Specific topics for evaluation.
Despite advances in medical management, patients submitted for heart transplantation procedures still are at risk to development of complications. This chapter will discuss some specific topics of pediatric heart transplantation, focusing on perioperative care: (i) recipient management, (ii) donor evaluation, (iii) immunosuppression, (iv) early postoperative management, (v) complications, and (vi) conclusions.
- heart transplantation
- perioperative period
- heart failure
- mechanical circulatory support
Heart transplantation (HT) has been the therapeutic option for patients with complex congenital heart disease and cardiomyopathies with heart failure (HF) refractory to conventional treatment [1, 2, 3, 4].
Despite advances in molecular biology, immunosuppressive drug therapy, the knowledge of the potential complications that may occur after the procedure are essential to improve the quality of life of patients and their survival.
In this chapter we will discuss:
Early postoperative management
2. Recipient management
The main types of pediatric heart diseases considered for heart transplantation are :
congenital heart diseases with or without ventricular dysfunction and/or in natural history evolution that do not present the possibility of a new therapeutic intervention;
patients undergoing heart transplantation due to graft vascular disease, rejection and/or graft failure.
The clinical manifestations of heart failure in children vary according to age of the patient and severity of disease. In infants, the most common signs and symptoms are poor weight gain, tachypnea and diaphoresis during feeding and fatigability. Young children may present abdominal pain, vomiting, nausea, poor appetite, fatigability, recurrent cough and failure to thrive. In adolescents, abdominal pain, anorexia, exercise intolerance, dyspnea, oedema or syncope may be found. Nowadays, heart failure in children can be classified and categorize of the stage and severity by the modified NYHA, stages of heart failure infants and children and recommended therapy (stage A, B, C and D), modified Ross classification and by INTERMACS, which can help in decision making. The INTERMACS classification was initially developed to consider the patient for mechanical circulatory support [5, 6, 7, 8]. Pediatric patients with stage D heart failure are listed for heart transplantation [1, 6].
The clinical status of patient: if the patient is in the intensive care unit receiving drugs with continuous infusions such as phosphodiesterase 3 (PDE3) inhibitors (milrinone) or epinephrine and anti-congestive medications; if the patient is with ventricular assist device or if the patient is at outpatient clinics.
The clinical status will determine if the patient is in priority or not for heart transplantation when listed;
The type of anti-congestive medications for heart failure: diuretics, drugs that reduce afterload (angiotensin-converting enzyme inhibitors), ivabradine, sacubitril/valsartan and beta-blockers (metoprolol succinate and carvedilol) for improvement of symptoms and reduction of cardiac work;
Pulmonary vascular resistance index (PVRI): children who are candidates for heart transplantation and who present a high pulmonary vascular resistance index should be considered for the use of pulmonary vasodilators inhaled and intravenous (nitric oxide, prostacyclins, nitroprusside and milrinone). Prolonged use of inotropic agents may reduce pulmonary resistance to pulmonary vascular resistance índex < 6 Woods units/m2 or transpulmonary gradient < 15 mmHg. Patients with pulmonary hypertension are refractory to medical therapy can be a candidate for mechanical assist devices to try to reduce the PVRI;
Nutritional assessment and support must be performed so that the patient can be adequately prepared for the surgical procedure and its recovery. Moderate to severe wasting and elevated weight/height are considered a risk for mortality during the waitlist. The restriction of fluids and sodium is part of the recommendations in the treatment of HF.
Physical rehabilitation: a physical rehabilitation regimen should also be part of the treatment;
Anticoagulation: children with severe ventricular dysfunction are at risk of thrombus formation therefore anticoagulation or anti-platelet aggregation should be considered if the patient has previous history of thrombus.
Immunizations: immunizations must be carried out according to the vaccination schedule.
Frailty is one of the major concerns due to chronic heart failure and is considered a prognostic factor of morbidity and mortality;
Pre-transplant specific assessments are in Table 1. They are performed according to the patient’s history and clinical conditions.
Laboratory tests for initial evaluation for heart transplantation are in Table 2. HLA antibody level greater than 70% is considered high and may compromise short- and medium-term survival outcomes after transplantation.
The assessment of the multidisciplinary team is fundamental for the success of long-term follow-up. The multidisciplinary team including nurse, psychologist, social worker, physiotherapist, dentist and nutritionist provides information about the patient as well as the family’s suitability for the transplant procedure. Psychosocial support is vital when the child becomes a candidate for heart transplantation, as there is a need to restructure the family routine as a result of outpatient follow-up.
|Mechanical assist device|
|Magnetic cardiac resonance|
Mechanical circulatory support has been an option for children with refractory heart failure.
