Recipient Criteria and Preoperative Assessment

Patients undergoing heart transplantation must have end-stage cardiac disease with limited life expectancy. Management options other than transplantation should be fully explored. These include optimization of medical therapy; coronary artery bypass graft surgery for patients with suitable coronary anatomy and reversible ischemia on viability testing; mitral valve repair for patients with severe mitral regurgitation; insertion of an implantable defibrillator for those with recurrent arrhythmias; and biventricular pacing for patients with prolonged intraventricular conduction. In addition, because of the shortage of suitable donors, patients with end-stage heart failure may be offered a ventricular-assist device as “destination” therapy (see Chapter 22).

The two main pathologies that give rise to end-stage cardiac failure necessitating heart transplantation are ischemic cardiomyopathy and the nonischemic cardiomyopathies (dilated, hypertrophic, restrictive), which make up about 45% of cases each.⁵ The remaining cases include valvular heart disease, congenital heart disease, and primary heart transplant failure. Inclusion and exclusion criteria for recipients of heart transplantation are outlined in Table 14-1.⁶

Table 14-1 Recipient Selection Criteria for Heart Transplantation

* Mancini DM, Eisen H, Kussmaul W, et al: Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 83:778-786, 1991. NYHA, New York Heart Association; VO_{2 max}, maximal exercise.

(Modified from Costanzo MR, Augustine S, Bourge R, et al: Selection and treatment of candidates for heart transplantation: a statement for health professionals from the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation 92:3539-3612, 1995.)

The assessment of a patient’s suitability for heart transplantation includes a right heart catheter study (see Chapter 5). This is a critical investigation because the presence of elevated pulmonary vascular resistance (>5 Wood units) contraindicates heart transplantation. A resistance level above 3 Wood units indicates an increased risk for postoperative right ventricular dysfunction.

A potential recipient is tested for ABO blood group and for the presence of antibodies to human leukocyte antigens (HLA). The latter is referred to as panelreactive antibodies and is expressed as the percentage of volunteer donor blood to which the patient’s serum reacts. A potential recipient with a high percentage of panel-reactive antibodies is less likely to have a negative (i.e., acceptable) cross-match with a potential organ donor and is therefore likely to have to wait longer for a suitable heart. Such a patient is also more likely to develop rejection following transplantation (see Hyperacute Rejection in the subsequent material).

Patients undergoing heart transplantation in the United States are typically extremely unwell: 70% are hospitalized; 25% require some form of mechanical cardiac support (ventricular-assist device or intraaortic balloon pump); and almost half are undergoing intravenous inotropic infusions.⁵ For patients with decompensated heart failure who are receiving inotropic drugs, the insertion of a ventricular-assist device prior to transplantation (i.e., as a bridge to transplantation rather than as destination therapy) may improve outcome after surgery.⁷

Evaluation of potential heart transplant recipients should be undertaken by a multidisciplinary team that is experienced in the management of severe heart failure and transplantation. This team includes cardiologists, cardiac surgeons, transplant coordinators, psychologists, social workers, dieticians, physiotherapists and, for critically ill patients, intensivists.

Donor Criteria and Management

As well as recipient criteria, donor criteria are vital in the decision to proceed with transplantation. An important criterion is the absence or low probability of coronary artery disease in the donor heart. For this reason, the upper donor age limit in most transplant units is 55 to 60 years.⁸ An echocardiogram is performed to assess valvular and ventricular function. The presence of segmental wall motion abnormalities is suggestive of myocardial ischemia or infarction and precludes the use of the organ. In some centers, coronary angiography is performed in potential donors who have risk factors for coronary artery disease.

The requirement for high-dose inotropic support in a donor is a relative contraindication to use of the heart for transplantation, particularly if it is associated with echocardiographic evidence of impaired ventricular function. The neuroendocrine failure that accompanies brain death is associated with marked vasodilation (see Chapter 38), and it usual for there to be some requirement for a vasopressor. The effects of neuroendocrine failure may be ameliorated by employing hormonal therapy (vasopressin, cortisol, triiodothyronine, insulin-glucose) in the donor. This regime may increase the number and quality of organs available for use in heart transplantation.

