Pediatric Heart Transplantation Periprocedural Care

Consent for cardiac transplantation should be obtained at the time of listing. The consent discussion should cover the potential benefits and risks of the procedure, as well as long-term morbidities and outcomes. In addition to the program and national outcome statistics, common co-morbidities such as rejection, infection, cancer, renal disease, coronary disease, and medication side effects are often discussed.

Patient and parental education should begin immediately after the decision to start a transplant evaluation is made. Verbal and written education about the transplant waiting period, peri-transplant care, post-transplant immunosuppressive and other medications, long-term care after cardiac transplant, and outcomes after cardiac transplant should be given. Due to the great amount of new information and tremendous stress that the family is under at this time, frequent reinforcement of the information should be made. Some transplant programs require a written test and/or an inpatient stay with the patient prior to discharge after transplantation.

The evaluation of potential patients for heart transplantation occurs in two phases. First, a comprehensive assessment of the patient is made to assure candidacy for transplantation. Following listing, continued, frequent patient assessment is required to ensure that the candidate is in the best medical condition possible when a donor heart becomes available.

Pre-transplant listing evaluation

The pre-listing evaluation should have a multi-disciplinary approach. Alternative therapies should be assessed and pursued if transplant deferral is possible. Medical, laboratory, and psycho-social evaluations should be undertaken prior to transplant listing.

Medical evaluation should include a thorough multi-system review and spec ialty consultation (ie, neurology, nephrology, gastroenterology, hepatology, infectious disease, genetics/metabolics, psychiatry/psychology) should be obtained if concerns are present. A nutritional assessment should be made and nutrition should be optimized.

Laboratory evaluation is undertaken to assess for end-organ dysfunction and factors that may adversely affect post-transplant outcomes (ie, infection, immune status, metabolic disease).

Psycho-social evaluation is made by a qualified social worker and should confirm a stable means of ensuring quality post-transplant care. Family dynamics, finances, and prior compliance to therapies are all indicators of a family's ability to provide adequate post-transplant medical care. In rare instances, temporary or permanent removal from the biological family is required due to the inability to provide adequate care.

Laboratory studies

The blood type is determined so that the patient can be listed for an appropriate organ. Knowing the recipient’s blood type is important, but  transplantation across ABO-incompatible blood types has become a routine option for infants who have acceptably low isohemagglutinin titers, and the recently introduced technique of intraoperative anti-A/B immunoadsorption appears to expand the candidate pool for ABO-incompatible heart transplantation to a significantly older population. ^[19]

Infection screening is carried out, including the following:

• Complete blood count (CBC) with differential
• Urine and blood cultures
• Cytomegalovirus (CMV) titer or CMV polymerase chain reaction (PCR)
• Hepatitis B surface antigen (HBsAg) test
• HIV test
• Rapid plasma reagin (RPR) test
• Toxoplasma titer
• Epstein-Barr virus (EBV) PCR
• Endotracheal tube (ETT) aspirate (if applicable)

Kidney function and liver function are assessed by measuring electrolyte, blood urea nitrogen (BUN), and creatinine levels and obtaining a liver profile. Pretransplant sensitization is evaluated by measuring panel-reactive antibody (PRA) levels.

Imaging studies

Head ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI) or magnetic resonance spectroscopy (MRS), and electroencephalography (EEG) are performed as appropriate to assess neurologic status. Chest radiography and renal ultrasonography are also helpful. Echocardiography is performed to assess cardiac anatomy and function.

Cardiac catheterization

Cardiac catheterization may be needed to assess anatomy, to rule out pulmonary venous drainage abnormalities, to assess pulmonary artery adequacy, and to assess pulmonary vascular resistance (PVR). Pulmonary artery pressure may be estimated by means of echocardiography, but a more formal analysis usually requires cardiac catheterization.

Recipients with elevated PVR are at increased risk for acute right-heart failure in the early posttransplant period. In the first few months of life, if the main and branch pulmonary arteries are of normal caliber and distribution, the elevated PVR of the newborn period usually normalizes rapidly soon after transplantation. If pulmonary venous obstruction is present, pulmonary artery pressures may not normalize as quickly.

Elevated PVR that is reactive (ie, responsive to vasodilator therapy) can usually be managed with oxygen or intravenous vasodilator therapy in the pretransplant period. This can reduce the PVR, which simplifies posttransplant management. Elevated PVR that is fixed is an indicator of significant risk for acute graft failure.

Monitoring while listed for transplant

Many pediatric patients awaiting heart transplantation can be managed out of the hospital. Evaluate patients on a frequent basis (at least monthly). Pay particular attention to any febrile illness because transplantation in the face of acute infection can be dangerous. Aggressive infection surveillance and treatment is warranted.

Extracorporeal membrane oxygenation (ECMO) is the standard of care for children who require short-term mechanical circulatory support (MCS). Although ECMO is frequently life-saving, approximately one-half of all children supported with ECMO fail to survive to hospital discharge. The use of a new generation of short-term circulatory support devices, known as temporary circulatory support (TCS) devices, as a bridge to transplant has risen rapidly in recent years, led by the growth of magnetically levitated centrifugal flow pumps. Studies have reported that TCS offers a significant survival advantage compared with conventional ECMO. ^[20]

The issue of vaccination may arise in this setting. Generally, vaccinations (especially live virus vaccines) are not given during the pretransplant waiting period; stimulation of the immune system should be avoided, given that a donor may become available at any time. However, if the child is believed capable of safely waiting at least 6 weeks for the transplant, administration of live virus vaccines (if age appropriate) before the procedure is probably better because live virus vaccines are commonly avoided entirely after transplantation.

