Pediatric Heart Transplantation Technique

Attention to detail during the procurement of the donor organ and gentle handling of the donor organ are as important as the implantation of the organ. Anatomic considerations in heart transplantation are diverse and should be reviewed according to the particular condition present in the recipient.

The donor operation must be tailored to the anatomic needs of the recipient. Recipient anomalies of pulmonary venous connection often require complete resection of the donor left atrium, with each donor pulmonary vein divided separately. In the case of anomalies of systemic venous return, extended removal of the superior vena cava, left innominate vein, and inferior vena cava may be required. For individuals with branch pulmonary artery or aortic hypoplasia, the donor branch pulmonary arteries and aortic arch may be required.

The pediatric cardioplegia solution used is usually either University of Wisconsin solution or Roe solution.

Meticulous care of the child awaiting transplant is essential to ensure the best possible outcome. For patients with ductal-dependent physiology, the lowest dose possible of prostaglandin (0.1-0.2 µg/kg/min) should be used. The authors usually use a peripherally inserted central catheter (PICC) line, with a second heparin lock in place in case the primary intravenous (IV) site is suddenly lost.

Oxygenation must be managed to balance the pulmonary and systemic blood flows. This may require adding nitrogen to the inspired gas mixture to render delivered oxygen at a fractional inspired oxygen (F_I O₂) of less than 0.21.

An important complication is a significantly restricted interatrial communication. Balloon atrial septostomy or surgical septectomy may be necessary. A protocol that incorporates stenting of the patent ductus arteriosus and pulmonary artery banding has been used in multiple centers to allow children with hypoplastic left heart syndrome (HLHS) to wait without prostaglandin E (PGE) infusion, even outside the hospital.

Among all children waiting for heart transplantation, the death rate before transplantation is approximately 15-20%. For infants with hypoplastic left heart syndrome (HLHS), mortality during the waiting period is significant when the wait is longer than about 3 months; these infants only occasionally survive until age 6 months. Among less critically ill children (United Network for Organ Sharing [UNOS] status II), pretransplant mortality by 12 months is about 10%.

In children with cardiomyopathy, the operative method of transplantation is the same as it is in adults (see Heart Transplantation). A median sternotomy is made, a thymectomy is performed, and the recipient’s native heart is exposed. If the donor heart is significantly larger than the native heart, the entire left pericardium anterior to the phrenic nerve is removed. Single venous and arterial cannulation is generally used.

See the image below.

A standard orthotopic technique using biatrial or bicaval connection is used. If necessary, modifications are made for anatomy specific to congenital heart disease, as follows.

In children with HLHS, the ductus arteriosus is isolated and cannulated for arterial perfusion through a stab wound in the distal main pulmonary artery. All aortic arch vessels are isolated with loose tourniquets during initial cooling in preparation for reconstruction. Implantation of the allograft is accomplished with systemic hypothermia; the atrial anastomoses are performed under low-flow perfusion, with the pulmonary artery clamped and systemic perfusion maintained by means of the arterial cannula positioned in the ductus arteriosus.

The aortic arch is then reconstructed under circulatory arrest with the arch vessel tourniquets tightened. The excision of ductal tissue at the duct’s entrance into the distal arch is important for providing secure aortic tissue for the anastomosis and for minimizing the likelihood of a post-transplant stenosis in this area. The pulmonary artery anastomosis is completed while the patient is rewarmed.

Other complex congenital heart anomalies, such as transposition of the great arteries, can often be managed by means of direct anastomosis if sufficient lengths of donor arterial and venous connections are procured.

Systemic venous anomalies (ie, left-sided inferior or superior vena cava) require redirecting venous blood flow to opposite side of the body via a combination of donor and recipient tissues. These low-pressure anastomoses are at risk of stenosis after transplantation.

Following all anastomoses and rewarming, the donor heart will frequently fibrillate, and defibrillation is required to restore sinus rhythm.  The patient is kept on cardiopulmonary bypass until adequate re-perfusion has occurred. Weaning from bypass is typically made with the addition of inotropic support, such as milrinone and epinephrine. Atrioventricular or ventricular pacing is frequently employed in the early post-transplant period. Inhaled nitric oxide is given to those with an increased risk of elevated pulmonary vascular resistance.

After control of bleeding is obtained, chest tubes are placed and the chest is closed in most instances.

