The history of heart transplantation spans almost a century. Canine heterotopic cardiac transplantation was first reported in 1905,¹ but such efforts were doomed by ignorance of the workings of the immune system (Box 23-1). Further research in the late 1950s and early 1960s set the stage for the first human cardiac transplant by Barnard in 1966.² However, there were few long-term survivors in this era because of continued deficiency in understanding and modulating the human immune system, and the procedure fell into general disfavor. Continued research at selected centers (such as Stanford University) and lessons learned from renal transplantation led to greater understanding of the technical issues and immunology required, and by the early 1980s, cardiac transplantation gained widespread acceptance as a realistic option for patients with end-stage cardiomyopathy.

BOX 23-1 Heart Transplantation

• Frequency of transplantation remains limited by donor supply.

• Pathophysiology before transplantation is primarily that of end-stage ventricular failure.

• Pathophysiology after transplantation reflects the effects of denervation.

• Allograft coronary vasculopathy is a frequent long-term complication.

Heart transplantation experienced explosive growth in the mid-to-late 1980s, but the annual number of heart transplants worldwide plateaued by the early 1990s at approximately 3500 per year.³ The factor limiting continued growth has been a shortage of suitable donors. As of January 2010, there were slightly more than 3000 patients on the United Network for Organ Sharing (UNOS) cardiac transplant waiting list (includes all U.S. candidates), whereas only 2028 heart transplants were performed in the United States during the 2009 calendar year. The median waiting time for a cardiac graft varies widely according to blood type (approximately 52 days for type AB recipients in contrast with 242 days for type O recipients listed for the period 2003–2004). In aggregate, approximately 30% to 37% of those patients on the heart transplant list had spent more than a year waiting for a transplant during 2007.⁴ Adult patients on the heart transplant waiting list are assigned a status of 1A, 1B, or 2. Status 1A patients require mechanical circulatory support, mechanical ventilation, high-dose or multiple inotropes, with continuous monitoring of left ventricular filling pressure. Status 1B patients require mechanical circulatory support beyond 30 days or inotropic support without continuous monitoring of left ventricular filling pressure. All other patients are classified as Status 2.⁴ The most frequent recipient indications for adult heart transplantation remain either idiopathic or ischemic cardiomyopathy. Other less common diagnoses include viral cardiomyopathy, systemic diseases such as amyloidosis, and complex congenital heart disease (CHD).

The 1-year survival rate after heart transplantation has been reported to be 79%, with a subsequent mortality rate of approximately 4%/year.³ There has been only slight improvement in the survival statistics over the past decade; the Organ Procurement and Transplant Network reports that the 1- and 3-year survival rates after heart transplantation for those transplanted in the United States during the period 1997–2004 was approximately 87% and 78%, respectively, at the time this chapter was written. One-year survival rate after repeat heart transplantation more than 6 months after the original procedure is slightly lower (63%) but substantially worse if performed within 6 months of the original grafting (39%).³ Risk factors for increased mortality have been associated with recipient factors (prior transplantation, poor human leukocyte antigen matching, ventilator dependence, age, and race), medical center factors (volume of heart transplants performed, ischemic time), and donor factors (race, sex, age). Early deaths most frequently are due to graft failure, whereas intermediate-term deaths are caused by acute rejection or infection. Late deaths after heart transplantation most frequently are due to allograft vasculopathy, post-transplant lymphoproliferative disease or other malignancy, and chronic rejection (Box 23-1).

Recipient Selection

Potential candidates for heart transplantation generally undergo a multidisciplinary evaluation including a complete history and physical examination, routine hematology, chemistries (to assess renal and hepatic function), viral serology, electrocardiography, chest radiography, pulmonary function tests, and right- and left-heart catheterization. Ambulatory electrocardiography, echocardiography, and nuclear gated scans are performed if necessary. The goals of this evaluation are to confirm a diagnosis of end-stage heart disease that is not amenable to other therapies and that will likely lead to death within 1 to 2 years, as well as to exclude extracardiac organ dysfunction that could lead to death soon after heart transplantation. Patients typically have New York Heart Association Class IV symptoms and a left ventricular ejection fraction less than 20%. Although most centers eschew a strict age cutoff, the candidate should have a “physiologic” age younger than 60. Detecting pulmonary hypertension and determining whether it is due to fixed elevation of pulmonary vascular resistance (PVR) is crucial; early mortality because of graft failure is threefold greater in patients with increased PVR (transpulmonary gradient > 15 mm Hg or PVR > 5 dynes•sec•cm⁻⁵).⁵ If increased PVR is detected, a larger donor heart, a heterotopic heart transplant, or a heart–lung transplant may be more appropriate. Active infection and recent pulmonary thromboembolism with pulmonary infarction are additional contraindications to heart transplantation. The results of this extensive evaluation should be tabulated and available to the anesthesia team at all times because heart transplantation is an emergency procedure.

