The first transplantation of a human heart was performed in South Africa in 1966. 1 By the end of the 1970s, transplantation was established as an effective therapy for end-stage cardiac failure. Over the next 25 years, improvements in donation and preservation of organs, selection of patients, post-operative management, and treatment of rejection have resulted in improved survival following transplantation in both adults and children. Consequently, orthotopic transplantation of the heart is now widely accepted as an important part of management for infants and children with severe forms of congenital cardiac disease and cardiomyopathy.
PATTERNS OF REFERRAL AND DEMOGRAPHICS OF TRANSPLANTATION OF THE HEART DURING CHILDHOOD
The factors affecting referral and listing of patients for cardiac transplantation are complex, but will include the availability and outcomes of alternative surgical strategies, availability of specific expertise, the patterns of referral to an individual centre, as well as societal and individual beliefs. Analysis of the natural history and outcomes must take all these factors into account. Besides reports from single centres, there are two main sources of data on outcomes for children following listing for transplantation and subsequent to transplantation. The registry of the International Society of Heart and Lung Transplantation 2 is an international registry, to which referral is voluntary except in the United States of America, where federal mandate requires all data from the United Network of Organ Sharing to be shared with the database of the International Society. The second source is the Pediatric Heart Transplant Study, a voluntary, research-based and event-driven multi-centric registry. It was established in 1993 in order to capture data relative to outcomes 3 from the Pediatric Heart Transplant Study. This source currently includes 3454 patients listed for transplantation, of whom 2452 patients underwent transplantation between January 1, 1993, and December 31, 2007. The data is supplied by 33 centres within North America and the United Kingdom.
According to the 10th annual report 2 of the International Society of Heart and Lung Transplantation registry, presented in 2007, the number of transplantations in children performed each year has remained stable, at approximately 375 to 400, since the mid-1990s, as has the distribution of ages ( Figs. 16-1 and 16-2 ). Geographical differences exist worldwide. For example, teenagers account for half of the recipients in Europe and other areas of the world, whereas in North America more infants undergo transplantation ( Fig. 16-3 ).
The underlying diagnoses prior to transplantation have changed over time. In infants younger than 1 year of age, congenital cardiac disease has remained the commonest underlying diagnosis, though the proportion of infant recipients with cardiomyopathy has almost doubled over time, increasing from one-sixth to one-third ( Fig. 16-4 ). Cardiomyopathy remains the main diagnosis amongst those aged from 1 to 10 years and amongst adolescents ( Figs. 16-5 and 16-6 ). Indications for transplantation also show geographic variation, with congenital cardiac disease and retransplantation both more common in North America compared with Europe ( Fig. 16-7 ). 2
OUTCOMES
Overall Survival
Overall survival for children listed for heart transplantation, including deaths prior to and after transplantation, as listed in the Pediatric Heart Transplant Study is 74%, 66%, and 59% at 1, 5, and 10 years respectively. 4 Overall survival from the time of listing is higher for patients with a diagnosis of cardiomyopathy compared to those with congenitally malformed hearts ( Fig. 16-8 ). 5 There is an effect of era, with improved survival at all times after listing in the period from 2003 through 2006 ( Fig. 16-9 ). 4
Mortality while Awaiting Transplantation
Death whilst waiting for transplantation reflects a combination of availability of donor organs, the medical state of the recipient, the underlying diagnosis, and the blood group. While modifying availability of organs is difficult, knowledge of the other factors that influence mortality during the period of waiting plays an important role in decision-making regarding appropriate timing for listing a patient for transplantation.