In general, management of the child who has undergone heart transplantation is similar to postoperative management for any pediatric cardiac procedure. There are, however, certain considerations that are specific to heart transplantation, as summarized below.

Post-transplant cardiac support

Inotropic support with a combination of milrinone, epinephrine, and dopamine is generally employed in the early post-transplant period (24-48 hours), due to the low cardiac output state seen after prolonged cardiopulmonary bypass and to aid in recovery of the donor heart.  If hypertension is present, additional afterload reducers and vasodilators may be needed.

Diuretics are generally started in the first 12-24 hours after transplant and continued for several weeks to months after transplant.

Post-transplant hypertension is common after weaning of inotropic support and intravenous vasodilators, and may require medical therapy.  Dihydropyridine calcium channel blockers (eg, amlodipine, nifedipine, nicardipine) are commonly employed due to their lack of nephrotoxic and cardiac side effects. Angiotensin-converting enzyme (ACE) inhibitors may not be the best option early, given the need for high-dose calcineurin inhibition, which compounds the nephrotoxic effects of ACE inhibitors.

In patients receiving prostaglandn E before transplantation, it is advisable to continue prostaglandin therapy for at least 1-2 days, then gradually taper it over 2-3 days so as to prevent rebound pulmonary hypertension.

The donor right ventricle is not tolerant of significant pulmonary hypertension; for this reason, acute graft failure is one of the largest contributors to early mortality. Optimal therapy includes the following:

• Sedation
• Vasodilator therapy
• Alkalization through hyperventilation
• Inotropic agents with minimal or reductive pulmonary vasoconstrictive effects
• Inhaled nitric oxide, when available
• Sildenafil has also been used

Many children receive donor organs that are larger than their native hearts. This leads to compression of lung parenchyma. Aggressive pulmonary toilet is indicated, and close observation for respiratory compromise is required, especially after the initial extubation.

Post-transplant immunosuppression

Numerous immunosuppression protocols exist for the perioperative and postoperative period, but most follow similar general principles. Immunosuppression can be broken down into two phases: induction and maintenance.

The goal of induction immunotherapy is to allow for the delay in initiation of maintenance immunosuppressants, which may adversely affect other organs recovering from pre-transplant and peri-transplant damage (ie, renal and hepatic dysfunction).The following are used for induction immunosuppression:

• Anti-thymocyte antibodies (ie, antithymocyte globulin [ATG])
• Anti–interleukin-2 (IL-2) antibodies (eg, basiliximab)
• Corticosteroids (eg, methylprednisolone, prednisone)
• Other immune modulators (eg, intravenous immunoglobulin [IVIg], rituximab)

After end-organ function has recovered sufficiently, maintanance immunosuppression is commenced. The following classes of immunosuppressive agents and combinations of agents are used:

• Calcineurin inhibitors (ie, cyclosporine, tacrolimus)
• Cell cycle inhibitors (ie, mycophenolate mofetil, azothiaprine)
• mTOR inhibitors (ie, sirolimus, everolimus)
• Corticosteroids (eg, prednisone)

At Loma Linda University, we use high-dose corticosteroids in the early peri-transplant periods (20 mg/kg intraoperatively and 20 mg/kg IV x 4 doses post-transplant) with ATG (1.5 mg/kg for 3-7 days, targeting a CD3 count of < 25 cells/mm³), and IVIg (2 g/kg total dose).  Maintenance immunosuppression consists of cyclosporine (target trough 200-250 ng/mL) or tacrolimus (target trough 12-15 ng/mL) with mycophenolate mofetil (target trough 2-5 ng/mL), which is started 2-3 days after transplantation (depending on renal function, PO status, white blood cell counts, and infection status). No maintenance corticosteroids are given.

The most appropriate initial immunosuppression protocol is not known. Every transplantation center likely has a different protocol. Clear data are difficult to obtain because of the small number of transplants performed each year and the lack of standardized practice across institutions.

In addition, whereas early rejection and survival are important therapeutic endpoints for research design, graft vasculopathy is the most important outcome measure. Vasculopathy does not become a significant issue for at least 5 years after transplantation. Much work remains to be conducted on this front.

Adjunct therapies with nystatin and ganciclovir or valganciclovir are initiated for 3-6 months for infectious prophylaxis. Some centers utilize trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis, as well. Aspirin and statins are given by some programs for coronary prophylaxis. Magnesium and bicarbonate supplementation are frequently needed early after transplant, when calcineurin levels are kept high.