Donor Selection and Graft Harvest

Once a brain-dead donor has been identified, the accepting transplant center must further evaluate the suitability of the allograft. Centers generally prefer donors to be free of previous cardiac illness and younger than 35 years because the incidence of coronary artery disease markedly increases at older ages. However, the relative shortage of suitable cardiac donors has forced many transplant centers to consider older donors without risk factors and symptoms of coronary artery disease. If it is necessary and the services are available at the donor hospital, the heart can be further evaluated by echocardiography (for regional wall motion abnormalities) or coronary angiography, to complement standard palpation of the coronaries in the operating room. The absence of sepsis, prolonged cardiac arrest, severe chest trauma, and a high inotrope requirement also are important. The donor is matched to the prospective recipient for ABO blood-type compatibility and size (within 20%, especially if the recipient has high PVR); a cross-match is performed only if the recipient’s preformed antibody screen is positive.

Donors can exhibit major hemodynamic and metabolic derangements that can adversely affect organ retrieval.⁶ Most brain-dead donors will be hemodynamically unstable.⁷ Reasons for such instability include hypovolemia (secondary to diuretics or diabetes insipidus), myocardial injury (possibly a result of “catecholamine storm” during periods of increased intracranial pressure), and inadequate sympathetic tone because of brainstem infarction. Donors often also have abnormalities of neuroendocrine function such as low T₃ and T₄ levels. Administration of T₃ to brain-dead animals improves ventricular function after transplantation⁸; T₃ administration has enabled decreases in inotropic support in some^9,¹⁰ but not all human studies.¹¹ Donor volume status should be assiduously monitored, and inotropic and vasopressor therapy should be guided by data from invasive monitors.

Donor cardiectomy is performed through a median sternotomy, usually simultaneously with recovery of other organs such as lungs, kidneys, and liver. Just before cardiac harvesting, the donor is heparinized and an intravenous cannula is placed in the ascending aorta for administration of conventional cardioplegia. The superior vena cava (SVC) is ligated and the inferior vena cava (IVC) transected to decompress the heart, simultaneous with the administration of cold hyperkalemic cardioplegia into the aortic root. The aorta is cross-clamped when the heart ceases to eject. The heart also is topically cooled with ice-cold saline. After arrest has been achieved, the pulmonary veins are severed, the SVC is transected, the ascending aorta is divided just proximal to the innominate artery, and the pulmonary artery (PA) is transected at its bifurcation. The heart is then prepared for transport by placing it in a sterile plastic bag that is placed, in turn, in another bag filled with ice-cold saline, all of which are carried in an ice chest. Of all the regimens tested, conventional cardioplegia has proved most effective in maintaining cardiac performance.¹² The upper time limit for ex vivo storage of human hearts appears to be approximately 6 hours.¹³

Surgical Procedures

Orthotopic Heart Transplantation

Orthotopic heart transplantation is carried out via a median sternotomy, and the general approach is similar to that used for coronary revascularization or valve replacement. Frequently, patients will have undergone a prior median sternotomy; repeat sternotomy is cautiously performed using an oscillating saw. The groin should be prepped and draped to provide a rapid route for cannulation for cardiopulmonary bypass (CPB) if necessary. After the pericardium is opened, the aorta is cannulated as distally as possible and the IVC and SVC are individually cannulated via the high right atrium. Manipulation of the heart before institution of CPB is limited if thrombus is detected in the heart with transesophageal echocardiography (TEE; Figure 23-1). After initiation of CPB and cross-clamping of the aorta, the heart is arrested and excised (Figure 23-2). The aorta and PA are separated and divided just above the level of their respective valves, and the atria are transected at their grooves. A variant of this classic approach totally excises both atria, mandating bicaval anastomoses. This technique may reduce the incidence of atrial arrhythmias, better preserve atrial function by avoiding tricuspid regurgitation, and enhance cardiac output (CO) after transplantation.^14,¹⁵

Figure 23-1 Transesophageal echocardiographic image of laminated intraventricular thrombus in the native left ventricular apex. If intracavitary thrombus is found, great caution is warranted during dissection before cardiopulmonary bypass to avoid systemic embolization.

Figure 23-2 Mediastinum after excision of the heart but before allograft placement.

