she is no longer an acceptable candidate for palliation. Significantly fewer centers support an early heart transplant before palliative procedures of any nature. As Morrow and coworkers pointed out, “Based on current donor availability, if all neonates with hypoplastic left heart syndrome were listed for transplant, less than 10% of all neonates listed would receive a heart.”4 As the debate rages on, it is the practice of our transplant center to offer a transplant only to those infants with aortic atresia or hypoplastic left heart syndrome whose anatomy or hemodynamics would preclude standard palliation.

Cardiomyopathies Cardiomyopathies in children remain poorly understood. Unlike adults, dilated cardiomyopathy in children is still considered mostly “idiopathic” (60% to 70% of these patients),5,6 although gene defects, metabolic disorders, and specific malformation syndromes are identified with increasing frequency. A significant number of these children are diagnosed in infancy.7,8 The outcomes of dilated cardiomyopathy in children vary. Up to a third of them will gradually improve, with the cardiomyopathy eventually resolving, and about one half of them will die within 5 years of diagnosis.7,9,10 Unfortunately, to date, a consistent, reliable marker for a poor prognosis has not been apparent, thus leaving the decision to list a given child for transplant to the discretion of the transplant team. Hypertrophic cardiomyopathy is occasionally considered an indication for a transplant, especially if accompanied by poor systolic function. Restrictive cardiomyopathy in children carries a very poor prognosis;11 it is often associated with elevations in pulmonary vascular resistance that could preclude a heart transplant alone. Therefore, such children

405 should be listed for a transplant as soon as possible, once the diagnosis is secure.

Retransplants The half-life of a graft in the pediatric age group is about 12 years,1 so an increasing number of adolescents have graft failure secondary to either coronary artery vasculopathy or to chronic rejection. The only currently proven therapy for late graft failure is a retransplant. This patient population is a particularly high-risk group, because they are an immunologic challenge for the transplant team.1,12

Evaluation of Candidates Once a child is referred to the transplant team, a thorough, multispecialty evaluation must be done to rule out any condition (physical or psychosocial) that would preclude transplantation. In addition, any anatomic or physiologic peculiarities must be delineated to identify special arrangements needed during the transplant (Table 1). Candidates must undergo neurologic evaluation that shows no major central nervous system (CNS) abnormalities or severe preexisting CNS injuries. They must be free of chromosomal abnormalities or syndromes that would seriously limit survival or perception of benefit from transplant. The candidate and family must undergo a rigorous psychosocial evaluation. The candidate’s family must be able to provide long-term supportive care and handle medical needs during the follow-up period. We make sure that there is no parental cognitive or psychiatric impairment severe enough to limit comprehension of the medical regimen, no evidence of parental or custodial child abuse or neglect, and no evidence of parental or custodial alcohol or substance abuse. The cardiovascular evaluation of the candidate must include a careful evaluation of the pulmonary vascular resistance and delineation of the pulmonary blood flow. Pulmonary hypertension frequently accompanies long-term impaired cardiac function, elevated left atrial pressures, and remodeling of the pulmonary vasculature (such as in cardiomyopathies with elevated wedge pressures) in restrictive cardiomyopathies or in congenital heart disease with left-toright shunts. Previous operations often cause distortion of the pulmonary arteries, resulting in uneven distribution of blood flow to the lung segments. Accessory sources of pulmonary blood flow are often seen in cyanotic patients (aortopulmonary collaterals). As a rule, echocardiography and cardiac catheterization, and possibly V/Q scan and chest CT or MRI, are performed to clarify the above issues. During cardiac catheterization, the pulmonary vascular resistance indexed to the body surface (PVRI) area is calculated. In cases of elevated PVRI, a number of vasodilators can be used acutely during the procedure to evaluate the pulmonary vasoreactivity. These vasodilators include oxygen, nitric oxide, milrinone, flolan, and recently, sildenafil. If the pulmonary vascular bed is nonreactive, the only option for the child is to be listed for a heart-lung transplant. According to the organ procurement and transplant network