Data from the Pediatric Heart Transplant Study for the period between 1993 and 2006 demonstrates mortality for all listed patients whilst waiting of 17% at 1 year. 4 Unsurprisingly, mortality during the period of waiting varies according to the state of the patient, with those listed at level 1A in the system used by the United Network for Organ Sharing having a mortality of 21%, compared to 7% for those listed as level 1B or 2. 4 A diagnosis of cardiomyopathy carries a lower mortality during this period of waiting than do other diagnoses ( Fig. 16-10 ). 5 Blood group O, in contrast, has been associated with a higher risk of death. 6 The mortality for infants during the period of waiting, at from 25% to 30%, has consistently been higher than that reported for older patients. 7-9
Survival after Transplantation
Data from the registry of the International Society of Heart and Lung Transplantation shows that survival after transplantation in the most recent era is 80%, 68%, and 58% for 1, 5, and 10 years respectively. 2 The survival after 20 years, while clearly reflecting transplantation during an earlier era, is 40% ( Fig. 16-11 ). 2 Looked at a different way, the same data shows a half-life for transplantation, defined as the time to 50% survival without death or retransplantation, of 15.8 years for those aged less than 1 year at transplantation, 14.2 years for those aged from 1 to 10 years, and 11.4 years for those older than 11 years. These differences are even more marked when conditional survival is examined, excluding mortality related to the procedure itself ( Figs. 16-12 and 16-13 ). Infants and neonates are relatively protected from later complications, while adolescents, who have lower mortality over the short term, are at increased risk of death or the need for retransplantation during long-term follow-up. Data from the Pediatric Heart Transplant Study is similar, showing that overall survival is generally good, with survival at 1 and 5 years of 85% and 75%. 4
When survival is analysed by era, significant improvements are revealed in the results of transplantation of the heart during childhood, primarily related to a reduction in mortality immediately subsequent to transplantation ( Fig. 16-14 ). Conditional survival for the different age groups within the period from 1999 through 2005 amplifies the difference between infants and adolescents, with infants having a conditional survival at 6 years of greater than 85%, while that of adolescents is approximately 65% ( Fig. 16-15 ).
The diagnosis before transplantation also modifies survival. There is a significantly higher early mortality for patients with congenitally malformed hearts, compared to those transplanted for cardiomyopathy (see Fig. 16-8 ), with a recent analysis of patients transplanted for dilated cardiomyopathy showing an overall survival of 73% at 10 years. 5
Risk Factors for Death
The risk factors for death in the first year following transplantation of the heart during childhood are outlined in Table 16-1 . They include a diagnosis of congenital cardiac disease, need for extracorporeal mechanical support, mechanical ventilation before transplantation, and retransplantation. 2 Risk factors for mortality during the first 5 years are similar ( Table 16-2 ), but female gender of both the recipient and the donor become additional risk factors. 2
| Variable | N | Relative Risk | P Value | 95% Confidence Interval |
|---|---|---|---|---|
| Congenital diagnosis, age = 0, on ECMO | 51 | 5.66 | <0.0001 | 3.54–9.06 |
| Congenital diagnosis, age >0, on ECMO | 48 | 4.30 | <0.0001 | 2.58–7.14 |
| Congenital diagnosis, age >0, no ECMO | 710 | 2.23 | <0.0001 | 1.70–2.91 |
| Congenital diagnosis, age = 0, on PGE | 201 | 2.12 | 0.0003 | 1.40–3.20 |
| Retransplant | 179 | 1.91 | 0.0029 | 1.25–2.92 |
| Congenital diagnosis, age = 0, no PGE or ECMO | 336 | 1.90 | 0.0004 | 1.33–2.70 |
| On ventilator | 581 | 1.45 | 0.0033 | 1.13–1.87 |
| Year of transplant: 1995–1996 vs. 1999–2000 | 547 | 1.43 | 0.0191 | 1.06–1.94 |
| Variable | N | Relative Risk | P value | 95% Confidence Interval |
|---|---|---|---|---|
| Congenital diagnosis, age = 0, ECMO | 21 | 3.11 | 0.0020 | 1.51–6.39 |
| Congenital diagnosis, age >0, ECMO | 23 | 2.72 | 0.0127 | 1.24–5.96 |
| Congenital diagnosis, age >0, no ECMO | 434 | 2.30 | <0.0001 | 1.66–3.18 |
| Retransplant | 104 | 2.17 | 0.0062 | 1.25–3.77 |
| Ventilator | 311 | 1.59 | 0.0026 | 1.18–2.16 |
| Hospitalized (including ICU) | 1224 | 1.49 | 0.0108 | 1.10–2.03 |
| Year of transplant: 1995–1996 vs. 1999–6/2001 | 547 | 1.43 | 0.0139 | 1.08–1.91 |
| Female recipient | 808 | 1.27 | 0.0489 | 1.00–1.62 |
| Female donor | 800 | 1.27 | 0.0494 | 1.00–1.60 |
Causes of Death
The causes of death reported to International Society of Heart and Lung Transplantation registry, stratified by time after transplantation, are summarised in Table 16-3 . 2 Similarly, the data from the Pediatric Heart Transplantation Study, outlining the causes and proportions of deaths within the first 5 years after transplantation, are summarised in Table 16-4 . Rejection, infection, failure of the primary graft, and sudden cardiac death are the major causes of death in children within the first 5 years. 10–12 Graft vasculopathy remains the leading cause of death in the longer term. This, combined with failure of the graft and acute rejection, accounted for about seven-tenths of deaths between 5 and 10 years after transplantation.
