Heart transplantation at Children's Memorial

ELFRIEDE PAHL, MD
CARL LEWIS BACKER, MD
CONSTANTINE MAVROUDIS, MD

aFall 1999

The first heart transplant  at Children's Memorial Hospital was performed on May 13, 1988.¹ That child was an 18-month-old girl with severe dilated cardiomyopathy who was critically ill and hospitalized for seven weeks while she waited for a donor. She was discharged from the hospital three weeks after her transplant, and survived 8 1/2 years until succumbing to transplant coronary artery disease, a universal occurrence after cardiac transplantation.²

As of October of 1999, 77 children have undergone heart transplantation at Children's Memorial Hospital. This makes our pediatric cardiac transplant program one of the top 10 programs in the nation.³ The last 30 transplants over the past 5 years have been performed without an operative mortality. The children who have had cardiac transplantation at Children's Memorial Hospital have been intensively followed, and we have published many studies regarding our clinical experience.^1,4,5,6 In addition to this clinical research, we have developed a complementary basic science research initiative to investigate important problems in the laboratory.^7,8,9 This highly successful clinical and research endeavor has been the result of tremendous collaboration between Cardiology, Cardiac Surgery, Pathology, and countless other CMH resources.

INDICATIONS

The indications for cardiac transplantation in infants and children fall into two main categories: dilated cardiomyopathy and structural heart disease not amenable to conventional cardiac surgical procedures. The goal of transplantation is to improve quality of life and life expectancy. The diagnoses leading to heart transplantation at Children's Memorial Hospital are shown in Table 1. The majority of transplants have been performed for cardiomyopathy. Dilated cardiomyopathy (24 patients) is the most common diagnosis, however, increasing numbers of patients have been transplanted for restrictive (7 patients) and anthracycline toxicity (7 patients) cardiomyopathy. Children who have had palliation of complex congenital heart disease are able to grow and achieve adolescence, and the proportion of patients being transplanted for structural heart disease has been increasing. This includes in particular patients who have a failing right ventricle after a Mustard procedure or a failed single ventricle after a Fontan procedure.

At Children's Memorial Hospital, we performed cardiac transplantation as primary therapy for 18 infants with hypoplastic left heart syndrome (HLHS) from 1988–1993.¹⁰ However, there has been a major shift in the treatment of newborns with HLHS at many centers, including ours, since 1993. We no longer routinely perform heart transplantation as initial therapy for HLHS. Because of improved outcomes, we now recommend staged reconstructive surgery beginning with an initial Norwood procedure. Coinciding with improvements in the outcome for the Norwood procedure, it became very difficult to get donor hearts for newborns, and many infants died on the waiting list. With increased experience and careful perioperative management, the number of babies surviving the Stage 1 Norwood procedure is currently > 80%, and it has become the procedure of choice at most centers. In calendar year 1999 so far, we have performed 5 Norwood procedures without mortality.

The optimal time for listing a patient for heart transplantation is based on a clinical judgement of life expectancy versus expected duration of time on the waiting list. Adolescents compete with adult recipients and often wait over one year for a transplant; neonates also have long waiting times due to a shortage of acceptable donors. These factors must all be weighed and a calculated judgement made to determine the optimal timing for listing for heart transplantation.

PRE-TRANSPLANT EVALUATION

The evaluation for cardiac transplantation includes consideration of any alternative treatment and the evaluation of co-existing medical conditions that may limit survival. The patient and family members are educated regarding the rigors of the post transplant regimen, including medications required, follow-up protocol, and the major limitations of transplantations. Table 2 lists the types of studies performed for the pre-transplant comprehensive evaluation.

A partial list of relative contraindications to pediatric cardiac transplant is shown in Table 3. Both active infection and malignancy make a successful outcome highly unlikely. High pulmonary artery pressures with an elevated pulmonary vascular resistance less than or equal to 6 indexed units' greatly increases the perioperative risk, although we have performed successful transplants in several such patients.⁴ We have also successfully transplanted patients with renal failure on dialysis, thus an assessment of the likelihood of reversibility of end-organ damage from low cardiac output is necessary. Multiple prior sternotomies may increase bleeding during the perioperative period, but are not a contraindication, and actually one-third of our transplants were performed in patients with prior cardiac surgery. Recurrent medical non-compliance, as well as alcohol, tobacco or other substance abuse are risk factors for poor outcome. Patients being considered for transplant would need to demonstrate a change in behavior before they would be listed. An assessment of family support systems and financial resources is also performed.

