Chapter 32 Cardiac Transplantation

• Indications for transplantation are cardiomyopathy and complex palliated congenital heart disease with severe myopathic ventricular dysfunction.

• Pediatric patients on inotropic support or circulatory support and who have life-threatening arrhythmia receive priority for available pediatric donors.

• Selection of the agent to initiate inotropic support has evolved from sympathomimetic agents (dobutamine/dopamine) to the phosphodiesterase inhibitor milrinone.

• Virtual crossmatch is now utilized in sensitized patients to improve organ allocation.

• It is imperative that immune suppression be initiated immediately after heart transplantation.

• The high-risk period for acute allograft rejection is in the first month after transplantation.

• Complications of immune supression are infection, acute renal failure, malignancy, and hyperglycemia.

It has now been a quarter of a century since the first successful pediatric heart transplant was performed at Stanford University.¹ The introduction of cyclosporine as the primary immune suppressant agent used in solid organ transplantation was a key discovery because it was the first selective immunosuppressive agent used in solid organ transplant recipients. It has spared corticosteroid use and has made heart transplantation a cost-effective procedure.² In the past 25 years, perioperative mortality has become negligible even in patients with the most complex congenital heart defects. Advances have occurred in our understanding of the immune system, and improvement in critical care management of both donor and recipient patients has resulted in an increased survival benefit. This chapter reviews critical care management of the pediatric patient with cardiopulmonary failure who is evaluated for orthotopic heart transplantation. Donor management, physiology of the transplanted heart, and preoperative and perioperative critical care all play important roles in the successful outcome of critically ill children with no option other than heart replacement surgery.

Indications for transplantation are cardiomyopathy and complex palliated congenital heart disease with severe myopathic ventricular dysfunction.³ The Pediatric Heart Transplant Study Group reviewed the causes of death after heart transplantation from a prospective database initiated in 1993. Patients were entered into the database on an intention-to-treat basis.⁴^–⁶ Using parametric data analysis with competing outcomes, death while waiting for transplant has been analyzed for all age groups, pretransplant diagnosis, blood type, and urgency status. Early death after heart transplant has been categorized as primary heart allograft failure. This includes inadequate preservation from long ischemic time and primary right ventricular failure from high pulmonary vascular resistance (PVR). Acute allograft rejection is an exceedingly rare event immediately after implantation. Late death after transplant is the result of posttransplant coronary vasculopathy, malignancy, or nonadherence to immune suppression regimens.^7,⁸

The technical complexities of heart transplantation in children with palliated congenital heart disease contributed to the early perioperative mortality, which exceeded 30%. In addition, difficulties in estimating PVR, variable pulmonary artery anatomy, and complications from multiple repeat thoracotomy and sternotomy all contributed to early morbidity and mortality.⁹ Solid organ preservation, surgical experience, and recipient selection have all improved with experience, resulting in reduced perioperative mortality that is equivalent to transplantation of the primary cardiomyopathic patient who has not had a previous sternotomy.^9,¹⁰ Primary transplantation in the neonate with hypoplastic left heart syndrome (HLHS) has caused controversy, because an acceptable surgical alternative is available and infant donor heart resources are limited.¹¹ In reviews from the Pediatric Heart Transplant Study Group Database, the mortality of infants waiting for donor heart availability exceeds 25%.⁴ In recent years, deaths while waiting for transplantation have decreased, but this decrease reflects the smaller number of infants listed and those who have opted for the Norwood procedure and single-ventricle palliation. The Norwood procedure does not preclude the possibility of future transplantation.

Late death after heart transplantation is related to either accelerated allograft coronary artery disease or primary malignancy.^12,¹³ The major cause of death in the adolescent heart transplant recipient is now noncompliance with the medical regimen.⁷ With the decrease in perioperative mortality, we now expect 5-year survival after heart transplantation to exceed 80%. From the newest survival data (International Society for Heart and Lung Transplantation 2009 Report), the transplant half-life (the time at which 50% of the recipients remain alive) is 11.3 years for teens and 15.8 years for infants.¹⁴ Rehospitalization after the first year is rare, and quality of life has been excellent.¹⁵

Critical Care of the Pediatric Patient Waiting for Heart Transplantation

An inadequate number of good donor hearts is available to satisfy the number of potential adult recipients. Statistics from the United Network for Organ Sharing (UNOS) demonstrate this discrepancy between the number of potential recipients for heart and lung transplants and the availability of potential donors.¹⁶ Donor availability for the pediatric patient is not as critical. Pediatric patients usually receive an appropriate donor offer unless they are infants or are adolescents of a size such that they are competing with critically ill adult patients. Guidelines from UNOS regarding organ distribution have changed to ensure that pediatric adolescent donors are available first to potential adolescent and young adult pediatric recipients for both heart and lungs.

For potential heart transplant recipients, urgency criteria have been established for the most critically ill patients. Pediatric patients on inotropic support or circulatory support or who have life-threatening arrhythmia receive priority for available donors (Box 32-1).

Management of the Potential Heart Transplant Recipient

The pretransplant management of the critically ill patient with end-stage myocardial dysfunction can determine the outcome of that patient after thoracic transplant. The principles of inotropic support, preservation of end-organ function, and attention to issues of nutrition and infection are the same for all critically ill patients in the pediatric intensive care unit.