Venous cannulas are present in the superior (SVC) and inferior vena cava (IVC), and the arterial cannula is present in the ascending aorta. A, Classic orthotopic technique. B, Bicaval anastomotic technique.

The donor graft then is implanted with every effort to maintain a cold tissue temperature, beginning with the left atrial (LA) anastomosis. If the foramen ovale is patent, it is sutured closed. The donor right atrium is opened by incising it from the IVC to the base of the right atrial (RA) appendage (to preserve the donor sinoatrial node), and the RA anastomosis is constructed. Alternatively, if the bicaval technique is used, individual IVC and SVC anastomoses are sewn. The donor and recipient pulmonary arteries are then brought together in an end- to-end manner, followed by the anastomosis of the donor to the recipient aorta. After removal of the aortic cross-clamp, the heart is de-aired via a vent in the ascending aorta. Just before weaning from CPB, one of the venous cannulae is withdrawn into the right atrium and the other removed. The patient is then weaned from CPB in the usual manner. After hemostasis is achieved, mediastinal tubes are placed for drainage, the pericardium is left open, and the wound is closed in the standard fashion.

Heterotopic Heart Transplantation

Although orthotopic placement of the cardiac graft is optimal for most patients, certain recipients are not candidates for the orthotopic operation, and instead the graft is placed in the right chest and connected to the circulation in parallel with the recipient heart. The two primary indications for heterotopic placement are significant irreversible pulmonary hypertension and gross size mismatch between the donor and recipient. Heterotopic placement may avoid the development of acute right ventricular (RV) failure in the unconditioned donor heart in the face of acutely increased RV afterload.

Donor harvesting for heterotopic placement is performed in the previously described manner, except that the azygos vein is ligated and divided to increase the length of the donor SVC; the PA is extensively dissected to provide the longest possible main and right PA; and the donor IVC and right pulmonary veins are oversewn, with the left pulmonary veins incised to create a single large orifice. The operation is performed via a median sternotomy in the recipient, but the right pleura is entered and excised. The recipient SVC is cannulated via the RA appendage, and the IVC via the lower right atrium. After arresting the recipient heart, the LA anastomosis is constructed by incising the recipient left atrium near the right superior pulmonary vein and extending this incision inferiorly, and then anastomosing the respective left atria. The recipient RA-SVC is then incised and anastomosed to the donor RA-SVC, after which the donor aorta is joined to the recipient aorta in an end-to-side manner. Finally, the donor PA is anastomosed to the recipient main PA in an end-to-side manner if it is sufficiently long; otherwise, they are joined via an interposed vascular graft (Figure 23-3).

Figure 23-3 Placement of heterotopic graft in the right chest, with anastomoses to the corresponding native left (LA) and right atria (RA), ascending aorta (AO), and an interposition graft to the native pulmonary artery (PA). LV, left ventricle; RV, right ventricle; SVC, superior vena cava.

(From Cooper DKC, Lanza LP: Heart Transplantation: The Present Status of Orthotopic and Heterotopic Heart Transplantation. Lancaster, United Kingdom, MTP Press, 1984.)

Special Situations

Mechanical ventricular assist devices (see Chapters 27 and 32) have been used successfully to “bridge” patients who would otherwise die of acute heart failure awaiting transplantation.¹⁶ The technique of transplantation is virtually identical in such patients to that for ordinary orthotopic transplantation. However, repeat sternotomy is obligatory. Placement of large-bore intravenous access is prudent because excessive hemorrhage can occur during the transplant procedure.

Rarely, patients will present for cardiac transplantation combined with transplantation of the liver.¹⁷ The cardiac allograft usually is implanted first to better enable the patient to survive potential hemodynamic instability associated with reperfusion of the hepatic allograft. Large-bore intravenous access is mandatory. Conventional full heparinization protocols or low-dose heparin with heparin-bonded circuits may be used. A venous cannula can be left in the right atrium at the completion of the heart transplant procedure to serve as a return site for subsequent venovenous bypass during liver transplantation.