C.S. Herrington and A.E. Tsirka

406 Table I Evaluation protocol

Consults

Laboratory Studies

Other studies

Pediatric transplant cardiology Pediatric transplant cardiovascular surgery Pediatric social worker Pediatric pulmonary medicine Pediatric neurology Pediatric neuropsychology for primary care provider Pediatric dietary Ob/Gyn consult for females > 16 years of age or sexually active Evaluation for STDs and birth control counseling Pediatric Transplant Coordinator for evaluation and teaching 1. Hematology CBC, platelet count, coagulation battery, fibrinogen, Factor V, Antithrombin III, protein C, protein S, Leiden Factor. 2. Chemistry Electrolytes, BUN, Creatinine, Glucose, Mg, PO4, FBS, serum electrophoresis HDL, LDL, cholesterol, triglycerides, liver function tests, creatinine clearance. 3. Virology Titers – CMV, EBV, (IgG, IgM, EBNA), EBV PCR Quantitative, VZ, HSV, Hepatitis Profile (all A, B, C), HIV – 1 & 2. 4. Immunology a. ABO type and screen b. HLA, A, B, C, and Dr typing, PRA and Anti-leukocyte Antibody Screening. c. Quantitative immunoglobulins 1. Chest x-ray – PA and lateral 2. Stool guaiacs ⴛ 3 3. 12 lead EKG 4. Cardiac cath; must include pulmonary artery pressures and resistance 5. Endomyocardial biopsy if necessary 6. ECHO 7. X-rays of thoracic and lumbar spine, hips 8. Bone age for children 9. Pulmonary function tests 10. Neuropsychology evaluation 11. Cardiopulmonary exercise test 12. 6-Minute walk tolerance test 13. Renal ultrasound 14. Initial growth chart PPD (5TU), mumps, and candida (adult doses of greater than 6 y/o), skin tests for patients with no prior history of positive PPD or verified TB. Pneumovax – Draw pneumococcal IgG antibodies prior to vaccine and 4-6 weeks after vaccine.

database, a total of 6 heart-lung transplants were performed in children in 2003, and a total of 6 heart-lung transplants were also performed in children in 2002. As of June 4, 2004, we have 26 children waiting on the United Network for Organ Sharing (UNOS) list for a heart-lung transplant. For these reasons, physicians are now creating management protocols to treat patients who may have otherwise been listed for a heart-lung transplant. It can be very difficult to distinguish whether the elevated pulmonary vascular resistance is fixed or just a representation of poor left ventricular function. At our center, patients with nonreactivity in the acute setting are first placed on inotropic agents to support the failing left ventricle. Subsequently, pulmonary vasodilators are added in an effort to improve pulmonary vascular resistance and transpulmonary gradient. If we are able to obtain a transpulmonary gradient less than 15 mm Hg and a pulmonary vascular resistance less than 6 Woods units per m2, the patient is listed for a heart transplant

alone. The patient is continued on intravenous (IV) inotropes and prostacyclin infusion until the time of the transplant. The pulmonary vasodilators are continued through the postoperative period. They are slowly weaned over months, per serial hemodynamic evaluations. At our center, we treated 2 patients with this protocol, and both had optimal posttransplant results. One patient required upwards of 13 months of a slow wean of pulmonary vasodilator therapy, but overall is doing well. This protocol has been well documented by the pediatric cardiac transplant program in St. Louis.13

Listing Guidelines UNOS allocates pediatric thoracic organs according to severity of disease, ABO blood typing, and size. Per the UNOS policies, “each patient awaiting heart transplantation is assigned a status code which corresponds to how medically urgent it is that the patient receive a transplant.”14 These