The most significant causes of death after heart transplantation are as follows ^[23] :

• Early graft failure (either primary or secondary to pulmonary hypertension)
• Allograft rejection
• Infection
• Allograft vasculopathy
• Malignancy

Allograft rejection

Preventing rejection while avoiding severe infections, kidney failure, and cancer is the biggest challenge facing the transplant physician. ^[24] Although an extensive discussion of important immunosuppressive agents is beyond the scope of this article, a brief review of immunosuppression strategies in pediatric heart transplantation is worthwhile. Broadly speaking, such strategies are built around the following 2 considerations:

• Induction versus no induction
• Dual-drug regimens versus triple-drug regimens

Note that none of these strategies have been studied in sufficiently large-scale, randomized, controlled studies. Rather, they have been extrapolated from adult thoracic and pediatric noncardiac solid-organ trials and adapted through application to and experience with pediatric heart transplantation.

Induction versus no induction

The use of monoclonal or polyclonal antibody T-cell–depleting agents (ie, induction therapy) has been controversial for years. Early in the history of transplantation, induction therapy was commonly used, but it fell out of favor because of concerns about overimmunosuppression with resultant infections and posttransplant lymphoproliferative disease (PTLD). However, there is now renewed interest in the use of induction therapy as a means of reducing or eliminating steroid use. Several studies have demonstrated the efficacy of this approach. ^{[25, 26]}

According to the heart-lung transplantation registry of the International Society for Heart and Lung Transplantation (ISHLT), the majority of pediatric patients who received a heart transplant were treated with induction strategies. Of those, about two-thirds received polyclonal antibody T-cell–depleting agents, and one-third received interleukin-2 receptor antagonist. At Loma Linda, rabbit-derived polyclonal antibody has been used in a steroid-avoidance regimen.

Dual versus triple therapy

Essentially, all regimens start with the foundation of a calcineurin inhibitor—either cyclosporine or tacrolimus. To date, only 1 small-scale trial has compared cyclosporine with tacrolimus in pediatric heart transplantation; it found the 2 agents to have essentially equivalent efficacy. ^[27]

Nevertheless, the pediatric heart transplant community has gradually shifted toward greater use of tacrolimus. According to the ISHLT, the use of tacrolimus at 1 year after transplantation has now surpassed that of cyclosporine. The main advantage of tacrolimus is its lack of cosmetic side effects (hirsutism and gingival hyperplasia). It has greater potency than cyclosporine on a milligram-for-milligram basis and is successfully used for patients with recurrent rejection.

Increased incidence of PTLD and greater frequency of posttransplant diabetes are concerns. Newer strategies that incorporate lower target levels have helped greatly with both of those concerns. Renal dysfunction is an adverse effect of both medications in this class.

Oral administration yields incomplete and variable results, with absolute bioavailability ranging from 17-22% in adults. In children, tacrolimus bioavailability is about 31%, though whole-blood concentrations in a study of 31 children younger than 12 years indicate that children require higher doses than adults to achieve similar trough concentrations. A high-fat meal reduces mean area under the curve (AUC) by 37%, whereas a high-carbohydrate meal decreases mean AUC by 28%. Peak concentrations are also reduced by 77% and 65%, respectively. ^[28]

Tacrolimus is not commercially available as a liquid preparation; the solution must be compounded in a local pharmacy, and this carries a potential for formulation errors. In addition, it is recommended that tacrolimus be administered on an empty stomach; this complicates its use in school-age children, who may have little time available before school. Many centers seem to achieve good results without strictly adhering to this suggestion; it is unknown whether these results are obtained by increasing the dose to overcome bioavailability issues.

At the author’s institution, cyclosporine was the preferred calcineurin inhibitor, but tacrolimus is being more widely used at this time. Target trough levels (whole blood, monoclonal assay) for cyclosporine are 200-250 ng/mL for the first 4 months, with reduction to 50-75 ng/mL by 1 year post-transplant, if the rejection history is acceptable. Transition to tacrolimus occurs at 1 year post-transplant or earlier. Tacrolimus levels are kept at 12-15 ng/mL during the first 4 months post-transplant and are gradually reduced to 4-5 ng/mL after 1 year post-transplant, depending on rejection status and the secondary immunosuppressive agent used.

In this institution, tacrolimus is used primarily for certain select high-risk candidates (eg, patients with multiple previous cardiac operations, patients with high panel-reactive antibody [PRA] levels, and African-American recipients), as well as for patients who have experienced recurrent rejection. A significant number of children experience problematic cosmetic side effects, especially those who require orthodontia, in whom gingival hyperplasia is counterproductive.