DONOR SELECTION AND PROCUREMENT

Like adult recipients, children are wait-listed through the Regional Organ Bank of Illinois (ROBI) and the United Network for Organ Sharing (UNOS). Each listing is specific for ABO compatibility and a certain weight range. In a few rare instances of fetal diagnosis of irreparable cardiac anomaly, babies are listed while still in utero with a plan to emergently deliver the child by C-section if a heart becomes available. If the strict size-matching criteria based on the adult experience were used, the supply of donor organs for children would be prohibitively small. We and other centers have, therefore, accepted organs from donors that are up to 2.5 times the recipient weight, particularly in infants.

Evaluation of donor function is made by reviewing the donor history, assessing the donor hemodynamic status and degree of inotropic support, and evaluating the EKG and echocardiogram. Final judgement of donor suitability is reserved for the visual inspection at the time of procurement. Diagnosis of cardiac donors as used at Children's Memorial Hospital included closed head trauma (n=27), gunshot wound to the head (n=12), intracranial event (n=10), sudden infant death (n=6), birth asphyxia (n=5), and other (n=17).

TECHNIQUE OF HEART TRANSPLANTATION

The cardiac procurement is performed through a median sternotomy, usually as part of a multi-organ procurement. We attempt to keep the total donor ischemia time under four hours, (i.e., the time that the donor heart is not beating and is stored in cold cardioplegic preservation solution). Donor heart procurement and the start of the recipient operation are coordinated to minimize donor heart ischemia time; one surgeon procures the donor heart while the other transplant surgeon begins the operation on the recipient. The recipient chest is opened through a median sternotomy and the child is placed on cardiopulmonary bypass. When the donor heart has arrived at Children's Memorial Hospital, the recipient native heart is excised. In pediatric patients, the original transplants were performed using the "right atrial" technique first described by Drs. Lower and Shumway. For transplant of the infant with HLHS, the technique requires replacement also of the hypoplastic aortic arch, which necessitates a period of circulatory arrest.¹⁰ For older children we and others have changed from the right atrial technique to using a "bicaval" anastomosis.

FIGURE 1 A AND B. "Right atrial" cardiac transplantation. In the first panel the recipient cardiectomy has been completed, leaving 4 anastomoses to be performed in the following sequence: 1) Left atrial (LA), 2) Aortic (Ao), 3) Right atrial (RA), 4) Pulmonary artery (PA). The donor heart is reperfused after the aortic anastomosis. In the second panel, the completed suture lines are shown and the cardiopulmonary bypass cannulae have been removed. (Illustration by R. Idriss.)

The technique of cardiac transplantation with a "right atrial" anastomosis is shown in Figure 1, and the technique with a "bicaval" anastomosis is shown in Figure 2.

FIGURE 2 A AND B. "Bicaval" cardiac transplantation. In the first panel the recipient cardiectomy has been completed. Note the entire recipient right atrium has been removed. The second panel shows the completed implant. The sequence of anastomoses are: 1) Left atrial (LA), 2) Aortic (Ao), 3) Inferior vena cava (IVC), 4) Pulmonary artery (PA), 5) Superior vena cava (SVC). Again, the donor heart is perfused after the aortic anastomosis. In the second panel, the completed suture lines are shown and the cardiopulmonary bypass cannulae have been removed. (Illustration by R. Idriss.)

With both techniques, the aortic cross clamp is removed after the left atrial and aortic anastomosis are completed in order to minimize the ischemia time of the donor heart. The mean donor ischemia time in our series is 2.4 hours.

