Basics
Description
Cardiac transplantation has become a common and ever-expanding surgical option for children with end-stage heart disease. �
Epidemiology
- Children comprise 12.5% of total cardiac transplantations performed annually.
- About 1/2 of children receiving transplants in the past 10 yr were <5 yr.
General Prevention
Transplantation is a therapy of last resort when heart disease has become refractory to maximal medical therapy, and when no other surgical procedure can reasonably restore a productive life. �
Etiology
- The 2 main indications for transplantation in pediatrics are cardiomyopathies and complex congenital heart disease (CHD):
- Cardiomyopathy is the indication for transplantation in 64% of adolescent recipients.
- Retransplantation accounts for 5% of all pediatric heart transplants
- CHD: 10-20% of children with CHD might eventually benefit from transplantation in their lifetime; 3% of adult transplantations are now for CHD:
- Primary operation: For example, pulmonary atresia, with intact septum and coronary sinusoids
- Previous biventricular repairs: Poor function and/or valvar regurgitation when further repair too risky
- Palliated single ventricle: Failed Fontan procedure
- Death while waiting for transplantation still approaches 30% in children, secondary to lack of donors.
Associated Conditions
- Orthotopic cardiac transplantation relative contraindications include:
- Inadequate pulmonary arteries
- Degenerative neurologic disease
- Pulmonary HTN with pulmonary vascular resistance index >6 despite maximal therapy
- End-stage renal, hepatic, or pulmonary disease, unless listed for the concomitant failed organ
- Inability to obtain necessary medical care after transplantation
- Presensitization to Human Leukocyte Antigen (HLA) is associated with a higher likelihood of a positive cross-match and may potentially lead to an increased incidence of humoral rejection post-transplantation. Some programs would require a prospective cross-match. Presensitization is more commonly recognized in patients with:
- Homograft material from prior cardiac surgery
- Ventricular assist devices
- A history of multiple blood transfusions
Diagnosis
Signs and symptoms: �
- Rejection: Usually no significant cardiovascular symptoms, unless severe, presenting as heart failure and/or shock. Mild to moderate rejection may be accompanied by:
- Tachycardia or arrhythmia
- Gallop rhythm
- Enlarged tender liver
- Pericardial effusion
- Fever
- Malaise in older children, irritability in infants
- Abdominal complaints resembling gastroenteritis or "flu"�
- Graft vasculopathy: Usually presenting late, may occur within 1st yr; a form of chronic rejection; symptoms depend upon severity and distribution of coronary obliteration; patients will not experience angina; common signs are:
- CHF in absence of rejection
- CHF persisting following adequate rejection treatment
- Arrhythmia: Atrial, ventricular, or progressive heart block
- Syncope
- Sudden death
History
- Have immunosuppressants been weaned prior to symptoms?
- Elicit history of noncompliance with immunosuppressant medications.
- Has patient been vomiting medications routinely?
- Recent growth spurt resulting in inadequate immunosuppressant levels?
- History of multiple rejection episodes or refractory rejection.
Physical Exam
Varies according to severity of cardiac compromise but may include 3rd heart sound (S3) gallop rhythm, tachycardia, soft heart tones, rales, enlarged liver, poor perfusion and peripheral pulses �
Tests
- ECG: Usually shows sinus rhythm and residual nonconducted, native P waves from recipient sinus node; findings indicative of rejection or coronary disease may or may not be present, including:
- Tachycardia
- Atrial or ventricular arrhythmias or progressive heart block
- Low voltage
- Increase in QRS duration
- New Q waves or ST-segment changes
- Endomyocardial biopsy: Right heart catheterization with endomyocardial biopsy is used by many centers on a routine decremental schedule postoperatively to evaluate for acute rejection:
- Abnormal hemodynamics may be 1st indication of rejection or coronary disease.
- Tissue diagnosis of rejection, however, often seen with normal hemodynamics.