Ideally, the donor heart’s ischemic time should be less than 6 hours. In one study, an ischemic time greater than 4 hours was associated with increased rates of early mortality.⁹ In an attempt to extend the safe ischemic time, continuous perfusion systems (as opposed to standard cold storage) have been developed. These systems are complicated and have not been widely adopted.

Recipient-Donor Matching

The matching of recipients and donor organs within a particular country (or group of countries) is typically under the control of a single allocation agency; in the United States, it is the United Network of Organ Sharing (UNOS). Based on UNOS criteria, thoracic organs are offered on the basis of geography, donor-recipient compatibility, and medical urgency:

Prevention of Infection

The combination of end-stage cardiac disease, major surgery, and immunosuppression increases the risk for developing nosocomial infections following heart transplantation. Protective isolation (see Chapter 35) is not required, but ideally, transplant recipients are nursed in a single room. Thorough hand washing is mandatory prior to all patient contact. The likelihood of infection is minimized by early extubation and early removal of intravascular catheters and drains.

Glucose intolerance is common in the early postoperative period because of the effects of corticosteroids, calcineurine inhibitors, and β agonists. Given the numerous adverse effects of hyperglycemia (see Chapter 36), particularly with respect to wound healing and infection, blood glucose levels should be tightly controlled, ideally kept between 80 and 110 mg/dl (4.5 to 6.6 mmol/l).¹³ In patients who have negative levels of cytomegalovirus (CMV) antibodies, all blood transfused should be leukocyte depleted or, alternatively, a white-cell filter should be used.

Immunosuppression

Immunosuppression regimens for heart transplant recipients are essentially the same as those for recipients of lung transplants (see Chapter 13). Standard immunosuppression consists of triple therapy: a calcineurine inhibitor, an antiproliferative agent, and a corticosteroid. The most commonly used regime consists of cyclosporine, mycophenolate mofetil, and prednisone.⁵ Induction therapy is used in less than 50% of patients.⁵

The monitoring of immunosuppression involves drug-level monitoring (for cyclosporine, tacrolimus, and sirolimus) and surveillance endomyocardial biopsies. These biopsies are usually performed once a week for the first few weeks.

Other Medication

In addition to its antihypertensive effect, diltiazem has two additional benefits for heart transplant recipients. First, it retards the development of transplant coronary disease,¹⁴ and second, it inhibits the metabolism of calcineurine inhibitors (see Chapter 13); diltiazem has a dose-sparing effect on these drugs. Pravastatin, as well as having beneficial effects on lipid profiles, has been shown to improve 1-year survival rates and to decrease the incidence of transplant coronary disease.¹⁵ Limited data on other statins are less compelling. Aspirin is indicated for the prevention of the complications of coronary artery disease.

Co-trimoxazole is administered twice weekly for at least 6 months as prophylaxis against Pneumocystis jirovecii (formerly P. carinii) and Toxoplasma gondii infections. Recipients free of the CMV antibody who receive a heart from a donor who has the CMV antibody are initially administered prophylactic ganciclovir intravenously and then valganciclovir orally for a period of at least 100 days.

Primary Graft Failure

The major cause of early mortality (fewer than 5 days after heart transplantation) is primary graft failure.⁵ Although this description includes left and right ventricular dysfunction, the latter is much more common. The graft may have suffered significant myocardial stunning due to prolonged ischemic arrest and inadequate myocardial protection. The graft will have come from a donor with normal pulmonary vascular resistance, whereas pulmonary vascular resistance is often chronically elevated in the recipient as a consequence of chronic heart failure. Added to this is the acute increase in pulmonary vascular resistance that occurs perioperatively due to the effects of CPB, lung atelectasis, acidosis, hypoxemia, and raised intrathoracic pressure. These problems are compounded if a small donor heart is used in a relatively large recipient. Diastolic dysfunction is a problem for both ventricles, but it is particularly poorly tolerated by the right ventricle because right ventricular performance is highly dependent on preload.

Acute right ventricular dysfunction manifests as raised central venous pressure, systemic hypotension, and falling pulmonary artery pressures. This constellation of problems is identical to that seen in pericardial tamponade. Thus, if either diagnosis is suspected, TEE is mandatory.