Pathophysiology before Transplantation

The pathophysiology of heart transplant candidates is predominantly end-stage cardiomyopathy. Normally, such patients will have both systolic dysfunction (characterized by decreased stroke volume and increased end-diastolic volume) and diastolic dysfunction, characterized by an increased intracardiac diastolic pressure. As compensatory mechanisms to maintain CO fail, the increased LV pressures lead to increases in pulmonary venous pressures and development of pulmonary vascular congestion and edema. A similar process occurs if RV failure also occurs. Autonomic sympathetic tone is increased in patients with heart failure, leading to generalized vasoconstriction, as well as salt and water retention. Vasoconstriction and ventricular dilation combine to substantially increase myocardial wall tension. Over time, the high levels of catecholamines lead to a decrease in the sensitivity of the heart and vasculature to these agents via a decrease in receptor density (i.e., “downregulation”) and a decrease in myocardial norepinephrine stores.¹⁸

Therapy of heart failure seeks to reverse or antagonize these processes (see Chapters 10, 32, and 34). Almost all candidates will be maintained on diuretics; hypokalemia and hypomagnesemia secondary to urinary losses are likely, and the anesthesiologist must be alert to the possibility that a patient is hypovolemic from excessive diuresis. Another mainstay of therapy is vasodilators (such as nitrates, hydralazine, and angiotensin-converting enzyme inhibitors), which decrease the impedance to LV emptying and improve cardiac function and survival in patients with end-stage heart failure.^19,²⁰ Paradoxically, slow incremental β-blockade with agents such as the β₁-antagonist metoprolol also can improve hemodynamics and exercise tolerance in some patients awaiting heart transplantation.²¹ Patients who are symptomatic despite these measures often will require inotropic therapy. Digoxin is an effective but weak inotrope, and its use is limited by toxic side effects. Phosphodiesterase inhibitors such as amrinone, milrinone, and enoximone are efficacious, but chronic therapy is restricted by concerns about increased mortality in those receiving these agents.^22,²³ Therefore, inotrope-dependent patients often are treated with intravenous infusions of β-adrenergic agonists such as dopamine or dobutamine. Patients refractory to even these measures may be supported with intra-aortic balloon counterpulsation, but its use is fraught with significant vascular complications and essentially immobilizes the patient. Many patients with low CO are maintained on anticoagulants such as warfarin to prevent pulmonary or systemic embolization, especially if they have atrial fibrillation.

Pathophysiology after Transplantation

The physiology of patients after heart transplantation is of interest not only to anesthesiologists in cardiac transplant centers but to the anesthesiology community at large because a substantial portion of these patients return for subsequent surgical procedures.^24,²⁵

Cardiac denervation is an unavoidable consequence of heart transplantation. Many long-term studies indicate that reinnervation is absent,^26,²⁷ or at best partial or incomplete,²⁸ in humans. Denervation does not significantly change baseline cardiac function,^29,³⁰ but it does substantially alter the cardiac response to demands for increased CO. Normally, increases in heart rate can rapidly increase CO, but this mechanism is not available to the transplanted heart. Heart rate increases only gradually with exercise, and this effect is mediated by circulating catecholamines.²⁶ Increases in CO in response to exercise are instead mostly mediated via an increase in stroke volume.³¹ Therefore, maintenance of adequate preload in cardiac transplant recipients is crucial. Lack of parasympathetic innervation probably is responsible for the gradual decrease in heart rate after exercise seen in transplant recipients, rather than the usual sharp decline.

Denervation has important implications in the choice of pharmacologic agents used after cardiac transplantation. Drugs that act indirectly on the heart via either the sympathetic (ephedrine) or parasympathetic (atropine, pancuronium, edrophonium) nervous systems generally will be ineffective. Drugs with a mixture of direct and indirect effects will exhibit only their direct effects (leading to the absence of the normal increase in refractory period of the atrioventricular node with digoxin,³² tachycardia with norepinephrine infusion, and bradycardia with neostigmine).³³ Thus, agents with direct cardiac effects (such as epinephrine or isoproterenol) are the drugs of choice for altering cardiac physiology after transplantation. However, the chronically high catecholamine levels found in cardiac transplant recipients may blunt the effect of α-adrenergic agents, as opposed to normal responses to β-adrenergic agents.³⁴

Allograft coronary vasculopathy remains the greatest threat to long-term survival after heart transplantation. Allografts are prone to the accelerated development of an unusual form of coronary atherosclerosis that is characterized by circumferential, diffuse involvement of entire coronary arterial segments, as opposed to the conventional form of coronary atherosclerosis with focal plaques often found in eccentric positions in proximal coronary arteries.³⁵ The pathophysiologic basis of this process remains elusive, but it is likely due to an immune cell–mediated activation of vascular endothelial cells to upregulate the production of smooth muscle cell growth factors.³⁶ More than half of all heart transplant recipients have evidence of concentric atherosclerosis 3 years after transplant, and more than 80% at 5 years.³⁷ Because afferent cardiac reinnervation is rare, a substantial portion of recipients with accelerated vasculopathy will have silent ischemia.³⁸ Noninvasive methods of detecting coronary atherosclerosis are insensitive for detecting allograft vasculopathy.³⁹ Furthermore, coronary angiography often underestimates the severity of allograft atherosclerosis⁴⁰; other diagnostic regimens such as intravascular ultrasound and dobutamine stress echocardiography may detect morphologic abnormalities or functional ischemia, respectively, in the absence of angiographically significant lesions.^35,^40,⁴¹ Therefore, the anesthesiologist should assume that there is a substantial risk for coronary vasculopathy in any heart transplant recipient beyond the first 2 years, regardless of symptoms, the results of noninvasive testing, and even angiography.