Lab
Common laboratory tests include monitoring of immunosuppressant levels, and potential toxic effects on bone marrow, kidney, and liver. �
Imaging
The cardiac evaluation of recipients may include: �
- CXR: A change in size of the cardiac silhouette may be the 1st objective evidence of rejection or pericardial effusion, particularly in long-term survivors. Hilar adenopathy can lead to suspicion of posttransplantation lymphoproliferative disease (PTLD).
- 2D echo: Function is usually normal in transplanted hearts unless rejection or severe coronary disease:
- Decreased fractional shortening
- Pericardial effusion
- New-onset myocardial hypertrophy or diastolic dysfunction
- Wall motion abnormalities
- Coronary angiograms: Serial angiograms are performed annually or biannually to evaluate graft vasculopathy. It is important to compare serial studies.
- Dobutamine stress echo: This modality is used to help define the presence of subtle graft vasculopathy not seen on angiography and to assess the functional severity of visible coronary disease.
Surgery
Serial cardiac catheterizations are required for myocardial biopsy, hemodynamics, and coronary angiography. �
Pathological Findings
- Cellular rejection is graded by presence and density of lymphocytic infiltrate in the myocardium with or without myocyte necrosis. Edema and hemorrhage can also be seen when severe.
- Humoral rejection usually lacks a cellular infiltrate but immunofluorescent antibody staining and complement fragment deposition can be seen in the myocardium, frequently associated with edema.
- Coronary disease consists of intimal hyperplasia in the vessels of the graft that can become obliterative.
Differential Diagnosis
The differential of complications in pediatric heart recipients relates to the cumulative side effects of immunosuppression or from ineffective immunosuppressive protection of the graft. Because symptoms are nonspecific, must differentiate between the most common major complications: �
- Rejection
- Infection
- Graft vasculopathy
- PTLD
- End-organ toxicity of immunosuppressants
Treatment
Medication
- Cardiac recipients are on multiple medications.
- Single-, double-, or triple-drug immunosuppression using combinations of:
- Cyclosporine
- Tacrolimus (FK506)
- Azathioprine
- Prednisone
- Mycophenolate mofetil
- Sirolimus
- Antihypertensive therapy (20-65%):
- Calcium channel blockers
- ACE inhibitors
- ARBs
- Possible beneficial effect of these three classes of antihypertensives in preventing graft vasculopathy.
- β-Blockers
- Cardiotonic therapy (digoxin, ACE inhibitors, diuretics) may be necessary transiently, at times following transplantation:
- During recovery from prolonged rejection
- CHF from coronary disease
- Perioperative right heart failure
- Lipid-altering drugs (statins) are used by some centers.
- 2 classes of drugs should be used with caution in transplant patients. Any liver-metabolized or long-acting medication can have profound effect on metabolism and levels of immunosuppressant drugs:
- Drugs cleared by, or affecting, the kidney: Immunosuppressants can potentiate the nephrotoxicity of commonly used medications.
- Drugs cleared by, or affecting, the kidney: Immunosuppressants can potentiate the nephrotoxicity of comm only used medications.
First Line
1st-line rejection treatment: �
Steroid boost, either IV or PO is the 1st-line treatment of rejection. Other strategies include: �
- Change main immunosuppressant drug or secondary drugs
Second Line
2nd-line rejection treatment: �
- Treatment for steroid-resistant rejection:
- Antilymphocyte globulin, OKT3, daclizumab, methotrexate, total lymphoid irradiation, photopheresis
- Treatment for humoral rejection:
- Plasmapheresis/exchange transfusion, IVIG, some centers use Cytoxan and/or rituximab
Additional Treatment
General Measures
- Patients with significant valvar regurgitation should receive endocarditis prophylaxis prior to dental work or invasive procedures that would normally require prophylaxis.
- Avoid undue exposure to infectious diseases.
- Live viral vaccines are contraindicated.
