History of Solid Organ Transplantation

Early attempts at solid organ transplantation were unsuccessful for many reasons. There was insufficient development of basic surgical techniques and methods for organ preservation, and also inadequate knowledge of the immune system and tissue rejection.

In the early 1950s steroids were used to suppress rejection, and this resulted in some successful kidney transplants. In 1954, Dr Joseph Murray²¹ performed the first truly successful kidney transplant between identical twins. Although human liver transplantation was attempted by Starzl in 1963,³² it was not successful until 1967. Also in 1967, the first successful human heart transplant was performed by Christiaan Barnard on a 55-year-old man who survived 18 days.

It wasn’t until the mid-1970s that the development of more effective immunosuppression resulted in substantial improvement in transplantation survival. The first successful pediatric heart transplant was performed in 1984. The 4-year-old recipient received a second heart transplant in 1989 and is currently alive and well.

Evolution of Immunosuppression

In the late 1950s, kidney transplantation with nonidentical twins was attempted, with pretreatment of 10 recipients using sublethal total body irradiation. Nine of the ten recipients died within a month. Death was caused by the effects of radiation and not allograft failure.

In the 1960s, the development of tissue typing and drugs such as 6-mercaptopurine and azathioprine resulted in improved transplantation outcomes. Combinations of irradiation, splenectomy, thymectomy, high-dose corticosteroids, and azathioprine were used in attempts to overcome rejection. However, this combination therapy was associated with a remarkably high rate of opportunistic and often multiple bacterial, fungal, viral, and protozoal infections. Many of the infections were undetected and untreated before death.

In the late 1960s through the 1990s, as knowledge of the immune system evolved and more effective antibacterial and antiviral drugs were developed, results of transplantation again improved. Therapy targeting specific immunoregulatory sites became possible. The first polyclonal antilymphocyte globulin was used in 1967. Cyclosporin, a calcineurin inhibitor, became available in the 1980s. This drug, in combination with azathioprine and steroids, has been credited with a dramatic improvement in transplant graft survival.

In 1994, the next advance in transplantation came with the introduction of mycophenolate mofetil (MMF) and tacrolimus (another calcineurin inhibitor). Tacrolimus has gradually supplanted cyclosporine in many posttransplant protocols, because tacrolimus has been associated with lower rates of steroid-resistant acute rejection than cyclosporin.²⁰ In contrast, MMF quickly and almost universally replaced azathioprine in posttransplant protocols.^20,22

There are three stages of immunosuppressive therapies: induction, maintenance, and antirejection therapy. Induction immunosuppression therapy refers to all medications given in intensified doses immediately after transplantation for the purpose of preventing acute rejection. Although the drugs may be continued after discharge for the first 30 days after transplant, they are usually not used long term for immunosuppression maintenance.

Maintenance immunosuppression therapy includes all immunomodulation medications given before, during, or after the transplant with the intention of maintaining them long term. Antirejection immunosuppression therapy includes all immunosuppressive medication administered for the purpose of treating an acute rejection episode during the initial posttransplant period or during a specific follow-up period, usually as long as 30 days after the diagnosis of acute rejection.

A combination of biologic agents (Table 17-1) and immunosuppressants (Table 17-2) are used to prevent and treat rejection. Because immunosuppressive regiments vary from institution to institution, providers should consult their institutional protocols and the institutional pharmacy to verify drugs and dosing regimens used.

Table 17-1 Biologic Agent

Overview

As of 2011, approximately 5437 pediatric heart transplants have been performed in the United States for recipients to the age of 17,²⁴ and many more have been performed worldwide.⁷ Pediatric patients less than 17 years of age comprise approximately 10% of all heart transplant recipients.²⁴

Heart transplantation is now an acceptable therapy for end-stage heart failure in infants, children, and adolescents (see, also, Chapter 8). One-year patient survival is 83% to 90%, with 5-year survival of 71% to 77%.²⁴ The graft survival is somewhat lower than patient survival (82%-89% 1-year and 68%-75% 5-year graft survival), with some children requiring retransplantation.²⁴ Unfortunately, about 20% of children and about 30% of infants less than 6 months of age who are waiting for a heart transplant die before receiving a heart.

Timing is crucial when listing a patient for a heart transplant, and the risks and benefits of transplantation must be evaluated in light of the limited donor pool. Bridge to transplant therapies such as extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs) are commonly needed for short- or long-term support (see Chapter 7). A recent review has demonstrated improved survival using the Berlin heart.¹⁶

Immediate Postoperative Care

After cardiac transplants, all patients are monitored in the critical care unit. Patients are usually intubated and receive mechanical ventilation for at least 24 hours. Antibiotics are usually continued until chest tubes and monitoring lines are removed. Daily chest radiographs are performed to verify endotracheal tube depth of insertion and monitor for evidence of pneumothorax, atelectasis, or pleural effusions, and to evaluate heart size and chest tube placement.

Close postoperative observation and cardiopulmonary support are needed to ensure adequate graft function and minimize risk of graft failure. Because hypoxia and metabolic acidosis can cause pulmonary vasoconstriction and worsen right heart failure, monitoring and therapy are planned to avoid both.

Pulse oximetry is monitored continuously to detect changes in arterial oxygenation and central venous oxygen saturation (S_CVO₂) is monitored frequently to evaluate the balance between oxygen delivery and utilization. Arterial blood gas analysis is performed on a scheduled basis and as needed to ensure that systemic arterial oxygenation, carbon dioxide tension, pH, and serum lactate are appropriate.