| Cause of Death | 0– 30 Days ( N = 164) | 31 Days– 1 Year ( N = 159) | >1–3 Years ( N = 144) | >3–5 Years ( N = 104) | >5–10 Years ( N = 184) | >10 Years ( N = 96) |
|---|---|---|---|---|---|---|
| CAV | 1 (0.6%) | 11 (6.9%) | 25 (17.4%) | 36 (34.6%) | 56 (30.4%) | 30 (31.3%) |
| Acute rejection | 19 (11.6%) | 30 (18.9%) | 32 (22.2%) | 14 (13.5%) | 27 (14.7%) | 7 (7.3%) |
| Lymphoma | 3 (1.9%) | 6 (4.2%) | 2 (1.9%) | 19 (10.3%) | 6 (6.3%) | |
| Malignancy, other | 1 (0.6%) | 1 (0.7%) | 2 (1.1%) | 6 (6.3%) | ||
| CMV | 3 (1.9%) | 1 (0.7%) | ||||
| Infection, non-CMV | 24 (14.6%) | 22 (13.8%) | 8 (5.6%) | 2 (1.9%) | 12 (6.5%) | 8 (8.3%) |
| Primary failure | 30 (18.3%) | 5 (3.1%) | 4 (2.8%) | 3 (2.9%) | 5 (2.7%) | 2 (2.1%) |
| Graft failure | 29 (17.7%) | 15 (9.4%) | 30 (20.8%) | 30 (28.8%) | 38 (20.7%) | 23 (24.0%) |
| Technical | 8 (4.9%) | 2 (1.4%) | 2 (1.1%) | |||
| Other | 14 (8.5%) | 10 (6.3%) | 16 (11.1%) | 9 (8.7%) | 14 (7.6%) | 2 (2.1%) |
| Multiple organ failure | 20 (12.2%) | 31 (19.5%) | 6 (4.2%) | 2 (1.9%) | 3 (1.6%) | 6 (6.3%) |
| Renal failure | 5 (3.1%) | 1 (0.7%) | 1 (1.0%) | |||
| Pulmonary | 8 (4.9%) | 17 (10.7%) | 8 (5.6%) | 6 (5.8%) | 3 (1.6%) | 5 (5.2%) |
| Cerebrovascular | 11 (6.7%) | 6 (3.8%) | 4 (2.8%) | 3 (1.6%) |
| PROBABILITY (%) OF DEATH | |||||||
|---|---|---|---|---|---|---|---|
| 0–5 yr | 0–6 mo | 7–12 mo | 2nd yr | 3rd yr | 4th yr | 5th yr | |
| Early graft failure | 4.7 | 4.7 | 0 | 0 | 0 | 0 | 0 |
| Rejection | 6.6 | 1.8 | 0.6 | 1.1 | 1.1 | 1 | 1 |
| Infection | 5.4 | 3.3 | 0.5 | 0.4 | 0.4 | 0.4 | 0.4 |
| Sudden death | 4.2 | 1.7 | 0.4 | 0.6 | 0.5 | 0.5 | 0.5 |
| Nonspecific graft failure | 2.4 | 0.3 | 0.3 | 0.5 | 0.5 | 0.5 | 0.4 |
| Malignancy | 1.2 | 0.1 | 0.1 | 0.2 | 0.2 | 0.2 | 0.2 |
| Coronary artery disease | 2.1 | 0.2 | 0.2 | 0.4 | 0.4 | 0.4 | 0.4 |
| Other | 2.6 | 1.9 | 0.3 | 0.2 | 0.1 | 0.1 | 0 |
| Total | 29.2 | 14.1 | 2.4 | 3.5 | 3.2 | 3.1 | 2.9 |
INDICATIONS AND CONTRAINDICATIONS TO TRANSPLANTATION
Assessment Prior to Transplantation
Careful assessment prior to transplantation is required in order, first, to identify indications for transplantation, second, to identify potentially reversible causes of end-stage heart failure and optimise management, and third, to identify confounding factors or contraindications that may preclude candidacy for transplantation. The general components required for a comprehensive assessment prior to transplantation are outlined in Box 16-1 . In addition to the assessment of the heart, consultation from an interdisciplinary team, including social workers, psychiatrists, physiotherapists, occupational therapists, specialists in adolescent medicine, and key medical services including nephrology and anaesthesia, are critical to the process. For example, renal and/or hepatic dysfunction has been associated with a reduction in intermediate and long-term survival, and must therefore be integrated into the assessment of risk for child and parents. Psychosocial assessment of the entire family is paramount. This is especially important when assessing adolescents, given the increasing awareness of the impact of non-compliance and risk-taking behaviours on survival of both the graft and the patient. 13
- •
Echocardiogram
- •
Cardiac catheterisation (haemodynamics, anatomy)
- •
MRI/MRA or CT angiography (anatomy)