Pediatric cardiac transplantation pediatric status codes do vary from the adult cardiac definitions. Status 1A is for a patient who: (a) requires assistance with a ventilator; (b) requires assistance with a mechanical assist device (eg, ECMO); (c) requires assistance with a balloon pump; (d) is less than 6 months old with congenital or acquired heart disease exhibiting reactive pulmonary hypertension at greater than 50% of systemic level. Such a patient may be treated with prostaglandin E (PGE) to maintain patency of the ductus arteriosus; (e) requires infusion of high-dose (e.g., dobutamine ⬎ 7.5 ␮g/kg/min or milrinone ⬎ 0.50 ␮g/kg/min) or multiple inotropes (e.g., addition of dopamine at ⬎ 5 ␮g/kg/min); or (f) does not meet the criteria specified in (a), (b), (c), (d), or (e), but has a life expectancy (without a heart transplant) of fewer than 14 days, because of, for example, refractory arrhythmia. Status 1B is for a patient who: (a) requires infusion of low dose single inotropes (e.g., dobutamine or dopamine ⬍ 7.5 ␮g/kg/min); (b) is less than 6 months old and does not meet the criteria for Status 1A; or (c) suffers from growth failure; i.e., is at the ⫹5th percentile for weight and/or height, or has loss of 1.5 standard deviations of expected growth (height or weight) based on the National Center for Health Statistics for pediatric growth curves. Patients who do not meet the criteria for listing as status 1A or 1B are listed as status 2. A recent UNOS policy change stipulates that a heart retrieved from an adolescent organ donor shall be allocated to a pediatric heart candidate (i.e., less than 18 years old at the time of listing) before the heart is allocated to an adult candidate. Although ABO-incompatible heart transplants have been performed in infants,15 our center’s policy is to only transplant hearts matched or compatible by ABO blood typing. Size matching is important in pediatric populations, and our policy is that we accept donors that weigh 80% to 160% of the recipient’s weight.

Preoperative Heart Failure Support It is not unusual for a child listed as a status 1A heart transplant candidate to wait up to 2 to 3 months or longer before an organ becomes available. In dire situations, the size of the child plays a significant role in our ability to provide preoperative support. The ideal mechanical bridge fulfills three objectives: (1) it can be partially or fully implanted, allowing for circulatory support in patients with irreversible cardiac failure; (2) it improves the patient’s hemodynamic status and reverses end-organ dysfunction; and (3) it allows for physical

407 rehabilitation to improve the patient’s overall condition and likelihood for successful transplant. Implantable devices have been used in children down to a body surface area of 0.7 m2. For young children smaller than that size, the most common mechanical support is ECMO, which is very successful at salvaging patients from acute cardiac decompensation. Many centers have successfully performed transplant for children off ECMO support with survival rates anywhere from 40% to 50%.8,9,10,16 Many centers have modified the ECMO circuit to remove the oxygenator, making the circuit more compatible for long-term support. While they are able to keep the child alive, the child still requires significant sedation and intubation, and ECMO use does not improve the patient’s overall condition. With the recent FDA Humanitarian Device Exception (HDE) approval for the Micromed DeBakey Ventricular Assist Device (VAD), pediatric cardiac transplant programs have a potential means of support for pediatric patients between age 5 and 16 years. Cleared as a humanitarian use device, this VAD use does require individual hospital Institutional Review Board (IRB) approval. It has been approved for pediatric patients aged 5 to 16 years with body surface area of 0.7 to 1.5 m2. Use of an implantable device will allow the child to be extubated, to undergo rehabilitation, and to be successfully supported for longer periods of time than previously possible.

Outcomes The Registry of the International Society for Heart and Lung Transplantation Sixth Official Pediatric Report showed a clear increase in patient survival based on era.1 For patients who underwent a transplant from 1982 through 1987, the expected half-life was 6.6 years. For patients transplanted from 1988 through 1992, the half-life increased to 11.7 years. In the most recent years, the survival rate has continued in such a fashion that the half-life is not yet calculable. As seen in (Fig. 1, the improved survival appears to occur within the first 1 to 2 months posttransplant. Thereafter, the curves are roughly parallel. Patients who underwent transplant in the most recent eras can look forward to improved outcomes. High mortality on the transplant waiting list, coupled with a dire need for hearts to be located quickly for infants less than 1 year of age, led some premier transplant centers to use ABO-incompatible donors for desperately ill infants. With the use of induction immunosuppression, plasma exchange during the transplant, and close monitoring, West and coworkers have reported success with their protocol for infants, with an 80% survival rate at one year.15,17 They published a study concerning 10 infants, all less than 14 months old (median age 2 months), who received incompatible hearts from 1996 through 2000 (follow-up ranged from 11 months to 4.6 years). They had 2 early deaths, with neither child showing evidence of rejection at autopsy. If this patient population has an acceptable long-term outcome, the door may be opened for centers to significantly reduce the waiting time for an available organ. Follow-up testing for pediatric heart transplant recipients