POSTOPERATIVE MANAGEMENT

All cardiac transplant recipients are initially recovered in the pediatric intensive care unit. They are all on mechanical ventilation for at least the first 24 hours. All patients are kept in strict reverse isolation, and standard care for the postoperative cardiac patient is performed. Because many pediatric patients will have had an elevated pulmonary resistance preoperatively, pulmonary vasodilators are an integral part of the postoperative pharmacologic regime.⁴ These vasodilators include inhaled nitric oxide and intravenous Milrinone, nitroglycerine, and dobutamine. Most patients are paralyzed with Pancuronium and mildly hyperventilated for at least the first 24 hours post-op. Isuprel is used to increase the heart rate and is titrated as needed. Immunosuppressive medications are discussed in a subsequent section.

LIMITATIONS OF HEART TRANSPLANTATION

Despite excellent perioperative and intermediate term survival, there are definite limitations to late survival because of the complications of cardiac rejection, graft vasculopathy, infection, and lymphoma.

Rejection is due to immunologic factors related to host recognition of the foreign graft. Despite lifelong treatment with immunosuppressive agents, rejection is the most common cause of death in patients who survive the first year post-transplant.³ Compliance with medication is essential. Rejection episodes, if detected early, can usually be reversed. The risk of rejection is highest in the first 3 months post-transplant, however rejection can also occur in the late survivors. We use a biopsy-driven protocol to detect rejection.⁵ This is the "gold standard" for the detection of rejection. Patients are taken to our cardiac catheterization laboratory, and either the internal jugular or femoral venous approach is used (Figure 3). After hemodynamics are recorded using a standard catheter, a bioptome is inserted and 5 to 6 small pieces of the endocardium of the right ventricle are obtained for microscopic review. The procedure takes approximately 30 to 45 minutes and patients are observed in the hospital for 6 hours afterward. The biopsy is read and graded by our cardiac pathologist, Dr. Susan Crawford. If rejection is diagnosed, we treat the patient with a 3-day pulse of intravenous steroids.

FIGURE 3. Biopsy techniques. Either the internal jugular or femoral vein can be cannulated percutaneously. The bioptome is passed transvenously into the right ventricle through a preformed venous sheath. Under fluoro-scopic guidance, small “bites” of the right ventricle are obtained for microscopic analysis.

Post transplant coronary artery disease (TCAD) occurs in children as well as adults and remains a challenging problem after heart transplantation.² TCAD is immune-based, although non-immune risk factors such as hyperlipidemia, hypertension, and obesity contribute to the process. TCAD is difficult to detect in the asymptomatic patient, thus we use annual surveillance consisting of coronary angiography, intracoronary ultrasound and dobutamine stress echocardiography. We currently attempt to provide risk reduction of TCAD by treatment of hyperlipidemia and hypertension, as well as efforts to reduce rejection episodes. We also are actively studying this phenomenon in the laboratory and recommend the use of captopril or other ACE-inhibitors in all patients.^7,9

One of the early fears of performing pediatric transplantation was that the child would be at risk for severe complications from common childhood diseases due to immunosuppression. In actual experience, with careful “triple therapy” immunosuppression, most common childhood illnesses are well-tolerated. Routine immunizations (except for live virus vaccines) should resume at 12 weeks post-transplant. Transplant recipients have a normal response to routine immunization with diptheria, pertussis, typhoid, and hepatitis B. Pediatric transplant recipients and their siblings should receive only inactivated polio. Measles, mumps, and rubella vaccines are not given to recipients. Varicella-Zoster immune globulin should be given to pediatric heart transplant recipients within 72 hours after exposure to chicken pox. Currently, varicella vaccine is given to siblings, but not to the transplant recipient. However, we routinely immunize patients for varicella at the time of their transplant evaluation if they are susceptible, and if we anticipate that the actual transplant is more than 4 weeks away. Any patient who is suspected of having an infection needs to be evaluated for opportunistic infections and treated appropriately. Most infections can be successfully treated. Bacterial infections are most common, with CMV and other viruses being less common. Of note, fungal infections (though rare) carry a high mortality.

Post-transplant lymphoproliferative disease (PTLD) is a serious complication of excessive immunosuppression, appears to be related to Epstein-Barr virus infection in children, and occurs in all solid organ transplant recipients. The incidence in children is higher than in adults, with reported instances ranging from 5 to 10% of the transplant population. Early in our experience, two patients died of PTLD. More recently, other patients have been treated successfully by carefully reducing their overall immunosuppression. One patient required chemotherapy. Early diagnosis and better surveillance methods as well as aggressive reduction in immunosuppressive medications have yielded better intermediate outcomes from PTLD.