Antiproliferative agents/cell-cycle toxins

Among the antiproliferative agents, azathioprine (AZA) had been the therapeutic mainstay. According to the ISHLT, however, mycophenolate mofetil (MMF) is now used in approximately 60% of pediatric patients who receive a heart transplant. Again, no prospective studies are available.

Cardiac allograft vasculopathy significantly affects long-term graft and patient survival. In adult cardiac transplant trials, MMF has been shown to decrease the progression of coronary intimal thickness. Like AZA, MMF can induce bone marrow suppression. ^{[29, 30]} The biggest challenge is the significant risk of gastrointestinal (GI) side effects, which affect patient tolerance of pharmacotherapy. A significant advantage of MMF is that the drug can be dosed to a therapeutic level.

At Loma Linda, MMF is given as part of the primary immunosuppression regimen. Dosing begins at 300 mg/m²/day or 40 mg/kg/day divided into 2 doses and is increased as tolerated to maintain a mycophenolic acid level of 2-5 µg/mL. Infants may require dosing every 8 hours.

Corticosteroids

Oral corticosteroids have been a mainstay of rejection prophylaxis since the early days of transplantation. However, in pediatric heart transplantation, reports from various centers over a number of years have documented effective rejection prophylaxis with steroid avoidance, early weaning to zero, or both.

Steroid avoidance is believed to require induction therapy. The newer immunosuppressive agents have given more confidence to transplant physicians who wish to wean to zero. Programs that use steroids typically start with oral prednisone at a dosage of 2 mg/kg/day and then wean over the first 3 months to a maintenance regimen of 0.1-0.3 mg/kg once daily or once every other day.

At Loma Linda, steroid avoidance has been practiced from program inception, with oral prednisone used only to treat children who experience allograft rejection or in whom no other combination is effective or tolerated. This approach has received some validation from the immunology literature, which has demonstrated that long-term glucocorticoid therapy leads to downregulation of cytoplasmic glucocorticoid receptor expression, as evidenced in T cells.

Sirolimus

The mammalian target of rapamycin (mTOR) inhibitor sirolimus is a newer agent that works synergistically with calcineurin inhibitors. A retrospective study by the Pediatric Heart Transplant Study Group of 2,531 patients undergoing primary heart transplantation from 2004 to 2013 with at least 1 year of follow-up found that 44 patients (7%) were on sirolimus at 1 year post transplant. Rates of survival and major transplant adverse events in patients receiving sirolimus were similar to those in patients not treated with sirolimus. ^[31]

At Loma Linda, sirolimus has been used in the following settings:

• For recurrent rejection
• In children with renal insufficiency (to decrease the calcineurin inhibitor dose or to eliminate the calcineurin inhibitor, used in conjunction with MMF)
• As solo therapy in the first few months after treatment for PTLD
• In children who have coronary intravascular evidence of moderate-to-severe cardiac allograft vasculopathy

Nonpharmacologic measures

The following 3 additional therapies are worth mentioning:

• Total lymphoid irradiation has been used in the treatment of recalcitrant rejection; it has become less necessary with the availability of newer immunosuppressive agents

• Plasmapheresis has been used either before transplantation in patients who are highly sensitized or after transplantation in patients who experience acute antibody-mediated rejection (AMR) or in whom AMR is anticipated

• Photophoresis involves extraction of lymphocytes from patients who were pretreated with psoralen, exposure of the lymphocytes to ultraviolet A light, and reinfusion ^[32] ; it has been helpful in the prevention and treatment of recurrent rejection, though no reports on its use in children have been published

Treatment of acute cellular rejection:

The mainstay of therapy for acute graft cellular rejection is high-dose IV or oral corticosteroid administration. An oral steroid taper is often used after IV treatment. No controlled studies regarding the appropriate dose have been reported.

At Loma Linda, acute rejection is treated with IV methylprednisolone at 20 mg/kg (not to exceed a dose of 500 mg) twice daily for 8 doses. Uncomplicated rejection diagnosed on the basis of biopsy findings alone may be treated with oral prednisone at 2 mg/kg/day for 3 days, with a taper to zero over 3 weeks.