With heart transplantation, a small heart is transplanted into a large pericardial cavity. Thus, a large volume of pericardial blood can accumulate without necessarily causing hemodynamic compromise. Echocardiographic evidence of chamber compression should be sought—in addition to a pericardial collection—before a diagnosis of tamponade is made.

The treatment of right ventricular failure is described in detail in Chapter 20. If the hemodynamic state continues to deteriorate despite maximal conventional therapy, mechanical support by means of a right ventricular assist device^16,17 or extracorporeal membrane oxygenation (ECMO) should be considered. ECMO may be superior to a right ventricular assist device in this situation,¹⁸ and it is certainly preferred if there is concomitant respiratory failure. Left ventricular dysfunction also may occur as a manifestation of primary graft failure. In severe cases, support with a biventricular assist device or ECMO is indicated.

As well as primary graft failure, myocardial ischemia due to the presence of donor coronary artery disease may cause ventricular dysfunction. ECG and TEE evidence of ischemia should be sought and, if confirmed, coronary angiography should be considered. The implications of raised troponin levels immediately after heart transplantation are unknown.

Hyperacute Rejection

Hyperacute rejection is an uncommon cause of primary graft failure that results from preformed antibodies directed against ABO or HLA antigens. The likelihood of the presence of anti-HLA antibodies is increased by previous exposure to blood-product transfusions (particularly platelets), mechanical support, pregnancy, and previous transplantation. The risk for forming antibodies is reduced with the use of leukocyte-depleted transfusions, and this should be mandatory for all potential transplant recipients. The development of hyperacute rejection is greatly reduced, but not eliminated, by performing a donor-recipient cross-match prior to transplantation. In patients with a high percentage of panel-reactive antibodies (<10%), perioperative plasmapheresis combined with immunoglobulin therapy may be used to reduce the incidence and severity of antibody-mediated (and cell-mediated) rejection. These interventions have allowed for transplantation between donors and recipients with positive cross-matches.¹⁹ Hyperacute rejection is manifested as severe biventricular failure that, in the absence of immediate retransplantation, is usually fatal.

Tricuspid Regurgitation

Tricuspid regurgitation may occur early after heart transplantation and is typically caused by right ventricular dysfunction or distortion of the tricuspid valve by the right atrial anastomosis. Tricuspid regurgitation that develops weeks or months later may be caused by graft dysfunction resulting from rejection or by damage to a valve leaflet or a subvalvular apparatus during endomyocardial biopsy. In one study, mild, moderate, and severe tricuspid regurgitation were identified intraoperatively by TEE in 9%, 10%, and 0.8% of heart transplant recipients, respectively.²⁰ In this study, the presence of even mild tricuspid regurgitation was associated with increased perioperative mortality rates. If moderate or severe tricuspid regurgitation is identified at the time of transplant surgery, immediate tricuspid repair may be considered. Medical treatment of tricuspid regurgitation involves inotropic support and careful control of intravascular volume by fluid restriction and diuretics.

Respiratory Failure

There are no causes of respiratory failure that are specific to heart transplant recipients. However, in patients with right ventricular dysfunction, right-to-left shunting across a patent foramen ovale must be considered as a cause of unexplained hypoxemia. If suspected, the diagnosis can be confirmed by TEE.

Bleeding

Bleeding is a common postoperative problem. Coagulation tests (aPTT, PT, fibrinogen, platelet count, thromboelastography) should be obtained in all heart transplant recipients on arrival in the intensive care unit and should be repeated after the administration of blood products. Hypothermia should be corrected but hyperthermia must be avoided. For actively bleeding patients, aprotinin may be continued into the early postoperative period, depending on the results of thromboelastography. For patients who received warfarin up until the time of the transplant, vitamin K (5 to 10 mg daily for 1 to 3 days) may be given if the prothrombin time is elevated. An algorithm for blood component therapy is provided in Figure 17-1.

Renal Failure and Fluid Overload

Renal replacement therapy is required in 10% to 15% of heart transplant recipients during the early postoperative period.^21,22 Preoperative renal dysfunction is strongly predictive of the development of postoperative renal dysfunction and is associated with an adverse outcome.²¹ In one study, a preoperative creatinine clearance of less than 50 ml/min was associated with a twofold increase in the 30-day mortality rate.⁹ Because of the risk of exacerbating tricuspid regurgitation by fluid overload, early institution of renal replacement therapy for oliguric renal failure is appropriate. Calcineurine inhibitors should be reduced or withheld during the period of renal failure and another agent such as sirolimus substituted.