- •
Exercise test
- •
Vascular ultrasound
- •
Blood group
- •
HLA antibody testing
- •
Chemistry
- •
Renal function
- •
Liver function
- •
Lipid profile
- •
Immunoglobulins
- •
- •
Haematology
- •
Infectious serologies
Indications
There are no absolute indications for transplantation of the heart during childhood given the wide variability in cardiac diagnoses and pathophysiology. Indications can be broadly divided into two groups, either life-saving ( Box 16-2 ) or life-enhancing. Life-enhancing indications include treatment of excessive disability, unacceptably poor quality of life, usually in the setting of poor myocardial function, complex unoperated congenital cardiac disease, and failed surgical treatment.
- •
End-stage myocardial failure due to
- •
Cardiomyopathies or myocarditis
- •
Congenital heart disease
- •
Post-cardiotomy heart failure
- •
Malignant arrhythmias refractory to medical therapy
- •
Complex congenital heart disease with no options for surgical palliation at an acceptable risk
- •
Unresectable cardiac tumours causing obstruction or ventricular dysfunction (systolic or diastolic)
- •
- •
Unresectable ventricular diverticula
Guidelines for listing adults for cardiac transplantation, based on a comparatively uniform population with cardiac failure and a predictable natural history, have been published by both the American Society of Transplantation 14 and the Canadian Cardiovascular Society. 1 They have limited applicability to transplantation during childhood. Specific guidelines are being developed for the populations of children and adults with congenitally malformed hearts. These strive to identify patients who are at the greatest risk of dying, and who will derive the greatest benefit from transplantation. There are two published consensus reports on the listing of children for cardiac transplantation, but these are predominantly based on the opinions of experts, and their recommendations remain the subject of debate. 15,16
Contraindications
The contraindications to transplantation of the heart during childhood included fixed pulmonary hypertension, pulmonary venous atresia or progressive stenosis, and severe hypoplasia of the pulmonary arteries or the thoracic aorta. Other contraindications include irreversible failure of multiple organs, a progressive systemic disease with early mortality independent of cardiac function, active infection, malignancy, multi-specific and high sensitisation to HLA antigens, morbid obesity, diabetes mellitus with end-organ damage, hypercoagulable states, and severe chromosomal, neurological, or syndromic abnormalities. Complicating factors that are no longer considered contraindications to cardiac transplantation include complex congenital cardiac disease, such as abnormalities of atrial arrangement, systemic venous abnormalities, anomalous pulmonary venous drainage without stenosis, and some pulmonary arterial anomalies, previous sternotomy or thoracotomy, reversible pulmonary hypertension, more minor non-cardiac congenital abnormalities, kyphoscoliosis with restrictive pulmonary disease, non-progressive or slowly progressive systemic diseases with life expectancies into the third or fourth decade such as genetic or metabolic cardiomyopathies, and diabetes mellitus without end-organ damage.