In patients with recurrent rejection or with acute rejection with hemodynamic compromise, anti–T-cell antibody preparations should be added. At Loma Linda, antithymocyte globulin 1.5 mg/kg/day is administered by slow IV infusion over 6 hours. This dosage is continued for 7-10 days. A lymphocyte profile should be obtained on day 3, with a target absolute CD3 count of less than 200 cells/mL. The use of high-dose IV immunoglobulin in the treatment of graft rejection may be beneficial.

Treatment of the rejection episode must be accompanied by evaluation of the causative mechanisms. If immunosuppressive doses have been faithfully given and the desired therapeutic levels have been maintained, either the desired level must be increased or the agent must be changed. Noncompliance must be suspected in any late rejection episode, especially with low drug levels and in the adolescent patient.

Treatment of antibody-mediated rejection:

Appropriate treatment of antibody-mediated rejection (AMR) is less clear, as is its diagnosis. AMR appears to play a signficant factor in allograft vasculopathy and in graft loss. Newer monoclonal antibodies targeting B-cells and terminal complement fixation are now being employed to treat preformed donor specific antibodies and AMR. Rituximab is an antibody targeting CD-20, which is present on memory B-cells.  Bortezomib is an antibody targeting plasma B-cells, while eculizumib targets complement binding and fixation.

Diagnosis of rejection

Rejection is diagnosed on the basis of clinical signs and symptoms, echocardiographic changes, and endomyocardial biopsy findings.

Clinical clues to rejection include the following:

• A decrease in the child’s activity or feeding
• Low-grade fever
• Persistent resting tachycardia
• Ventricular ectopy
• S ₃ gallop
• Tachypnea or dyspnea
• Hepatic congestion
• Ileus
• Other signs or symptoms of low cardiac output

Echocardiographic criteria for rejection are somewhat controversial but include findings reflective of an increase in left ventricular mass, impairment of systolic and diastolic function, ^[33] new pericardial effusion, and new mitral insufficiency. Some have advocated tissue Doppler imaging to improve the sensitivity of echocardiographic diagnosis of rejection. ^[34]

Electrocardiographic (ECG) analysis may be of some use, with significant lowering of voltage indicating a risk for rejection. Signal-averaged ECG may reveal an abnormal strain pattern with rejection. ^[35]

Cardiac functional biomarkers have been advocated for the diagnosis of rejection. B-type natriuretic peptides have been used, although the levels of these substances vary widely and demonstrate an overlap between normal and rejection. They may be most useful in the emergency department setting, where a normal value can provide reassurance that rejection is unlikely.

Gene expression profiling is also under investigation, but its applicability to pediatrics is controversial. Endomyocardial biopsies are the criterion standard and are graded according to the criteria of the ISHLT, with treatment generally initiated only when biopsy samples demonstrate a 2R (ie, 2 or more foci lymphocytic infiltration with associated myocyte damage) or greater histology. ^[36]

AMR is becoming increasingly recognized. Preformed antibodies have long been known to create the potential for hyperacute rejection in the early posttransplant period. ^[37] Retrospective crossmatching should be performed, and consideration should be given to plasmapheresis in the setting of a positive crossmatch finding and graft dysfunction. Anti-CD20 monoclonal antibody has also been used in this setting, to reduce production of antidonor antibodies.

De novo development of anti–human leukocyte antigen (HLA) antibodies, particularly to class II, has been associated with an increased incidence of allograft vasculopathy. Many centers now test for the presence of C4d on endomyocardial biopsy specimens, especially in the face of graft dysfunction, as a marker of antibody-mediated rejection.

Infection

Infection is an expected complication: a significant number of recipients experience 1 or more potentially serious infections in the first few months after transplantation. These early postoperative infections are usually bacterial and include wound infections, pneumonia, bacteremia, and urinary tract infections. CMV infection is a significant complication. Pneumocystis jirovecii infections occur but are less frequent. Other opportunistic infections should be anticipated and aggressively treated when present.