Anesthetic Management

Preoperative Evaluation and Preparation

The preoperative period often is marked by severe time constraints because of the impending arrival of the donor heart. Nevertheless, a rapid history should screen for last oral intake, recent anticoagulant use, intercurrent deterioration of ventricular function, or change in anginal pattern; a physical examination should evaluate present volume status, and a laboratory review (if available) and a chest radiograph should detect the presence of renal, hepatic, or pulmonary dysfunction. Many hospitalized patients will be supported with inotropic infusions and/or an intra-aortic balloon pump, and the infusion rates and timing of the latter should be reviewed.

Equipment and drugs similar to those usually used for routine cases requiring CPB should be prepared. A β-agonist such as epinephrine should be readily available both in bolus form and as an infusion to rapidly treat ventricular failure; and an α-agonist such as phenylephrine or norepinephrine is useful to compensate for the vasodilatory effects of anesthetics because even small decreases in preload and afterload can lead to catastrophic changes in CO and coronary perfusion in these patients.

Placement of invasive monitoring before induction will facilitate rapid and accurate response to hemodynamic events during induction. In addition to standard noninvasive monitoring, an arterial catheter and a PA catheter (with a long sterile sheath to allow partial removal during graft implantation) are placed after judicious use of sedation and local anesthetics. Placing the arterial catheter in a central site rather than the radial artery will avoid the discrepancy between radial and central arterial pressure often seen after CPB, but it also may be necessary to cannulate a femoral artery for arterial inflow for CPB if there has been a prior sternotomy. Floating the PA catheter into correct position may be difficult because of cardiac chamber dilation and severe tricuspid regurgitation. Large-bore intravenous access is mandatory, especially if a sternotomy has been previously performed, in which case external defibrillator/pacing patches also may be useful. The overall hemodynamic “picture” should be evaluated and optimized insofar as possible just before induction. If the hemodynamics seem tenuous, then starting or increasing an inotrope infusion may be advisable.

Induction

Most patients presenting for heart transplantation will not be in a fasting state and should be considered to have a “full stomach.” Therefore, the induction technique should aim to rapidly achieve control of the airway to prevent aspiration while avoiding myocardial depression. A regimen combining a short-acting hypnotic with minimal myocardial depression (etomidate, 0.3 mg/kg), a moderate dose of narcotic to blunt the tachycardic response to laryngoscopy and intubation (fentanyl, 10 μg/kg), and succinylcholine (1.5 mg/kg) is popular ⁴²; high-dose narcotic techniques with or without benzodiazepines also have been advocated.^43,⁴⁴ Vasodilation should be countered with an α-agonist. Anesthesia can be maintained with additional narcotic and sedatives (benzodiazepines or scopolamine).^44,⁴⁵

Intraoperative Management

After induction, the stomach can be decompressed with an orogastric tube and a TEE probe introduced while the bladder is catheterized. A complete TEE examination often will reveal useful information not immediately available from other sources, such as the presence of cardiac thrombi (see Figure 23-1), ventricular volume and contractility, and atherosclerosis of the ascending aorta and aortic arch. Cross-matched blood should be immediately available once surgery commences, especially if the patient has had a previous sternotomy; patients not previously exposed to cytomegalovirus should receive blood from donors who are likewise cytomegalovirus negative. Sternotomy and cannulation for CPB are performed as indicated earlier. The period before CPB often is uneventful, apart from arrhythmias and slow recovery of coronary perfusion because of manipulation of the heart during dissection and cannulation. The PA catheter should be withdrawn from the right heart before completion of bicaval cannulation.

Once CPB is initiated, ventilation is discontinued and the absence of a thrill in the carotid arteries is documented. Most patients will have an excess of intravascular volume, and administration of a diuretic and/or the use of hemofiltration via the pump may be beneficial by increasing the hemoglobin concentration. A dose of glucocorticoid (methylprednisolone, 500 mg) is administered as the last anastomosis is being completed before release of the aortic cross-clamp to attenuate any hyperacute immune response. During the period of reperfusion an infusion of an inotrope is begun for both inotropy and chronotropy. TEE is used to monitor whether the cardiac chambers are adequately de-aired before weaning from CPB.