MEDICATIONS

Immunosuppressive agents

• Cyclosporine (CSA) selectively inhibits the interleukin-2 driven proliferation of activated T-lymphocytes. CSA has been the mainstay of immunosuppressive treatment in our heart transplant population. The use of CSA has resulted in fewer and less severe rejection episodes and fewer severe infections. CSA levels are monitored routinely to minimize toxicity. CSA's main side effects are nephrotoxicity and hypertension, and cosmetic side effects include gingival hypertrophy and hirsutism. High levels of CSA may cause seizures and tremors. There is no question that it was the introduction of CSA in the early 1980s that made successful pediatric heart transplantation possible.
• Tacrolimus (Prograf or FK-506), a macrolide antibiotic, is a new medication that is much more potent on a per milligram dose than cyclosporine, but acts with a similar mechanism as a calcineurin inhibitor. It has a greater side effect profile than CSA, thus we have not routinely switched our patients if they are doing well on CSA. A few of our patients with refractory rejection take Prograf instead of CSA.
• Imuran (azathioprine) is an antimetabolite that is used in conjunction with CSA. Historically it preceded the use of CSA. A side effect is bone marrow suppression.
• Cellcept (mycophenolate mofetil) is a newer agent that is gradually replacing azathioprine. It acts as an antimetabolite to purine. This drug appears to be well tolerated and may have better long-term effects in reducing post-transplant coronary artery disease and late rejection. The main side effects are gastrointestinal complaints and, more rarely, neutropenia.
• Prednisone is a nonspecific anti-inflammatory agent with many side effects, however, it is a very important anti-rejection medication especially in the first year post-transplant. Many programs, including ours, have made aggressive attempts to try to wean patients off steroids after the first 6 months post-transplant to optimize growth, and reduce long term effects of chronic steroid therapy. Augmentation of steroid dosage short term is the first line treatment of acute rejection.

Anti-hypertensive medications

ACE-inhibitors such as Enalapril and Captopril, as well as calcium channel blockers, are commonly used and essential for minimizing hypertension post transplantation. In our laboratory model we demonstrated that Captopril reduces TCAD, and that Diltiazem does not.^7,8

Aspirin

We use daily aspirin on all patients for its antiplatelet effect and potential benefit in reducing graft coronary artery disease.

Antibiotic prophylactic medications

During the first year, and in selected patients afterward, Pneumocystis prophylaxis is done with trimethoprim/sulfamethoxazole (Bactrim). Nystatin is used daily for candidal prophylaxis. Various regimens have been used for CMV prophylaxis, acyclovir in the past, and gangcyclovir currently.

FOLLOW-UP PROTOCOL

The first year post-transplantation involves intense follow-up with our transplant team. Traditionally, anywhere from 8 to 12 biopsies are performed, however we have decreased the number of biopsies in infants. We believe biopsy is the gold standard to detect rejection, and we believe it is important to detect rejection early, before it has severe hemodynamic significance. Because transplant recipients have a high incidence of lipid abnormalities, we have initiated therapy with Pravastatin, an HMG-COA reductase inhibitor, in hopes of reducing this risk factor for the development of TCAD.

After one year post-transplantation, the patient has a coronary angiogram, which is repeated on an annual basis. We have recently also added dobutamine stress echocardiography and intravascular coronary ultrasound to our surveillance protocol for attempting to detect TCAD. Echocardiograms are generally performed every six months after the first year post-transplantation, and blood work is obtained every two to three months, in particular cyclosporine levels and complete blood counts. Lipid profiles are obtained as needed, but at least once a year, since many of our patients have hypercholesterolemia.