A review of data from a multi-institutional registry of 1854 pediatric heart transplant recipients by Zaoutis et al noted 139 invasive fungal infections in 123 patients. The most common pathogens were yeasts (66.2%), molds (15.8%), and P jirovecii (13%). Candida species accounted for 90% of the yeast infections, and Aspergillus species accounted for 82% of the mold infections. Of patients with invasive fungal infections, 49% died within 6 months after transplantation, with risk and mortality being highest in those who required mechanical support and those with a history of previous surgery. ^[38]

Guidelines from the ISHLT recommend considering IV antifungal prophylaxis for infants (< 1 year of age) with an open chest and/or requiring extracorporeal membrane oxygenation (ECMO) support in the perioperative period (class IIb). The ISHLT recommends instituting prophylaxis for P jirovecii for a minimum of 3 months and up to a maximum of 24 months postoperatively. ^[39]

Malignancy

Malignancy, usually post-transplant lymphoproliferative disease (PTLD) associated with Epstein-Barr virus (EBV) infection, occurs in 2-10% of children. ^{[40, 41]} When the histology is low grade (polymorphous hyperplasia), PTLD usually responds to short-term cessation of immunosuppression. Higher-grade PTLD (lymphomas) are treated with a modified chemotherapeutic regimen that consists of cyclophosphamide every 3-4 weeks for 4-6 months accompanied by anti-CD20 monoclonal antibody (rituximab) for tumors that express CD20 (see Posttransplant Lymphoproliferative Disease).

Clinical protocols for prevention of PTLD are currently being explored. These include serial monitoring of EBV polymerase chain reaction (PCR) and intervening with ganciclovir or valganciclovir with or without serial infusions of IV immunoglobulin in an attempt to decrease the viral load while the patient’s immune system develops an adequate response to the infection. Rituximab has also been studied for PTLD prevention. ^[42]

In the face of acute EBV infection, the immunosuppression should be minimized as much as possible. However, rejection and graft vasculopathy have been suggested as important risks of excessively reducing immunosuppressive medications, especially in patients who have undergone heart transplantation.

Once the patient is infected, the EBV PCR viral load counts can widely vary. The development of PTLD is not always accompanied by high PCR counts.

Allograft vasculopathy

Allograft vasculopathy has emerged as the most important limiting factor for long-term survival. At 10 years after transplantation, significant allograft vasculopathy has developed in as many as 20% of recipients.

Because the donor heart is denervated, children with graft vasculopathy rarely present with angina. They may have atypical angina, such as shoulder or back pain or, more frequently, abdominal pain. They may also present with syncope or sudden death. Significant vasculopathy that causes changes in cardiac function and is confirmed by coronary angiography is probably best treated with retransplantation.

Other modalities that have been useful in the diagnosis of allograft vasculopathy include treadmill testing and dobutamine stress echocardiography. Adult heart transplantation data suggest that calcium channel blockers and statins may help prevent allograft vasculopathy. Some pediatric data suggest that the same effect is seen in children. Although some transplantation centers use these agents in all children, others use them only in high-risk patients.

Intravascular ultrasonography has been used extensively to assess coronary artery disease and especially to evaluate different immunosuppressive regimens in adult patients who have received a heart transplant. Abnormalities detected with this modality have been shown to predict later development of significant cardiac events. Few reports have described the use of intravascular ultrasonography in children, but it has been suggested as a more sensitive assessment of graft vasculopathy.

mTOR inhibitors have been shown to decrease the incidence of graft vasculopathy in adults who have received a heart transplant; in 1 report, the disease was reversed. ^[43] The use of mTOR inhibitors in children is currently being explored.

Nephrotoxicity

Nephrotoxicity is the most import nonlethal complication of pediatric heart transplantation. Hypertension, metabolic acidosis, and other metabolic abnormalities may be observed with varying frequency. Adjusting the calcineurin inhibitor to the lowest level possible helps ameliorate these problems. Minimizing steroid dosing also helps significantly with hypertension and with issues relating to growth and bone density.

Newer immunosuppressive strategies to minimize nephrotoxicity have used the synergistic properties between calcineurin inhibitors and sirolimus or everolimus to lower the calcineurin inhibitor dose. ^[44] A combination of sirolimus and MMF has also been used as a non–calcineurin inhibitor immunosuppressive regimen.

Pulmonary complications

Chronic respiratory complications are being recognized with increased frequency. In 1 report, they occurred in 50% of patients. Bronchiectasis was reported in 17% of patients; obstructive sleep apnea was diagnosed in 7%. Sirolimus-associated pneumonitis has been described.

Metabolic abnormalities

Hyperlipidemia is found in a higher proportion of pediatric heart transplant recipients. It appears to be more common in patients receiving cyclosporine than in those receiving tacrolimus. It is also more common in children who are on long-term steroid therapy and those who are being treated with sirolimus. Posttransplant diabetes has also been described; it occurs more frequently in children treated with tacrolimus, steroids, or both.