Gastrointestinal Complications

Diarrhea, nausea, and vomiting can occur as side effects of immunosuppressant therapy, particularly of mycophenolate or, less commonly, secondary to infection by CMV. Serious gastrointestinal complications such as cholecystitis, pancreatitis, gastrointestinal bleeding, and mesenteric ischemia are more common after heart transplantation than after other types of cardiac surgery.^23,24 This may reflect the debilitated preoperative state and complicated postoperative course of many heart transplant recipients. Nonspecific signs, such as abdominal distension, abdominal pain, and intolerance of enteral feeds must be thoroughly investigated because they may represent serious underlying illness.

Acute Rejection

Acute rejection, detected by surveillance endomyocardial biopsy, is usually clinically silent. Severe episodes of acute rejection can present with arrhythmias, raised jugular venous pressure, hypotension, or echocardiographic evidence of ventricular dysfunction. There may be nonspecific symptoms and signs, including fever, malaise, and weight gain. Treatment of symptomatic or histologically severe acute rejection is by means of intravenous corticosteroids and, occasionally, antilymphocytic agents.

Monitoring for acute rejection by using biochemical markers (e.g., troponin and brain natriuretic peptide) or echocardiographic and ECG parameters remains experimental.

Infection

Infective complications that occur after heart transplantation are similar to those that occur after lung transplantation (see Chapter 13). In the first month the most common infections are bacterial, often by nosocomial organisms such as Pseudomonas aeruginosa. Viral and fungal infections are usually encountered a little later, 1 to 2 months after surgery, whereas protozoal infections by organisms such as Giardia species usually have a peak occurrence several months after transplantation.

Systemic Embolism

Left atrial thrombosis occurs in up to 50% of patients who have undergone heart transplantation by means of conventional surgical techniques, with systemic embolism occurring in 6% to 14%.^26,27 The incidence of left atrial thrombosis is markedly reduced when the “total transplant” surgical technique is used.²⁷ If thrombus is identified, anticoagulation with warfarin is indicated.

Transplant Coronary Disease Caused by Chronic Rejection

Chronic rejection is manifested as an atypical, aggressive form of coronary artery disease. In contrast to conventional atherosclerosis, transplant coronary disease is associated with intimal hyperplasia, is commonly concentric and diffuse, and in many cases involves small branch arteries.²⁸

From 1 to 5 years after transplantation, coronary disease is the leading cause of death, with an incidence on coronary angiography of 50% at 5 years.^25,29 Intravascular ultrasound studies show an incidence of subclinical disease of up to 75% at 1 year.³⁰ Coronary disease may also be detected as wall motion abnormalities on surveillance echocardiography or stress imaging. Initially, transplant coronary disease is usually clinically silent, although a small number of patients develop angina, presumably due to partial reinnervation of the graft. Eventually patients develop congestive cardiac failure.

Transplant coronary disease is poorly responsive to percutaneous coronary intervention and bypass graft surgery. These procedures provide only short-term benefit and are considered palliative.³¹ Prognosis is poor; 1-year survival after the first ischemic event is less than 20%.³² Recently, some hope has been provided by the observation that sirolimus retards the development of coronary artery vasculopathy.^33,34

Malignancy

Beyond 5 years after transplantation, malignancy surpasses vasculopathy as the major cause of death, with an incidence of 24% at 7 years (see Fig 14-1).²⁵ The vast majority of cancers are of the skin, which occur in 18% of patients at 7 years.⁵ The remainder are predominantly solid organ neoplasms or lymphoproliferative disorders. These malignancies can often be ameliorated by a reduction in immunosuppression. Transplant recipients are strongly advised to protect their skin against sun exposure and refrain from smoking.

Other Complications

As with lung transplant recipients, heart transplant recipients are subject to significant problems over the longer term; they might be subject to chronic renal failure, hypertension, diabetes, gout, hirsutism, or osteoporosis.