Kishan Dwarakanath, Anne L. Rother, and Charles D. Collard
1. Nonischemic cardiomyopathy (53%) is the most common pretransplant diagnosis worldwide.
2. Nearly 70% of recipients in the United States require some form of life support prior to cardiac transplantation. For example, in the United States, the number of pretransplant patients with ventricular assist devices has risen dramatically over the recent years.
3. Increased preoperative pulmonary vascular resistance in the recipient is predictive of early graft dysfunction and increased mortality related to an increased incidence of right heart dysfunction.
4. Because of intact spinal reflexes, transplant donors may exhibit hypertension, tachycardia, and muscles movement. These responses do not indicate cerebral function or pain perception.
5. During orthotopic cardiac transplantation, the cardiac autonomic plexus is transected, leaving the transplanted heart without autonomic innervation. Inotropes are utilized in the postbypass period.
6. Right ventricular failure is a significant cause of early morbidity and mortality accounting for nearly 20% of early deaths after transplantation. RV failure and increased pulmonary vascular resistance in the postbypass period can be often challenging for the cardiac anesthesiologist to manage.
7. Cardiac allograft vasculopathy (CAV) is a form of graft failure. Unlike atherosclerotic CAD, CAV is characterized by diffuse intimal hyperplasia.
8. In contrast to the non-transplanted patient, where increases in cardiac output can be quickly achieved through a sympathetically mediated increase in heart rate, the cardiac transplanted patient, whose sympathetic innervation to the heart will be interrupted, tends to require an increase in preload in order to increase cardiac output.
9. Autonomic denervation of the heart alters the pharmacodynamic response of many drugs (Table 16.8). Drugs that act directly on the heart are effective.
10. Regional or general anesthesia has been successfully utilized in the postcardiac transplant patient for surgical procedures. For any selected anesthetic technique, maintenance of preload is essential (see keypoint 8 above).
ALTHOUGH “DESTINATION THERAPY” USING MECHANICAL circulatory support (MCS) devices has increasingly become a viable option, cardiac transplantation remains the gold standard for the treatment of heart failure (HF) refractory to medical therapy . Since the first human cardiac transplant by Christiaan Barnard in 1967, over 89,000 cardiac transplants have been performed worldwide . Currently, approximately 3,500 cardiac transplants are performed per annum, with approximately 2,200 occurring in the United States . Despite an increasingly high-risk patient population, survival rates continue to improve due to advances in immunosuppression, surgical technique, perioperative management, and the diagnosis and treatment of allograft rejection . In the United States, cardiac transplantation is limited to member centers of the United Network for Organ Sharing (UNOS). UNOS, in turn, administers the Organ Procurement and Transplantation Network (OPTN) which maintains the only national patient transplant waiting list in the United States.
I. Heart failure
More than 5 million American adults carry a diagnosis of HF, with an incidence of 670,000 per year . The American College of Cardiology (ACC) and the American Heart Association (AHA) define HF as a clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with, or eject blood. The majority of patients with HF owe their symptoms to impairment of left ventricular (LV) myocardial function . Because volume overload is not necessarily present, the term “HF” is now preferred to the older term “congestive HF.”
The New York Heart Association (NYHA) scale is used to quantify the degree of functional limitation imposed by HF. Most patients with HF, however, do not show an uninterrupted and inexorable progression along the NYHA scale . In 2005, the ACC/AHA created a staging scheme reflective of the fact that HF has established risk factors, a clear progression, and specific treatments at each stage that can reduce morbidity and mortality (Fig. 16.1). Patients presenting for heart transplantation invariably present in Stage D, refractory HF.
Nonischemic cardiomyopathy (53%) is the most common pretransplant diagnosis worldwide . Ischemic cardiomyopathy accounts for 38%, with valvular cardiomyopathy, retransplantation, and congenital heart disease accounting for the remaining percentage of adult heart transplant recipients.
Figure 16.1 Stages in the development of HF and recommended therapy. (From Jessup M, Abraham WT, Casey DE, et al. Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults. Circulation. 2009;119:e391–e479.)
The neurohormonal model portrays HF as a progressive disorder initiated by an index event, which either damages the myocardium directly or disrupts the ability of the myocardium to generate force . HF progression is characterized by declining ventricular function and activation of compensatory adrenergic, and salt and water retention pathways. Ejection fraction (EF) is initially maintained by increases in LV end-diastolic volume, myocardial fiber length, and adrenergically mediated increases in myocardial contractility. LV remodeling takes place during this time, and while initially adaptive, may independently contribute to HF progression . The chronic overexpression of molecular mediators of compensation (e.g., norepinephrine, angiotensin II, endothelin, natriuretic peptides, aldosterone, and tumor necrosis factor) may lead to deleterious effects on cardiac myocytes and their extracellular matrix [6,7]. The result is progressive LV dilation, as well as decreasing EF and cardiac output (CO). Fatigue, dyspnea, and signs of fluid retention develop. Other organ systems such as the liver and kidneys become compromised by persistent decreases in CO and elevated venous pressures. With continued progression of HF, stroke volume (SV) becomes unresponsive to increases in preload, and increases in afterload are poorly tolerated (Fig. 16.2). Chronic exposure to circulating catecholamines may result in downregulation of myocardial b1-adrenergic receptors, making the heart less responsive to inotropic therapy.