ECMO in children should be considered to provide adequate systemic perfusion and oxygenation for myocardial recovery after cardiopulmonary bypass or in patients as a bridge for heart transplantation and considered for long-term mechanical circulatory support (MCS). The use of ventricular assist device (VAD) has been increased for bridge to heart transplantation, decision or destination. The type of VAD depends on the weight, body superface área and pulmonary hypertension. In general, infants are candidates for paracorporeal MCS and adolescents for implanted ones. The prevalence of children waiting for heart transplantation with MCS has been increased in the last years (Table 3).
|Complete blood count|
|Liver and kidney profile|
|Albumin and total proteins|
|BNP and pro-BNP|
|Parasitological examination of faeces|
|Serology for infections such as hepatitis, HIV, toxoplasmosis, Epstein-Barr virus, Chagas disease, PCR for CMV and EBV|
|Panel reactive antibody percentage: magnitude of sensitization of the pre-transplant patient (immune panel) with HLA typing|
3. Donor assessment
The potential donor must be evaluated in relation to the recipient. The topics for donor evaluation in children are in Table 4. Pre-existing cardiac anomalies such as coronary artery disease, valve anomalies, left ventricular hypertrophy, donor cardiac function, donor-recipient size matching should be addressed before accepting the potential donor.
|Weight and height|
|Determination of cause of death|
|Past medical history|
|Serology for infections such as hepatitis, HIV, toxoplasmosis, Epstein-Barr virus, Chagas disease, PCR for CMV and EBV|
Recently, ISHLT Pediatric Consensus (DOAM) describes the principal recommendations for acceptance of the pediatric donor .
Donation after Circulatory Death (DCD) should be performed in centres with experience in marginal donor hearts, perioperative mechanical support, the use of ex-situ organ perfusion devices for preservation and transportation.
ABO-incompatible heart transplant procedure has been performed in children in some centres with results similar to ABO compatible due to the scarcity of donors.
Induction therapy can be defined as prophylactic immunosuppressive therapy in the perioperative period, usually with cytolytic agents, to reduce the incidence of early rejection (Table 5). Nowadays, the use of induction therapy has increased and is not associated with an increase in infection and malignancy .
|1. Calcineurin inhibitors|
|2. Antiproliferative regimen:|
|4. Proliferation signal inhibitors|
Different classes of drugs are used for initial and maintenance immunosuppression in children.
The most used initial regimens are composed of the association of corticosteroids, calcineurin inhibitors and antiproliferative agents (Table 5).
The use of tacrolimus as a calcineurin inhibitor and the replacement of Azathioprine as an antiproliferative agent with mycophenolate is the current trend in most centres worldwide.
Proliferation signal inhibitors (everolimus and sirolimus) are used in renal failure, graft vascular disease and lymphoproliferative disease in combination with a calcineurin inhibitor or in monotherapy (Table 5).
In children, it is important to address the avoidance of steroids as maintenance drug therapy due to failure to adequate height development.
5. Perioperative management
|Systemic blood pressure|
|Central venous pressure|
|Pulmonary artery wedge pressure|
|Arterial oxygen saturation|
|Mixed venous saturation|
|Vital signs (temperature, heart rate, respiratory rate)|
In perioperative period, the main complications of transplantation can be inherent to transplantation, such as early graft dysfunction, right ventricular dysfunction, hyperacute rejection as well as due to the immunosuppressive medication itself: infection, systemic arterial hypertension and renal failure (Tables 7 and 8). In the late postoperative period, coronary allograft vasculopathy, tumour, primary graft dysfunction are some causes of long-term complications.
|Tricuspid valve regurgitation|
|Right ventricular dysfunction|
|Mechanical circulatory support|
|Early allograft dysfunction|
Rejection has been reported as the main cause of death after transplantation. The diagnosis of rejection is made by a combination of clinical signs and symptoms, non-invasive tests and/or endomyocardial biopsy, using the International Society of Cardiac and Lung Transplantation (ISHLT) criteria . Several noninvasive methods have been reported such as echocardiography, cardiac magnetic resonance, electrocardiogram, Gallium-67 as well as biomarkers of injury or immunoreactivity such as BNP, troponin and donor-specific antibodies (DSA) for rejection surveillance in pediatric heart transplantation. These non-invasive methods have been described as high degree of specificity and low sensitivity and are useful for identifying those without rejection episodes. Therefore, endomyocardial biopsy is still the gold standard for rejection although there are risks related to the procedure such as venous occlusion, radiation and perforation.