Close outpatient follow-up is essential to ensure long-term success. The highest risk of complications occurs in the first few months after transplantation, so the child should remain near the transplantation center for the initial follow-up. The following is an outline of the outpatient testing schedule at the author’s institution (Loma Linda University Children’s Hospital).

• Physician visits take place twice weekly for 6 weeks, then less frequently as the rejection-free interval increases. The minimum visit frequency is monthly for the first year and every 3 months thereafter.
• Echocardiography is performed twice weekly for 4 weeks, then less often as the rejection-free interval increases; after the initial period, it should be performed at the same time as the routine physician visits. In patients who have undergone arch reconstruction, full-study echocardiography is performed at 1 month, 3 months, and 12 months to evaluate the aortic arch.
• Brain natriuretic peptide (BNP)  or N-terminal pro b–type natriuretic peptide (NT-proBNP) levels are measured with each echocardiogram.
• Electrocardiography (ECG) is performed monthly until 1 year after transplantation, and then every 3 months thereafter.
• Chest radiography is performed monthly for 3 months, at 12 months, and then annually.

Calcineurin inhibitor (cyclosporine or tacrolimus) trough levels are assessed on the following schedule:

• Twice weekly for 2 weeks after discharge
• Weekly for 4 weeks
• Monthly for the first year
• Every 3 months thereafter

Target cyclosporine levels (with a favorable rejection history) are 200-250 ng/mL for 4 months and are gradually reduced of the first post-transplant year to a goal of 50-75 ng/mL thereafter (depending on the secondary immunosuppression agent). Tacrolimus trough levels are maintained at 12-15 ng/mL for 4 months, then gradually reduced during the first post-transplant year to a goal of 4-5 ng/mL (depending of the secondary immunosuppression agent), if rejection history is favorable.

Mycophenolate mofetil (MMF) levels are checked concurrently with calcineurin inhibitor levels. Mycophenolic acid levels are maintained at 2-5 µg/mL (not to exceed 30 mg/kg/dose). Note that immunosuppression blood level targets are only starting points. Adjustments may be needed in the individual child because of rejection history and side effect profile.

Mammalian target of rapamycin (mTOR) inhibitors (sirolimus or everolimus) are rapidly gaining acceptance as secondary immunosuppressive agents, as a result of adult transplant studies showing improvement in cardiac allograft vasculopathy and renal dysfunction (due to lower calcineurin inhibitor requirements). Because of concerns about impaired wound healing, mTOR inhibitors are typically not initiated until at least several months after transplant. mTOR inhibitor leves are routinely checked with calcineurin inhibitor levels, with initial sirolimus targets of 8-10 ng/mL and everolimus targets of 5-8 ng/mL; those decrease to 4-5 ng/mL and 3-5 ng/mL, respectively, over the first post-transplant year. Infants frequently require reduced dosing intervals (ie, more doses per day).

The use of genomics to evaluate the response to immunosuppressive medication and to assess the risk of rejection and graft vasculopathy is being studied; this is interesting and potentially treatment-shifting work. Gene array techniques that measure up-regulation and down-regulation of peripheral blood gene markers are also being studied as a means of individually assessing the degree of immunosuppression and, thus, the risk of rejection and infection. ^[21]

A CBC with platelets is obtained every 2 weeks for 2 months, then monthly for the first year, and every 3 months thereafter. Levels of basic electrolytes are obtained at the same time as the CBC count for the first year, with a complete metabolic profile (including magnesium levels) obtained every 3 months.

The CMV immunoglobulin G (IgG) titer is assessed at 6 months, 12 months, and then annually until conversion. EBV PCR is assessed every 3 months. HIV and HBsAg tests are obtained at 6 months.

Renal function is assessed via a BMP every 2 weeks for 2 months, then monthly for the first year, and every 3 months thereafter. Standard calculations to assess glomerular filtration rate (GFR) based on creatinine in individuals receiving calcineurin inhibition may not be accurate and alternative methods or calcuations should be used. ^[22]

Renal ultrasonography is performed as needed.

The endomyocardial biopsy follow-up schedule varies according to age at transplantation, as follows:

• Up to 2 years of age – Annually
• Age 2-8 years – At 1 month, 3 months, 12 months, and annually thereafter
• Age 9 years and older – Before discharge, at 1 month, 2 months, 3 months, 6 months, 12 months, and annually thereafter

Some programs have reduced the frequency of biopsy in younger children to less than one per year (eg, every 2 or 5 years) after the first post-transplant year. Donor-specific antibody (DSA) monitoring is obtained with each biopsy.

Coronary angiography is performed annually, starting at the first anniversary of transplantation. Intravascular ultrasonography is performed at age 6 years and every other year thereafter unless previous intravascular ultrasonography demonstrated Stanford class 4 findings.

All routine vaccinations, except for live virus vaccines (eg, oral polio, varicella, and measles-mumps-rubella [MMR] vaccines), should be administered, starting as early as 6 weeks after transplantation.

Standard preoperative precautions are made prior to transplantation. Patients should be made NPO prior to the procedure and preoperative laboratories are obtained (ie, blood type/crossmatch, CBC, comprehensive metabolic profile, prothrombin time with international normalized ratio [INR], activated partial thromboplastin time [aPTT]).

Blood products should be ordered and made available in the operating room. Central arterial and venous catheters should be placed in the operating room and the patient is intubated for the procedure.

Some individuals with significant pre-transplant HLA sensitization will undergo desensitization therapy prior to transplantation, which may include anti-B cell antibodies, intravenous immunoglobulins, plasmapheresis, or plasma exchange in the operating room. For ABO-incompatible heart transplantation, intraoperative anti-A/B immunoadsorption can be used to reduce blood product utilization compared with plasma exchange. ^[19]

Isohemagglutinin titers are followed closely for infants and young children undergoing ABO-incompatible heart transplantation.