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Pediatric Heart Transplantation Technique

  • Author: Richard E Chinnock, MD; more...
 
Updated: Nov 13, 2014
 

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.

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.

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 Denver 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 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%.

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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 r View 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 posttransplant stenosis in this area. The pulmonary artery anastomosis is completed while the patient is rewarmed.

Other complex congenital heart anomalies, such as transposition of the great arteries, can often be managed by means of direct anastomosis if sufficient lengths of donor arterial and venous connections are procured.

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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.

In patients receiving PGE 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 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.

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.

A number of protocols exist for immunosuppression in the perioperative and postoperative period. The following protocol is used at Loma Linda University Children’s Hospital:

  • Cyclosporine is begun at 0.1 mg/kg/h 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 250-300 ng/mL
  • Methylprednisolone is administered at 20 mg/kg IV every 12 hours for 4 doses
  • In recipients older than 30 days, antithymocyte globulin induction therapy is administered at 1.5 mg/kg once daily for the first 5 days
  • Mycophenolate mofetil (MMF) is administered IV or orally at 500 mg/m 2 twice daily; dosing is adjusted as necessary to maintain an MMF level of 2.5-5 µg/mL and a white blood cell (WBC) count of at least 4 × 10 9/L

The most appropriate initial immunosuppression protocol is not known. Every transplantation center likely has a different protocol. Clear data are difficult to obtain because of the small number of transplants performed each year and the need for centers to standardize practice across institutions.

In addition, 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.

Adjunctive therapy includes IV immune globulin 2 g/kg, administered as 500 mg/kg/day given over 12 hours for 4 days, beginning right after transplantation. Ranitidine is administered while the patient is receiving methylprednisolone. Ganciclovir is administered IV for 2 weeks in recipients who are positive for cytomegalovirus (CMV) or who receive an organ from a CMV-positive donor. Aspirin 3-5 mg/kg/day is administered if the platelet count persistently exceeds 500 × 109/L.

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Complications

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

Allograft rejection

Preventing rejection while avoiding severe infections, renal failure, and cancer is the biggest challenge facing the transplant physician.[7] Although 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.[8, 9]

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 these, about two-thirds used polyclonal antibody T-cell–depleting agents, and one-third used 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.

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 these concerns.

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.

Tacrolimus is not commercially available as a liquid preparation; the solution must be compounded in a local pharmacy, and this carries a potential for 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 is generally the preferred calcineurin inhibitor. Target trough levels (whole blood, monoclonal assay) are 250-300 ng/mL for the first 6 months, 200-250 ng/mL for the next 6 months, and 125-150 ng/mL thereafter if the rejection history is acceptable.

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 sustain problematic cosmetic side effects, especially those who require orthodontia, in whom gingival hyperplasia is counterproductive.

Antiproliferative agents

Among the antiproliferative agents, azathioprine (AZA) has been the therapeutic mainstay. According to the ISHLT, however, 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 effects.[10, 11] The 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 divided into 2 doses and is increased as tolerated to maintain a mycophenolic acid level of 2.5-5 µg/mL.

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 those 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. 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 side effects.

At Loma Linda, sirolimus has been used 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, and 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, treatment with ultraviolet A light, and reinfusion [12] ; 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 rejection

The mainstay of therapy for acute graft 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 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.

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

Diagnosis of rejection

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

Clinical clues to rejection include a decrease in the child’s activity or feeding, low-grade fever, persistent resting tachycardia, ventricular ectopy, S3 gallop, tachypnea or dyspnea, hepatic congestion, ileus, and other signs or symptoms of low cardiac output.

Echocardiographic criteria for rejection are somewhat controversial but include findings reflective of an increase in left ventricular mass, impairment of systolic and diastolic function, new pericardial effusion, and new mitral insufficiency. Some have advocated tissue Doppler imaging to improve the sensitivity of echocardiographic diagnosis of rejection.[13]

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.[14]

Cardiac functional biomarkers have been advocated for the diagnosis of rejection. B-type natriuretic peptides have been used, although the levels of these substances widely vary 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 occurring only for biopsy samples that demonstrate a 2R (ie, 2 or more foci lymphocytic infiltration with associated myocyte damage) or greater histology.[15]

Antibody-mediated rejection is becoming increasingly recognized. Preformed antibodies have long been known to create the potential for hyperacute rejection in the early posttransplant period.[16] Retrospective 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 jiroveci (carinii) infections occur but are less frequent. Other opportunistic infections should be anticipated and aggressively treated when present.

Using data from a multi-institutional registry of 1854 patients, Zaoutis et al reported on the risk factors and outcomes of children with invasive fungal infections after heart transplantation and noted 139 invasive fungal infections in 123 patients. The most common infections were from yeasts (66.2%), molds (15.8%), and P jiroveci (13%). Candida species accounted for 90% of the yeast infections, and Aspergillus species accounted for 82% of the mold infections.

Of those 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. The researchers suggested that strategies for prophylaxis against invasive fungal infections should be considered and that further study was warranted.

Malignancy

Malignancy, usually PTLD associated with Epstein-Barr virus (EBV) infection, occurs in 2-10% of children.[17, 18] When the histology is low-grade (polymorphous hyperplasia), it usually responds to short-term cessation of immunosuppression. Higher-grade lymphomas are treated with a modified chemotherapeutic regimen that consists of cyclophosphamide every 3-4 weeks for 4-6 months accompanied by anti-CD20 monoclonal antibody (rituximab) for tumors that express CD20 (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.

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

Once 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 that is diagnosed by means of 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 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors 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. The 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 to lower the calcineurin inhibitor dose.[19] A 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.

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Contributor Information and Disclosures
Author

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

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

Disclosure: Received grant/research funds from Roche Pharmaceuticals for other.

Acknowledgements

Richard G Ohye, MD Head, Division of Pediatric Cardiovascular Surgery; Program Director, Pediatric Cardiac Surgery Fellowship, University of Michigan Medical Center

Richard G Ohye, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Thoracic Surgery, American College of Cardiology, American College of Chest Physicians, American College of Surgeons, Association for Academic Surgery, Congenital Heart Surgeons Society, International Society for Heart and Lung Transplantation, Society of Thoracic Surgeons, and Society of University Surgeons

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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