Weaning from bypass begins after ventilation is resumed and the cannula in the SVC is removed. The donor heart should be paced if bradycardia is present despite the inotropic infusion. Once the patient is separated from CPB, the PA catheter can be advanced into position. Patients with increased PVR are at risk for acute RV failure and may benefit from a pulmonary vasodilator such as prostaglandin E₁ (0.05 to 0.15 μg/kg/min).⁴⁶ Rarely, such patients will require support with a RV assist device.⁴⁷ TEE often will provide additional useful information about right- and left-heart function and volume, and document normal flow dynamics through the anastomoses. Unless a bicaval anastomosis was created, a ridge of redundant tissue will be evident in the left atrium and should not cause alarm (see Videos 1A and 1B, available online).

Protamine then is given to reverse heparin’s effect after satisfactory weaning from CPB. Continued coagulopathy despite adequate protamine is common after heart transplantation, especially if there has been a prior sternotomy. Treatment is similar to that used for other postbypass coagulopathies: meticulous attention to surgical hemostasis, empiric administration of platelets, and subsequent addition of fresh-frozen plasma and cryoprecipitate guided by subsequent coagulation studies (see Chapters 17, 30 and 31). After adequate hemostasis is achieved, the wound is closed in standard fashion and the patient transported to the intensive care unit (ICU).

Postoperative Management and Complications

Management in the ICU after the conclusion of the procedure essentially is a continuation of the anesthetic management after CPB.⁴⁸ The electrocardiogram; arterial, central venous, and/or PA pressures; and arterial oxygen saturation are monitored continuously. Cardiac recipients will continue to require β-adrenergic infusions for chronotropy and inotropy for up to 3 to 4 days. Vasodilators may be necessary to control arterial hypertension and decrease impedance to LV ejection. Patients can be weaned from ventilatory support and extubated when the hemodynamics are stable and hemorrhage has ceased. The immunosuppressive regimen of choice (typically consisting of cyclosporine, azathioprine, and prednisone, or tacrolimus and prednisone) should be started after arrival in the ICU. Invasive monitoring can be withdrawn as the inotropic support is weaned, and mediastinal tubes removed after drainage subsides (usually after 24 hours). Patients usually can be discharged from the ICU after 2 or 3 days (see Chapters 33–35).

Early complications after heart transplantation include acute and hyperacute rejection, cardiac failure, systemic and pulmonary hypertension, cardiac arrhythmias, renal failure, and infection. Hyperacute rejection is an extremely rare but devastating syndrome mediated by preformed recipient cytotoxic antibodies against donor heart antigens. The donor heart immediately becomes cyanotic from microvascular thrombosis and ultimately ceases to contract.⁴⁹ This syndrome is lethal unless the patient can be supported mechanically until a suitable heart is found. Acute rejection is a constant threat in the early postoperative period and may present in many forms (e.g., low CO, arrhythmias). Acute rejection occurs most frequently during the initial 6 months after transplantation, so its presence is monitored by serial endomyocardial biopsies, with additional biopsies to evaluate any acute changes in clinical status. Detection of rejection mandates an aggressive increase in the level of immunosuppression, usually including pulses of glucocorticoid or a change from cyclosporine to tacrolimus. Low CO after transplantation may reflect a number of causative factors: hypovolemia, inadequate adrenergic stimulation, myocardial injury during harvesting, acute rejection, tamponade, or sepsis. Therapy should be guided by invasive monitoring, TEE, and endomyocardial biopsy. Systemic hypertension may be caused by pain, so adequate analgesia should be obtained before treating blood pressure with a vasodilator. Because fixed pulmonary hypertension will have been excluded during the recipient evaluation, pulmonary hypertension after heart transplantation usually will be transient and responsive to vasodilators such as prostaglandin E₁, nitrates, or hydralazine after either orthotopic or heterotopic placement.^50,⁵¹ Atrial and ventricular tachyarrhythmias are common after heart transplantation⁵²; once rejection has been ruled out as a cause, antiarrhythmics are used for conversion or control (except those acting via indirect mechanisms such as digoxin, or those with negative inotropic properties such as β-blockers and calcium channel blockers). Almost all recipients will require either β-adrenergic agonists or pacing to increase heart rate in the immediate perioperative period, but 10% to 25% of recipients also will require permanent pacing.^53,⁵⁴ Renal function often improves immediately after transplantation, but immunosuppressives such as cyclosporine and tacrolimus may impair renal function.^55,⁵⁶ Finally, infection is a constant threat to immunosuppressed recipients. Bacterial pneumonia is frequent early in the postoperative period, with opportunistic viral and fungal infections becoming more common after the first several weeks (see Chapter 37).