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Figure 1 Actuarial survival by era for pediatric heart transplants performed between January 1982 and June 2001. Reprinted with permission from Boucek MM, Edwards LB, Keck BM, et al: The Registry of the International Society for Heart and Lung Transplantation: Sixth Official Pediatric Report—2003. J Heart Lung Transplant 22(6):636-652, 2003. © 2003 International Society for Heart and Lung Transplantation.

includes the gold standard of cardiac catheterization and biopsy. Most centers have incorporated some method of noninvasive monitoring to minimize routine use of biopsies. Immunosuppressive regimens still consist of the use of a calcineurin inhibitor combined with a cell cycle inhibitor and steroids. No evidence exists that heart transplant recipients can be successfully withdrawn from all immunosuppression. At our center, we have been able to successfully wean our recipients to a two-drug regimen, eliminating steroid support after the first year. Rapamycin has successfully been used in the pediatric population. At our center, it is reserved for patients with hemodynamically significant rejection or who have undergone a retransplant due to rejection or coronary artery disease. A unique issue that pediatric transplant teams encounter is the preservation of normal somatic growth and neurodevelopment. Hirsch and coworkers18 found that the height and weight of infant heart transplant recipients remain within 2 standard deviations of those expected for age, even though such recipients tend to be smaller sized. Steroid use has no effect on height in older pediatric heart transplant recipients, but there is a trend toward slower growth in infant recipients who remain on steroids.19 Infant heart transplant recipients attain a lower IQ score than their peers and often have learning disabilities.20,21 It is unclear, however, if this is caused by the transplant or by the underlying heart disease.

Late Complications Coronary Artery Vasculopathy Transplant coronary artery vasculopathy (CAV) is a complex disease that is the premier cause of late graft loss.1 Angioplasty of the lesions, with the use of stents, can provide tem-

porary relief. However, a retransplant is the only proven therapy to date. Pharmacologic approaches used in adults have not been systematically studied in children. At our center, we use rapamycin for secondary prevention of CAV in patients with early angiographic signs of disease, but we have found that disease progression is not influenced by rapamycin in patients with advanced disease.

Posttransplant Lymphoproliferative Disease (PTLD) A large proportion of pediatric patients are naïve to EpsteinBarr virus at the time of their transplant. Seroconversion can occur with the transplant or at any time posttransplant. Seroconversion during immunosuppression confers a markedly increased chance of developing posttransplant lymphoproliferative disease (PTLD). The form of immunosuppression used does play a role in the timing and onset of PTLD. In a study of 35 patients studied at the University of Minnesota who underwent a transplant from 1986 through 2000, the mean time from seroconversion to diagnosis of PTLD was six years. For patients treated with FK506, the mean time between seroconversion and PTLD diagnosis was 14 months (unpublished data, Braunlin et al). Once the patient seroconverts, the EBVPCR is a useful guide to predict the onset of PTLD. At our center, we have found that among recipients with an EBVPCR of fewer than 100 viral copies per 100,000 white blood cells (20 of 35 recipients), no recipient developed PTLD.22 But in those with an EBV-PCR greater than 100 viral copies per 100,000 white blood cells (15 of 35 recipients), 46%

Pediatric cardiac transplantation developed PTLD. Current strategies to combat PTLD once it has developed include reduced immunosuppression, use of antiviral agents, interferon, and, more recently, antiCD20 antibodies along with chemotherapy. In conclusion, pediatric heart transplant patients continue to present many challenges to the medical community. These challenges include the timing of listing for transplant, the design of the operative procedure, use of mechanical assist devices, treatment of elevated pulmonary vascular resistance, postoperative immunosuppression, and PTLD. Despite these challenges, pediatric heart transplants in complex pediatric patients can be accomplished with excellent survival rates.