Elevated pulmonary vascular resistance is an independent risk factor for death both early and late after transplantation. 17,18 The threshold which precludes transplantation is ill-defined, as there is a continuum of increasing risk as pulmonary vascular resistance rises. By convention, a pulmonary vascular resistance of greater than 6 Wood units per meter squared has been considered a contraindication. Intermediate outcomes have been reported nonetheless, for children with pulmonary vascular resistances greater than 6 Wood units, with mortality of 12% and a fall in resistance to less than 4 Wood units when assessed 10 days after transplantation. 18 In another experience, however, one-third of patients with resistances greater than 6 Wood units developed right ventricular failure, with mortality of 15%, with no patient having a resistance less than 6 Wood units developing right ventricular failure. 19 Despite these problems, five-sixths of patients with pulmonary vascular resistances greater than 6 and an indexed pulmonary vascular resistance greater than 9 were successfully transplanted. Both these studies concluded that it is the reactivity of the vascular bed, as opposed to the absolute measure of resistance, which is correlated with outcome. There is a role, therefore, for testing pulmonary vasoreactivity as part of the assessment prior to transplantation.
Accurate assessment of pulmonary vascular resistance and/or vasoreactivity with any diagnosis of functionally univentricular physiology, some complex malformations with variable sources of flow of blood to the lungs, or restrictive cardiomyopathy, nonetheless, may be challenging if not impossible, albeit that the risk of pulmonary hypertension and/or right-sided cardiac failure after transplantation in the population of infants with functionally univentricular hearts is low. 20 Timing of listing with a diagnosis of restrictive cardiomyopathy remains controversial. The most recent guidelines recommend listing at, or shortly after, the time of diagnosis due to the limited effect of medical therapies, and concern about the development of a non-reactive pulmonary vascular bed. 16
SPECIAL CONSIDERATIONS
Neonatal Advantage and ABO-incompatible Transplantation
The published data from the registries, and specific institutional experience, increasingly show advantages to successful neonatal transplantation. 2,21,22 As outlined above, there is consistent evidence from survival curves that infants transplanted at an age of less than 6 months have improved survival when assessed up to 10 years after transplantation in comparison with older age groups (see Figs. 16-11 to 16-13 ). The reports from the Pediatric Heart Transplant Study show lower rates of rejection and graft vasculopathy in the population of infants. 23,24 Furthermore, data from Loma Linda University Medical Center shows that infants with hypoplastic left heart syndrome, transplanted at less than 1 month of age have a higher survival rate, 77% at 10 years, and less graft loss, than infants transplanted from 1 to 6 months of age, only 54% of this latter group surviving at 10 years. 21,22 The biggest challenge to transplantation during neonatal and infant life remains the availability of donors, which has not changed appreciably over the last decade. Consequently, strategies are being developed to expand the donor pool, or improve utilisation of available organs, one example of which is ABO-incompatible transplantation.
Such transplantation between donors and recipients incompatible for their major blood groups is usually contraindicated because of a high risk of hyperacute rejection mediated via activation of complement. Newborn infants, however, do not produce the isohemagglutinins responsible for the blood groups, and their complement system is not fully developed. It has now been shown heart transplantation across ABO blood groups is possible during infancy, reflecting the immaturity of the infant immune system or even representing the first human example of immune tolerance. 25 An advantage of such transplantation is a reduction in deaths during the period of waiting. In an analysis of risk factors relative to the strategy of listing, failure to list for an ABO-incompatible graft and high clinical status emerged as the only factors associated with mortality. 26 A strategy to accept ABO-incompatible hearts from donors for transplantation into infants significantly improved the likelihood of transplantation and reduced deaths whilst waiting, at the same time not adversely altering outcomes.