Figure 16.2 Pressure–volume (P–V) relationships in a normal heart and a heart with end-stage dilated cardiomyopathy (DCM). Shown are the LV P–V loops (dotted lines) obtained from a normal heart and a heart with end-stage DCM following an increase in afterload. The slope depicts the LV end-systolic P–V relationship. Note that the myopathic heart SV is markedly decreased by increases in afterload. (From Clark NJ, Martin RD. Anesthetic considerations for patients undergoing cardiac transplantation. J Cardiothorac Anesth. 1988;2:519–542, with permission.)
C. Medical management of HF
1. Therapeutic goals
The therapeutic goal for HF management is to slow or halt the progression from Stage A to D. Lifestyle modifications and selected pharmacotherapy are the mainstays of therapy for Stages A and B. When Stage C is reached, combination pharmacotherapy includes diuresis, interruption of the renin–angiotensin axis, and b-blockade. Selective use of direct vasodilators and inotropes is also indicated. Utilization of cardiac resynchronization therapy (CRT) and/or an implantable defibrillator may be recommended. Despite optimum medical management, some patients will progress to Stage D, refractory HF. Chronic intravenous (IV) inotropes, mechanical support devices, and heart transplantation are the only measures available for palliation or treatment.
Inotropic agents commonly used to treat cardiac failure include digitalis, catecholamines, and phosphodiesterase-III (PDE) inhibitors. Digitalis, in combination with b-blockers, is effective in treating HF complicated by atrial fibrillation, but does not confer increased survival . Administered orally, digitalis exerts a positive inotropic effect by inhibiting the myocardial cell sodium pump and increasing cytosolic calcium concentrations. Digitalis also prolongs atrioventricular conduction time, leading to a decrease in heart rate. Digitalis blood levels should be monitored as significant side effects including atrial and ventricular arrhythmias can occur, particularly in the presence of hypokalemia.
Myocardial b1-adrenergic receptor stimulation by IV administration of catecholamines, such as epinephrine, norepinephrine, dobutamine, or dopamine, is often used to improve cardiac performance, diuresis, and clinical stability. PDE inhibitors, such as milrinone, may also be used. PDE inhibitors combine both positive inotropic and vasodilatory activity by inhibiting cyclic adenosine monophosphate (cAMP) metabolism. Occasionally, patients may not be weaned from IV inotropic support despite repeated attempts. At such times, an indwelling IV cannula may be placed to allow for the continuous infusion of an inotrope for patients awaiting transplantation, or to facilitate home palliation. However, the use of chronic inotrope has not been shown to increase survival .
Diuretics provide symptomatic relief to HF patients more quickly than any other class of drug, and are the only class of drug used in HF that can adequately control fluid retention. Classes of diuretics used include the loop diuretics (e.g., furosemide, bumetanide, torsemide) and the thiazide diuretics (e.g., hydrochlorothiazide, metolazone). Adverse diuretic effects include electrolyte disturbances (particularly of potassium and magnesium), hypotension, intravascular volume depletion, and azotemia.
c. Renin–angiotensin–aldosterone system inhibitors
The renin–angiotensin–aldosterone system may be inhibited by angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or the aldosterone receptor. In combination with b1-antagonists, ACEIs have been shown to reduce HF progression by interfering with the neurohormonal pathways that modulate LV remodeling; ACEIs alleviate symptoms, enhance the overall sense of well-being, and reduce the risk of hospitalization and death in patients with HF . Adverse effects of ACEIs include hypotension, worsening renal function, and hyperkalemia. If the adverse effects of ACEIs cannot be tolerated, ARBs may be considered as an alternative. The propensity of ARBs to increase serum potassium levels limits their usage in patients with impaired renal function. Aldosterone exerts an adverse effect on heart structure and function independent of angiotensin II . Spironolactone is the most widely used aldosterone antagonist in HF patients, although eplerenone has been studied in HF after myocardial infarction.