Surgery
Posttransplantation surgical intervention would include retransplantation, the only alternative for advanced transplant coronary disease. Indications for retransplantation include: �
- Rapidly progressive graft arteriopathy with or without ischemia
- Stable arteriopathy with severe CHF
- Severe acute rejection unresponsive to therapy (outcome poor in this group, considered by most to be a contraindication)
In-Patient Considerations
Admission Criteria
- Posttransplantation admissions are usually for complications of immunosuppressant medications.
- Inadequate immunosuppression results in rejection or coronary artery disease.
- Overimmunosuppression may occur early postoperatively or following treatment for rejection and can result in admissions for infections or PTLD.
Discharge Criteria
- Discharge criteria vary by diagnosis and treatment.
- During the 1st yr of follow-up, 1/2 of pediatric cardiac recipients required rehospitalization for illness:
- Rejection hospitalization: 25%
- Infection hospitalization: 35%
- During the 4th posttransplantation year, 75% of children did not require hospitalization:
- Rejection hospitalization: 5%
- Infection hospitalization: 10%
Ongoing Care
Follow-Up Recommendations
Transplant recipients must be followed lifelong. �
Diet
A low-fat, healthful diet is recommended. �
Patient Education
- Continuing education about the necessity for strict compliance with immunosuppressant medications is required throughout patients' lives:
- Significant, chronic noncompliance carries a 60% mortality risk.
- Adolescent patients have a high incidence of noncompliance.
- The family and patient should be educated about signs and symptoms of rejection, as well as infection precautions.
- Activity:
- No activity restrictions for transplant recipients; regular physical activity and exercise is advisable for rehabilitation.
Prognosis
Postop course in transplant recipients varies with degree of pretransplantation debilitation and morbidity. More stable children recover quickly with the addition of normal heart function. �
Female heart transplant recipients can have successful pregnancies without apparent risk to the newborn from immunosuppressants. �
Complications
- End-organ toxicity of Immunosuppressants:
- Causes of death in ISHLT Pediatric Registry:
- Increased perioperative mortality (25%) in infants transplanted for CHD compared with older children with CHD or other infants with cardiomyopathy (10%).
- Most common causes of death during the 1st yr posttransplantation were acute rejection (20%) then infection (15%).
- Acute (20%) then chronic rejection/coronary disease (15%) is the most common cause from 1-3 yr posttransplantation.
- Beyond 3 yr posttransplantation, coronary disease/graft failure is responsible for about 1/2 of the deaths.
- Malignancy remains an infrequent cause of death until >10 yr posttransplant, when it accounts for ~6% of deaths.
- 7% at 2 yr, 25% incidence within 7 yr.
Additional Reading
1
Kirk �R, Edwards �LB, Aurora �P. Registry of the International Society of Heart and Lung Transplantation: Twelfth Official Pediatric Heart Transplantation Report-2009. J Heart Lung Transplant. 2009;28:993. �[View Abstract] 2
Lamour �JM, Addonizio �LJ.
Pediatric heart transplantation. In: Edwards �N, Chen �J, Mazzeo �P, Cardiac Transplantation: The Columbia University Medical Center/New York-Presbyterian Hospital Manual. Totowa, NJ: Humana Press, Totowa, 2004. 3
Ross �M, Kouretas �P, Gamberg �P. 10- and 20-year survivors of pediatric orthotopic heart transplantation. J Heart Lung Transplant. 2006;25:261-270. �[View Abstract] 4
Zuppan �CW, Wells �LM, Kerstetter �JC. Cause of Death in Pediatric and Infant Heart Transplant Recipients: Review of a 20-year, single-institution cohort. J Heart Lung Transplant. 2009;28:579-584. �[View Abstract]
Codes
ICD9
- V42.1 Heart replaced by transplant
- 996.83 Complications of transplanted heart
SNOMED
233932001 cardiac transplant disorder (disorder) �