Pediatric Considerations

In the pediatric population, dilated cardiomyopathy and complex congenital heart defects are the primary indications for heart transplantation. Although the number of donors and recipients has remained stable in recent years, the overall survival has improved in children undergoing heart transplantation. Factors that contribute to this trend are enhanced preservation of the donor heart, improved selection of recipients and donors, and refinements in surgical techniques and immunosuppressive therapy.⁵⁷

Cardiac transplantation is recommended when the child’s expected survival is less than 1 year. In some centers, this therapy is offered as the primary intervention to the infant born with hypoplastic left-heart syndrome. The perioperative and intraoperative management of these infants undergoing heart transplant have been extensively reviewed.⁵⁸

The preoperative assessment for heart transplantation in the patient with complex CHD might be more extensive depending on the heart defect and previous corrective or palliative procedures. Similar to the child with dilated cardiomyopathy, assessment of the indexed pulmonary vascular resistance (PVRI) is essential.⁵⁷ In adults, a PVRI greater than 5 units and a transpulmonary gradient greater than 15 mm Hg are contraindications for transplantation. In children, the acceptable PVRI is less than 10 units, but it is not unusual for a pediatric heart transplant candidate to have a PVRI greater than 10 units. In one pediatric cardiac center, 20% of the transplanted patients had PVRIs greater than 6 units. However, in the 6 to 10 unit range, the child is at risk for acute RV failure because the donor’s right ventricle is thin walled and the myocardium has been ischemic. If the PVRI decreases significantly in the catheterization laboratory, with a trial of vasodilator testing, hyperventilation, 100% O₂, and nitric oxide, the candidate is acceptable for transplant. If the PVRI remains borderline, the candidate is admitted to the hospital for a 1- or 2-week trial with milrinone and dobutamine. If the PVRI then falls, transplantation is offered. These patients might benefit from pulmonary vasodilation therapy during weaning from CPB and in the ICU.

Another aspect to be emphasized in the pretransplant evaluation of these patients with complex CHD is the need for a detailed anatomic evaluation. It is not uncommon for this group of patients to have branch PA stenosis or discontinuous pulmonary arteries. Anomalies of systemic and pulmonary veins are associated with atrial isomerism, and different surgical techniques are needed to address these issues during transplantation. High-output failure may develop in the recipient with large aortopulmonary collaterals in the postoperative period. Although the donor ischemic time, ICU days, and total hospital days are prolonged in these patients, the outcome is comparable with the patient with dilated cardiomyopathy after heart transplantation.

Cardiac transplantation also is offered to patients with the so-called failed Fontan for physiologic repair of cardiac defects with single ventricle. They present with protein-losing enteropathy, chronic liver disease, and pulmonary arteriovenous malformations. These malformations may complicate the postoperative course. If they are large enough, moderate-to-severe hypoxemia may lead to primary graft failure. Small malformations may regress with time.

In some recipients, the circulation is supported by extracorporeal membrane oxygenation (ECMO) or a ventricular assist device before transplantation. Prolonged support is associated with bleeding, sepsis, and multiorgan dysfunction. It is not uncommon to list an infant who is on ECMO for heart transplant after a failed Norwood procedure. Transportation of this infant to the operating room can be quite complicated.

Besides determining the blood type (ABO), it is important to assess for the presence of antibodies against human histocompatability leukocyte antigen.⁵⁹ Antibodies against human histocompatability leukocyte antigen may have developed in the recipient who was exposed to blood products during palliation for complex CHD. Hyperacute rejection may lead to graft loss in the operating room in this setting. The risk for primary graft failure is greater if more than mild systolic dysfunction was present in the donor heart before transplantation. In pediatrics, the donor-recipient heart size matching in weight ranges between 80% and 300%. At surgery, the bicaval technique is preferred.

As in adults, sedation before surgery is provided with benzodiazepines or scopolamine. Full-stomach precautions generally are taken. Induction of anesthesia is accomplished with etomidate (0.2 to 0.3 mg/kg), fentanyl, and a muscle relaxant (succinylcholine or a nondepolarizer). Titration to vital signs is important. Frequently, the groin vessels are exposed for urgent cannulation before sternotomy, and during this procedure fewer narcotics are required. If hemodynamics are adequate, a volatile agent can be used. An opioid with a benzodiazepine is used for maintenance of anesthesia. Recall of operative events has been documented in young adolescents. A PA catheter is useful in the older child, but just an RV catheter can be used when there are concerns about pulmonary hypertension.