6.1 Rejection treatment
Treatment of rejection should be directed towards the underlying aetiology, as well as the severity of the condition based on clinical, laboratory and pathological findings.
6.2 Acute cellular rejection
Mild and asymptomatic (1R)—does not require treatment due to the high rate of spontaneous resolution and the absence of association with reduced long-term survival and graft vascular disease.
Moderate and severe cell rejection (ISHLT ≥ 2R) (Figure 3)—should be treated with enhanced immunosuppression. If a patient with signs of ventricular dysfunction and needs vasoactive drugs, methylprednisolone therapy and anti-thymocyte globulin association is recommended. MCS should be considered if there is hemodynamic instability.
6.3 Humoral rejection
It includes the same schemes used to treat cell rejection, with high doses of corticosteroids and lymphocytolytic agents. Additionally, intravenous immunoglobulin and plasmapheresis to remove circulating antibodies and specific therapies to target B cells (cyclophosphamide, mycophenolate and rituximab) can be used (Figure 4).
Heart transplantation is an option for refractory heart failure in children with cardiomyopathies and complex heart diseases. It is a highly complex clinical-surgical therapy that involves a specialized multidisciplinary team so that child care can be performed successfully. Nowadays, the Pediatric Heart Transplantation Society (PHTS) has developed a database where clinical trials and robust research have been performed for the best care of this fragile pediatric population.
Dr. Luiz Benvenuti from the Pathology Department for the pictures of rejection.
Kirk R, Dipchand AI, Rosenthal DN, et al. The International Society for Heart and Lung Transplantation Guidelines for the management of pediatric heart failure: Executive summary. The Journal of Heart and Lung Transplantation. 2014; 33(9):888-909
Lipshultz SE, Law YM, Asante-Korang A, et al. Cardiomyopathy in children: Classification and diagnosis: A scientific statement from the American Heart Association. Circulation. 2019; 140. CIR000682
Law YM, Lal AK, Chen S, et al. Diagnosis and management of myocarditis in children: A Scientific Statement from the American Heart Association. Circulation. 2021; 144(6):e123-e135
Roeleveld PP, Axelrod DM, Klugman D, et al. Hypoplastic left heart syndrome: From fetus to fontan. Cardiology in the Young. 2018; 28(11):1275-1288
Ross RD. The Rossclassification for heart failure in children after 25 years: A review and an age-stratified revision. Pediatric Cardiology. 2012; 33(8):1295-1300. DOI: 10.1007/s00246-012-0306-8
Rosenthal D, Chrisant MR, Edens E, et al. International Society for Heart and Lung Transplantation: Practice guidelines for management of heart failure in children. The Journal of Heart and Lung Transplantation. 2004; 23:1313-1333
Morales DLS, Rossano JW, VanderPluym C, et al. Third Annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) Report: Preimplant Characteristics and Outcomes. The Annals of Thoracic Surgery. 2019; 107(4):993-1004
Baumgartner H, DeBacker J, Babu-Narayan SV, et al. 2020 ESC guidelines for the management ofadult congenital heart disease. European Heart Journal. 2020; 00:1-83
Kirk R, Dipchand AI, Davies RR, et al. ISHLT consensus statement on donor organ acceptability and management in pediatric heart transplantation. The Journal of Heart and Lung Transplantation. 2020; 39(4):331-341
Daly KP. Contemporary transplantation immunosuppression: Balancing on the immunosuppression seesaw. Pediatric Transplantation; 13:52
Azeka E, Auler JO Jr, Marcial MB, et al. Heart transplantation in children: Clinical outcome during the early postoperative period. Pediatric Transplantation. 2005; 9(4):491-497
Gajarski R, Blume ED, Urschel S, et al. Infection and malignancy after pediatric heart transplantation: The role of induction therapy. The Journal of Heart and Lung Transplantation. 2011; 30(3):299-308
Mowers KL, Simpson KE, Gazit AZ, et al. Moderate-severe primary graft dysfunction after pediatric heart transplantation. Pediatric Transplantation. 2019; 23(2):e13340
Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. The Journal of Heart and Lung Transplantation. 2005; 24(11):1710-1720
Dipchand AI, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: Seventeenth official pediatric heart transplantation report--2014; focus theme: Retransplantation. The Journal of Heart and Lung Transplantation. 2014; 33(10):985-995
L’Huillier AG, Dipchand AI, Ng VL, et al. Posttransplant lymphoproliferative disorder in pediatric patients: Survival rates according to primary sites of occurrence and a proposed clinical categorization. American Journal of Transplantation. 2019