A report has now been compiled of the follow-up over 10 years of the largest cohort of recipients of ABO-incompatible transplantations. 27 Survival, the incidence of rejection, graft vasculopathy, and development of lymphoproliferative disorders subsequent to transplantation were no different from the ABO-compatible population followed in the same institution ( Table 16-5 ). It remains to be proven whether there are immunological advantages such as tolerance or accommodation of the graft, but ABO-incompatible transplantation for infants is increasingly being adopted in centres worldwide. The optimal selection criterions for suitability for ABO-incompatible transplantation remain ill defined. In general, the younger the patient the better, but successful transplantation has been performed in recipients as old as 3 years. Antibody-mediated rejection has been reported, with titres of antibodies as low as 1 to 8, while there are reports of rejection-free survival with titres as high as 1 to 128. 28 Assessment should be made by a cardiologist experienced in ABO-incompatible transplantation on an individual basis, taking into account age, blood group, isohaemagglutinin titres, and clinical state.
| ABO-I ( N = 35) | ABO-C ( N = 45) | |
|---|---|---|
| Actuarial survival–1 yr | 81% | 80% |
| Actuarial survival–7 yr | 75% | 74% |
| EBV disease or PTLD | 4 (11%) | 5 (11%) |
| Graft vasculopathy | 4 (11%) | 5 (11%) |
| Mild | 2 | 1 |
| Severe | 2 | 4 |
| Wait-time (median) | 25 days | 26 days |
HLA Sensitisation
Screening panel reactive antibody testing is performed on patients prior to transplantation in an effort to identify the potential presence of anti-HLA antibodies and minimise the risk of antibody-mediated rejection. High panel reactive antibody titres, greater than 10%, are associated with an increased incidence of rejection and reduced survival. 29,30 Common sensitizing events in children include repair of congenitally malformed hearts, specifically those achieved using homograft material, 31 and the use of ventricular assist devices. 32 There are many reports of transplantation in highly sensitised patients, nonetheless, and/or across a positive crossmatch, with reasonable results over the intermediate term. 28 A variety of strategies have been used to lower the titres of antibodies, and/or manage the rejection in sensitised patients. A detailed discussion is beyond the scope of this chapter, but most protocols include plasmapheresis immediately before and after transplantation with, variably, the use of intravenous immunoglobulin, rituximab, cyclophosphamide, and treatment with antimetabolites. 28,33,34
Mechanical Support as a Bridge to Transplantation
Mechanical circulatory support is increasingly being used as a bridge to transplantation ( Fig. 16-16 ). 35 Indications for such support continue to evolve as the availability of devices changes. In general, mechanical support should be considered when low cardiac output results in end-organ dysfunction despite maximal medical therapy. The mainstay for support in children has been extracorporeal membrane oxygenation, 36–38 which can sustain up to three-fifths of children to transplantation. 39,40 In the experience at Toronto, the mean duration of mechanical support was 6 days, and almost four-fifths of patients survived to be discharged from hospital. 41 Higher levels of creatinine before and during extracorporeal oxygenation, fungal infection, and high exposure to blood products, were factors for poor outcome. Patients supported using extracorporeal membrane oxygenation may have successful outcomes despite circumstances that previously may have been considered relative contraindications, such as cardiac arrest, or systemic bacterial infections. The approach should still be viewed, nonetheless, as a short-term bridge to cardiac transplantation because of the time-related risks for complications, such as infection, bleeding, and impairment of end organs. Consequently, devices capable of providing assistance over a longer term are now replacing extracorporeal membrane oxygenation.
Ventricular assist devices, primarily developed for adults, have been used in adolescents and larger children, 35,42 and there is increasing experience with smaller devices 43 specifically designed for infants and children. As opposed to those receiving extracorporeal membrane oxygenation, patients supported with a ventricular assist device can usually be mobile and undergo physical and nutritional rehabilitation while awaiting transplantation. In a recent multi-centric review of outcomes, the median duration of support by ventricular assist device in children was 70 days, 35 with successful bridging in from two-thirds to four-fifths of patients. 35,42,43 As expected, results have improved with increasing experience ( Fig. 16-17 ), 35 but serious morbidity, including stroke, bleeding, and malfunction of the devices remain common, occurring in one-third of cases. Survival is lowest in those of younger age, and in those with congenitally malformed hearts ( Fig. 16-18 ). 35 The current devices require extracorporeal pumps and pumping consoles, making them rather cumbersome. There are several fully implantable devices in development with the aim of long-term support to bridge children to transplantation and/or recovery. 44