Evaluation of the potential heart transplant recipient requires a careful pretransplant hemodynamic assessment. This information can guide the fluid and inotropic therapy by optimizing preload and afterload while waiting for organ availability. The critical hemodynamic information influencing the function of the donor heart is an assessment of pulmonary artery pressure and PVR in the recipient before implantation. High PVR is associated with an increased perioperative transplant mortality rate and adverse long-term outcome.^17,¹⁸ A transpulmonary gradient greater than 15 mm Hg (mean pulmonary arterial pressure minus mean left atrial pressure) is associated with a higher incidence of heart graft dysfunction.¹⁸ Preoperative hemodynamic assessment should include measurement of both left and right heart pressures with interventions to manipulate the PVR if elevated. Remeasuring hemodynamics with FiO₂ of 1, nitric oxide, prostacyclin, and aggressive vasodilator therapy to decrease systemic vascular resistance (SVR) can help determine whether the patient is a heart transplant candidate or if he or she should be considered for lung or heart and lung transplantation.^19,²⁰

Inotropic Support

Critically ill children with myopathic ventricular dysfunction severe enough for them to be in the intensive care unit are on inotropic support. These agents increase contractility through a common pathway of increasing intracellular levels of cyclic adenylate monophosphate (cAMP). Increased cytoplasmic levels of cAMP cause increased release of calcium from the sarcoplasmic reticulum and increase contractile force generation. Increases in cAMP occur either by β-adrenergic–mediated stimulation (increase in production) or phosphodiesterase III (PDE III) inhibition (decreased degradation). Milrinone has proven to be a well-tolerated agent. Intravenous administration of milrinone increases cardiac output and reduces cardiac filling pressures, PVR, and SVR, with minimal effect on heart rate. Milrinone has been well studied in the pediatric population, and the benefit is primarily related to effect on SVR and PVR rather than inotropy.^21,²² Milrinone is initiated at doses of 0.25 μg/kg/min and increased to 1 μg/kg/min without adverse effects. Although atrial and ventricular ectopy are less common with milrinone than dobutamine, ventricular ectopy/ventricular tachycardia can occur with the initiation of milrinone therapy. Tachyphylaxis is unusual with this agent. Milrinone has a long half-life and should be used cautiously in patients with hypotension. This drug is primarily excreted in the urine, so concentrations can increase in the presence of renal failure. We have observed severe hypotension and renal dysfunction precipitated by use of an angiotensin-converting enzyme inhibitor in a patient already on milrinone infusion. The addition of low-dose dobutamine (5-10 μg/kg/min) or epinephrine (dose 0.01-0.05 μg/kg/min) can help stabilize the critically ill child who is not responding adequately to milrinone therapy alone.

Nesiritide, a recombinant B-type natriuretic peptide, is now approved for treatment of acutely decompensated heart failure. Endogenous B-type natriuretic peptide is a cardiac hormone produced by the failing heart, and nesiritide is identical to the naturally occurring peptide. Nesiritide reduces preload and afterload, leading to increases in cardiac output/index without reflex tachycardia or direct inotropic effect. In addition, this drug promotes natriuresis and diuresis, and suppresses the renin-angiotensin axis and endogenous catecholamines. Although this drug has not been studied extensively in the pediatric age group, in our and others’ experiences, it has been found to be a safe and effective adjunctive therapy.^23,²⁴

Mechanical Support

Most patients waiting for transplantation who are on inotropic support do not remain hemodynamically stable indefinitely. Progressive end-organ dysfunction ensues, requiring escalation of support that includes multiple inotropic agents, in addition to respiratory and circulatory support. Mechanical circulatory support has become an important addition to the treatment armamentarium for the infant or child with decompensated heart failure and low cardiac output unresponsive to pharmacologic maneuvers.²⁵ Options include extracorporeal membrane oxygenation (ECMO), intra-aortic balloon, and left and right ventricular assist devices. Experience with ECMO as a bridge to heart transplantation has been reported by several pediatric transplant centers.^26,²⁷ ECMO support can be used for 2 to 3 weeks without major complications from bleeding or infection, extending the window for donor organ availability. Isolated ventricular support devices, such as the Thoratec, Berlin Heart,²⁸ and DeBakey centrifugal pump, are now available for children.^29,³⁰ The Berlin Heart EXCOR has become the primary extrcorporeal circulatory device in infants and children. The current data from Berlin Heart show there have been a total of 698 patients supported for more than 47,000 days with this pneumatic-driven device (personal communication, Berlin Heart). The longest time of support in an individual patient was 902 days, with an average of 68 days of support before transplantation, explant, or death. The pediatric demography is that this device is used for all pediatric age ranges, but the mean age of 5 years and the median age of 2 years reflect the benefit in small children because of the availability of a pump size that can deliver 10-mL stroke volume. Actuarial survival of patients at 1 year who have been bridged to heart transplant or explanted now exceeds 80% (personal communication, Berlin Heart). In the past, use of these devices had always been considered extraordinary and usually proposed in patients with severe end-organ dysfunction. Placement of a device in a patient with multisystem organ failure usually results in a poor outcome. We propose that these devices be placed early, before end-organ dysfunction; doing so will enable rehabilitation of the patient, who then becomes a more optimal candidate for organ transplantation.