QUALITY OF LIFE

ISHLT Pediatric Registry data indicates that at 3 years post-operatively, over 95% of recipients have no activity limitations.3 Quality of life is excellent. Patients return to school and have no restrictions in gym class. Longitudinal studies of linear growth of pediatric heart transplant recipients indicate that growth is not normal. However, there are many variables such as preoperative growth failure caused by chronic disease, prolonged hospitalization, and other factors that make such studies difficult. Most pediatric heart transplant recipients are somewhat short for their age. Chronic prednisone may play a role. Developmental delay as measured by the Denver Development Screening has not been documented. The majority of our patients have mild reduced exercise capacity on formal exercise study.

Survival after pediatric heart transplantation was reported by the International Registry to be 60% at 7 years and 50% at 10 years.³ At CMH our operative survival is 93%, and our 5 year survival is 70%. In the past 5 years, we have had no perioperative deaths (n=30), and 1-year survival for patients transplanted in the current era is greater than 95%. We have serially evaluated the cardiac index, left ventricular volume, and ejection fraction following heart transplants in both infants and children, and found that cardiac output remained normal as indexed to the patient's body surface area and that there is a steady appropriate rise in left ventricular end diastolic volume.⁶ The donor heart grows appropriately with the child!

CONCLUSIONS

Heart transplantation can be performed in both neonates and children with a low operative mortality and excellent long-term survival. Currently this is the only therapy available for children with end-stage cardiomyopathy and structural heart disease not amenable to conventional surgical therapy. For neonates with HLHS, we now recommend staged reconstruction beginning with a Norwood procedure. In older children, proper recipient selection, particularly with regard to pulmonary vascular resistance and its response to vasodilators, may decrease perioperative mortality. With future improvements leading to more selective medications, non-invasive detection of rejection, and hopefully prevention of coronary disease, we hope that our long-term outcomes will continue to improve. The future also holds the promise of the ability to induce tolerance, use of xenografts which would alleviate the organ shortage problem, and more specific immunosuppressive agents with less toxicity. We believe pediatric heart transplantation is excellent therapy for children with end-stage cardiac failure.

8 Click here for more information about the heart transplantation program at Children's Memorial Hospital.

REFERENCES

1. Backer CL, Zales VR, Idriss FS, Mavroudis C: Heart transplantation in infants and children. J Heart Lung Transplant 1992;11:1311–1319.

2. Pahl E, Zales VR, Fricker FJ, Addonizio LJ: Post-transplant coronary artery disease in children: A multicenter national survey. Circulation. 1994;90:(II)-II56–II60.

3. Boucek MM, Novick RJ, Bennett LE, et al.: The registry of the International Society of Heart and Lung Transplantation: Second official pediatric report—1998. J Heart Lung Transplant 1998;17:1141–1160.

4. Zales VR, Pahl E, Backer CL, et al.: Pharmacologic reduction of pretransplantation pulmonary vascular resistance predicts outcome after pediatric heart transplantation. J Heart Lung Transplant 1993;12:965–973.

5. Zales VR, Crawford S, Backer CL, et al.: The role of endomyocardial biopsy rejection surveillance in pediatric cardiac transplantation. J Am Coll Cardiol 1994;23:766–771.

6. Zales VR, Wright KL, Pahl E, et al.: Normal left ventricular muscle mass and mass/volume ratio after pediatric cardiac transplantation. Circulation 1994;90:[Part II]: II61–II65.

7. Kobayashi J, Crawford SE, Backer CL, et al.: Captopril reduces graft coronary artery disease in a rat heterotopic transplant model. Circulation 1993;88(II)286–290.

8. Takami H, Backer CL, Crawford SE, Pahl E, Mavroudis C: Diltiazem preserves direct vasodilator response but fails to suppress intimal proliferation in rat allograft coronary artery disease. J Heart Lung Transplant 1996;15:67–77.

9. Crawford SE, Huang L, Hseuh W, et al.: Captopril and platelet- activating factor (PAF) antagonist prevent cardiac allograft vasculopathy in rats: Role of endogenous PAF and PAF-like compounds. J Heart Lung Transplant 1999;18:470–477.

10. Backer CL, Idriss FS, Zales VR, Mavroudis C: Cardiac transplantation for hypoplastic left heart syndrome: a modified technique. Ann Thorac Surg 1990;50:894–898.

Copyright © 2008 by Children’s Memorial Hospital. All rights reserved.