Hemodynamic status is also closely monitored, including continuous display and recording of heart rate and rhythm and intraarterial pressure, and at least hourly recording of central venous pressure. If a pulmonary artery catheter is in place, then pulmonary artery (PA) pressure, PA wedge pressure, and mixed venous oxygen saturation are monitored. Pulmonary artery pressure monitoring is helpful in determining the severity of pulmonary hypertension and response to therapy, particularly during administration and weaning of inotropes and vasodilators (including inhaled nitric oxide). The pulmonary artery wedge pressure will rise in the presence of left ventricular dysfunction, and the mixed venous oxygen saturation reflects the balance of systemic oxygen delivery with tissue oxygen consumption.

If a PA catheter is not in place, evaluation of the balance between oxygen delivery and consumption is accomplished through frequent evaluation of central venous oxygen saturation (S_CVO₂), typically drawn from a central venous catheter placed in the superior vena cava. The difference between arterial and central venous oxygen saturation is typically 30% if cardiac output is adequate (for further information, see Chapter 6, Clinical Recognition and Management of Shock, Use of Central Venous Oxygen Saturation). If arterial oxygen content is stable, a fall in S_CVO₂ indicates either a fall in cardiac output or an increase in tissue oxygen consumption. If a central venous catheter is not in place, a venous sample can be drawn simultaneous with an arterial blood gas sample to assess arterial and venous oxygen saturations and evaluate the balance of oxygen delivery and consumption.

Laboratory tests evaluated on a frequent basis include: complete blood count with differential, basic metabolic panel, ionized calcium, magnesium, coagulation panel, and liver function tests. Serum electrolytes are monitored frequently because electrolyte imbalances can cause cardiac arrhythmias in the postoperative period.

Viral surveillance is common before the transplant and weekly during the acute postoperative period. Bacterial cultures are also performed as needed when fever occurs beyond 48 hours postoperatively.

Both perioperative and immediate postoperative management focus on optimizing allograft function. Challenges to the function of a newly transplanted heart include: denervation, graft ischemia, and acclimation to the recipient’s hemodynamics.⁷ The newly transplanted heart has a relatively fixed stroke volume; therefore, an increased heart rate is necessary to augment cardiac output. The heart rate can be increased through administration of inotropes or with atrial pacing.

Systolic function of the transplanted heart typically recovers rapidly, despite the ischemic insult that occurs between harvest and transplant. By comparison, the diastolic function may require weeks to recover and may respond to administration of low-dose inotropes in the early postoperative period. If the ischemic time was short and the recipient’s pulmonary vascular resistance (PVR) is low, only short-term inotropic therapy is likely to be needed after the transplant.

The transplanted heart is no longer innervated by sympathetic nervous system fibers, and the vagal effects on the heart are blunted. Therefore, if sympathetic nervous system stimulation is needed, the child should receive exogenous catecholamines. Sympathomimetics that stimulate alpha-2 and beta-receptors are likely to be more effective than those that stimulate alpha-1 (innervated) receptors. For this reason, dobutamine is likely to produce more significant effects on heart rate and contractility than dopamine.

The most common postoperative complications include: pulmonary hypertension, acute allograft dysfunction, arrhythmias, vasodilatory heart failure, renal dysfunction, and hypertension. These complications are presented in more detail in the text that immediately follows.

Posttransplant Immunosuppression

The survival of the transplanted heart relies heavily on immunosuppressive therapy. Ideally the goal of immunosuppression is to manipulate the immune response to promote tolerance to the foreign antigens, without rendering the recipient vulnerable to infection.¹

Induction immunosuppression is started in the perioperative period. Many institutions begin administration of calcineurin inhibitors, such as cyclosporine or tacrolimus, before the start of the transplant surgery. High-dose corticosteroids are given intraoperatively and continued for 48 hours; they are then either discontinued or tapered to a low-dose maintenance regimen.¹

Additional immunosuppressive medications may be given postoperatively in the form of polyclonal antibodies such as antithymocyte globulin (ATG). The maintenance immunosuppressive regimen uses the “triple therapy” approach: a calcineurin inhibitor (cyclosporine or tacrolimus), mycophenolate mofetil (MMF), and corticosteroids (see Tables 17-1 and 17-2).

Rejection

Most pediatric heart transplant recipients experience at least one rejection episode during their lives, with a majority of these occurring during the first 3 months after transplantation.⁷ Clinical evaluation of rejection is important but can be misleading, especially in the pediatric population, because the inflammatory response associated with an infection can mimic the presentation of rejection.¹ Clinical signs of rejection can include vague signs such as fatigue, irritability, gastrointestinal problems (e.g., vomiting, diarrhea, or poor feeding), or the development of specific cardiovascular signs such as heart failure, low cardiac output, or arrhythmias.

Cellular rejection, often referred to as T-cell-mediated rejection, is most common and is characterized by an infiltration of the heart by lymphocytes. The treatment options include optimizing current immunosuppressive therapy plus the administration of high-dose corticosteroids for mild cases of rejection and antithymocyte globulin (ATG) or muromonab CD-3 (OKT3) for severe cases of rejection (see Table 17-1).

Humoral- or antibody-mediated rejection occurs when donor-specific antibodies attack the transplanted allograft. This type of rejection is B-cell mediated and is associated with a higher rate of graft loss, development of transplant vasculopathy, and decreased long-term survival.⁷ Treatment for humoral rejection includes the use of high-dose corticosteroids, ATG, cyclophosphamide, and plasmapheresis.

Although the most effective way to detect rejection is through an endomyocardial biopsy (see Fig. 8-72), studies are underway to develop less invasive methods for rejection surveillance. Biohumoral markers such as B-type natriuretic peptide (BNP) and vascular endothelial growth factors (VEGF) are currently being studied as markers for rejection. Elevated BNP levels at 1 year or more posttransplant are associated with worse graft survival in pediatric heart transplant patients.²⁸