Lung transplantation

History and Epidemiology

Although the first human lung transplant was performed in 1963, surgical technical problems and inadequate preservation and immunosuppression regimens prevented widespread acceptance of this procedure until the mid-1980s (Box 23-2). Advances in these areas have since made lung transplantation a viable option for many patients with end-stage lung disease. For the period January 1, 1985, to June 30, 2008, a total of 29,732 lung transplants were reported to the Registry of the International Society for Heart and Lung Transplantation.³ The frequency of both single- and double-lung transplants increased exponentially during the period up until 1993, with the sharpest growth in unilateral transplants. According to data collected by UNOS between 2000 and 2002, the annual frequency of lung transplantation has remained stagnant, with the total number still averaging in the vicinity of 1000. This is unchanged from the time between 1993 and 1995, when the numbers first leveled off. Further growth in lung transplantation is constrained by a shortage of donor organs, with demand for organs still vastly exceeding supply. This may potentially be exacerbated by data that were published in 2009, revealing that double-lung transplant afforded fewer hospitalizations and potentially better long-term survival.⁶⁰

BOX 23-2 Lung Transplantation

• Broader donor criteria have decreased the time from listing to transplantation.

• Nitric oxide minimizes reperfusion injury.

• Donor lungs should be ventilated with a protective strategy (low inspired oxygen, low tidal volume/inspired pressure) after transplantation.

It is estimated that in excess of a million individuals with end-stage lung disease are potential recipients of lung transplants.⁶¹ Some had hoped that non–heart-beating donors would provide an alternative source of organs, but this has not been the case. The Organ Procurement and Transplantation Network currently registers approximately 4000 patients for lung transplantation. This number does not accurately reflect the number of organs required because some patients will require bilateral lung transplantation. Average time to transplant increased to as much as 451 days in 1999; however, recently, that time has again decreased significantly. Currently, about one fourth of patients are transplanted within 251 days. Most of this improvement has been seen with recipients who are 50 years and older. One explanation for this may be increasing leniency in organ-selection criteria. This seems not to have been associated with increasing mortality rates. Mortality for patients on the waiting list also has continued to decline, from a 1993 high of close to 250 per 1000 patient-years to approximately 140 in 2002. Although some of this improvement may be ascribed to better medical management of patients on the waiting list, it is also likely due to broadened criteria for acceptance for transplantation and subsequent inclusion of patients with less severe illness.

Increased experience with lung transplantation has been accompanied by a decrease in both operative and long-term mortality. For example, 30-day mortality rate for double-lung transplantation decreased from 44% in 1988 to 13.6% in 1991, whereas that for single-lung transplantation decreased from 22.7% to 12.6%.⁶² As of the end of 2008, 3-year actuarial survival for recipients of both single- and double-lung transplants performed in the era 1992 to 1995 was approximately between 56% and 67% depending on recipient age percentage, which is a trend of continuing improvement of the periods preceding 2005.³ Even better survival data have been reported from centers with extensive experience with these procedures (1-year survival rates of 82% for double-lung recipients and 90% for single-lung recipients).⁶³ Infection is the most frequent cause of death in the first year after transplant, but this is superseded in later years by bronchiolitis obliterans.³ Notable is that 21% of all lung transplants were performed at 21 centers around the world averaging 50 procedures per year.³

Some of the most challenging patients are those with cystic fibrosis. The 1-year survival rate of 79% and 5-year survival rate of 57% after lung transplantation has shown that despite the high incidence of poor nutrition and the almost ubiquitous colonization by multidrug-resistant organisms, these patients can still successfully undergo lung transplantation with acceptable outcomes data.⁶⁴

It is a sign of the maturity of lung transplantation procedures that survival data for “redo” lung transplantation also are becoming available. A late-1991 survey of centers reported that actuarial survival after redo transplantation was significantly worse than that of first-time recipients (e.g., 35% vs. > 75% at 1 year),⁶⁵ and subsequent data have confirmed this observation.³ Infection and multiorgan failure before repeat transplant are associated with an almost uniformly fatal outcome. Subsequent data from UNOS, however, have shown an improvement, with the 1-year survival rate at 66.3% in the retransplant patients as compared with 83.8% in the primary transplant population. This is, however, significantly worse at 3 years, with repeat survival rate at 38.8% compared with 63.2%.