References 1. Boucek MM, Edwards LB, Keck BM, et al: The Registry of the International Society for Heart and Lung Transplantation: Sixth Official Pediatric Report—2003. J Heart Lung Transplant 22:636-652, 2003 2. Williams WG, McCrindle BW, Ashburn DA, et al: Outcomes of 829 neonates with complete transposition of the great arteries 12-17 years after repair. Eur J Cardiothorac Surg 24:1-9, 2003 3. Sittiwangkul R, Azakie A, Van Arsdell GS, et al: Outcomes of tricuspid atresia in the Fontan era. Ann Thorac Surg 77:889-894, 2004 4. Morrow WR, Naftel D, Chinnock R, et al: Outcome of listing for heart transplantation in infants younger than six months: Predictors of death and interval to transplantation. J Heart Lung Transplant 16:1255-1266, 1997 5. Tsirka A, Trinkhaus K, Chen SC, et al: Improved outcomes of pediatric dilated cardiomyopathy with utilization of cardiac transplantation. J Am Coll Cardiol 44:391-397, 2004 6. Lipshultz SE, Sleeper LA, Towbin JA, et al: The incidence of pediatric cardiomyopathy in two regions of the United States. N Engl J Med 348:1647-1655, 2003 7. Fricker FJ, Addonizio L, Bernstein D, et al: Heart transplantation in children: Indications. Pediatr Transplant 3:333-342, 1999 8. del Nido PJ, Armitage JM, Fricker FJ, et al: Extracorporeal membrane

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oxygenation support as a bridge to pediatric heart transplantation. Circ 90:II66-II69, 1994 Mehta U, Laks H, Sadeghi A, et al: Extracorporeal membrane oxygenation for cardiac support in pediatric patients. The American Surgeon 66:879-886, 2000 del Nido PJ: Extracorporeal membrane oxygenation for cardiac support in children. Ann Thorac Surg 61:336-339, 1996 Denfield SW, Rosenthal G, Gajarski RJ, et al: Restrictive cardiomyopathies in childhood. Etiologies and natural history. Tex Heart Inst J 24:38-44, 1997 Dearani JA, Razzouk AJ, Gundry SR, et al: Pediatric cardiac retransplantation: Intermediate-term results. Ann Thorac Surg 71:66-70, 2001 Kao B, Balzer DT, Huddleston CV, et al: Long-term prostacyclin infusion to reduce pulmonary hypertension in a pediatric cardiac transplant candidate prior to transplantation. J Heart Lung Transplant 20: 785-788, 2001 http://www.unos.org/PoliciesandBylaws/policies/docs/policy_9.doc. Organ Distribution: Allocation of Thoracic Organs, 2003 West LJ, Pollock-Barziv SM, Dipchand AI, et al: ABO-incompatible heart transplantation in infants. N Engl J Med 344:793-800, 2001 Kirshbom PM, Bridges ND, Myung RJ, et al: Use of extracorporeal membrane oxygenation in pediatric thoracic organ transplantation. J Thorac Cardiovasc Surg 123:130-136, 2002 Dellgren G, Coles JG: Pediatric heart transplantation: Improving results in high-risk patients. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 4:103-114, 2001 Hirsch R, Huddleston CB, Mendeloff EN, et al: Infant and donor organ growth after heart transplantation in neonates with hypoplastic left heart syndrome. J Heart Lung Transplant 15:1093-1100, 1996 http://www.ishlt.org/registries/slides.asp. 2003. Ikle L, Hale K, Fashaw L, et al: Developmental outcome of patients with hypoplastic left heart syndrome treated with heart transplantation. J Pediatr 142:20-25, 2003 Baum M, Freier MC, Freeman KR, et al: Developmental outcomes and cognitive functioning in infant and child heart transplant recipients. Prog Pediatr Cardiol 11:159-163, 2000 Van Bergen AH, Hafemeyer KL, Herrington CS, et al: EBV-PCR predicts susceptibility to post transplantation lymphoproliferative disease in pediatric heart transplant recipients. Circulation 104(Suppl II):677, 2001