Vasodilators are used in the acute treatment of HF to reduce myocardial preload and afterload, thereby reducing myocardial work and oxygen demand. Nitrates (e.g., nitroglycerine and sodium nitroprusside) may also be useful for relieving the symptoms of pulmonary edema by reducing ventricular filling pressures and afterload. b-Type natriuretic peptide (nesiritide) is used effectively for the medical management of decompensated HF . Nesiritide, an arterial and venous dilator, acts by increasing cyclic guanosylmonophosphate (cGMP) . In hospitalized patients, the use of nesiritide was associated with a dose-dependent reduction of pulmonary capillary wedge pressure (PCWP), right atrial pressure, and mean pulmonary artery (PA) pressure, along with improvements in cardiac index and clinical outcome . However, a clear benefit in terms of morbidity and mortality has not been demonstrated for the use of nesiritide in acute or chronic HF .
e. β-Adrenergic receptor blockade
In combination with interruption of the renin–angiotensin–aldosterone axis and diuresis, b-adrenergic receptor blockade is the standard treatment for HF. Carvedilol, bisoprolol, and sustained release metoprolol have been demonstrated to be effective in reducing mortality in patients with chronic HF . Chronic adrenergic stimulation is initially supportive to the failing heart, but may lead to progression of HF through neurohormonally mediated LV remodeling. b-Blockers likely exert their benefit through attenuation of this influence. Adverse reactions to b-blockers in patients with HF include fluid retention, fatigue, bradycardia, heart block, and hypotension.
Patients with HF are at increased risk of thromboembolism as a result of low CO and a high incidence of coexistent atrial fibrillation. Long-term prophylactic anticoagulation with agents such as coumadin is common and may contribute to perioperative bleeding at the time of cardiac transplantation.
g. Cardiac implantable electronic devices (CIEDs)
CIEDs broadly consist of devices that seek to manage bradyarrhythmias (pacemakers), tachyarrhythmias (implantable cardiac defibrillators), and ventricular dyssynchrony (biventricular pacing/CRT). These devices are used to slow HF progression and reduce the incidence of sudden death [5,10]. Their presence may complicate the placement of central venous catheters and require the involvement of an electrophysiology team for interrogation and reprogramming .
D. Mechanical circulatory support (MCS) devices
Nearly 70% of recipients in the United States require some form of life support prior to heart transplantation . These include IV medications, mechanical ventilation, intra-aortic balloon pumps (IABPs), extracorporeal life support (ELS), total artificial hearts (TAH), and ventricular assist devices (VADs). IV medications, IABPs, ELS, and extracorporeal VADs are useful in temporizing a hospitalized patient with cardiogenic shock. Intracorporeal MCS devices offer the potential for discharge to home and may yield the greatest potential improvement in quality of life for patients with Class D HF who are awaiting heart transplant.
In the United States, the number of patients undergoing heart transplantation with a pre-existent VAD has risen dramatically (16% in 1999 vs. 29% in 2008) . The increased use of VADs has resulted in an increase in the number of outpatients being transplanted (39% to 48%), and has in part contributed to a decline in the heart transplant waiting list mortality secondary to their use as a bridge to transplantation . Six-month survival while being supported on a VAD approaches 75% . However, the influence of VADs on post–heart- transplant survival is controversial, with some studies suggesting an increased 6-mo mortality after transplant, while more recent studies suggest no increase in mortality [14–17]. Confounding the task of answering these questions is the rapid evolution of the devices being used, and problems inherent in applying results from earlier pulsatile devices to more recent continuous-flow devices.
II. Cardiac transplant recipient characteristics
Between 1999 and 2008, the number of active transplant candidates in the United States declined by 32%, despite an increase of 20% between 2007 and 2008 . The decline has taken place despite an increasing number of patients with Stage D HF. In 1999, UNOS modified its listing system to be two-tiered (Table 16.1), and in 2006, UNOS modified the allocation of donor hearts to expand organ sharing within geographic regions. In 2007, the median time to transplantation was 113 days. Among adults, there was an increase in the number of candidates >65 yrs (9% in 1999 vs. 14% in 2008) . Among all age groups, there was an increase in congenital heart disease as a primary diagnosis (4.4% in 1999 vs. 8.9% in 2008), and a decrease in coronary artery disease (CAD) as a primary diagnosis (47% in 1999 vs. 40% in 2008) . Finally, the percentage of patients classified as 1A or 1B has increased dramatically (18% in 1999 vs. 46% in 2008) . The reduction in waiting list mortality and increases in Category 1A and 1B candidates may be in part due to the impact of VADs.
Table 16.1 UNOS listing criteria for heart transplantation
A. Cardiac transplantation indications
Indications for heart transplantation are listed in Table 16.2 [5,18]. Potential cardiac transplant candidates must have all reversible causes of HF excluded, and their medical management optimized.
Table 16.2 Indications for heart transplantation
B. Cardiac transplantation contraindications
There has been a gradual relaxation in the cardiac transplantation exclusion criteria as experience with increasingly complex cases has grown . Absolute exclusion criteria have been simplified (Table 16.3) .
Increased preoperative pulmonary vascular resistance (PVR) is predictive of early graft dysfunction and increased mortality because of an increased incidence of right heart dysfunction . Methods used to quantify the severity of pulmonary HTN include calculation of PVR and the transpulmonary gradient (mean PA pressure − PCWP). At most centers, patients are not considered orthotopic cardiac transplant candidates if they demonstrate a PVR >6 Wood units or transpulmonary gradient >15 mm Hg without evidence of pharmacologic reversibility . The reversibility of pulmonary HTN can be evaluated by vasodilator administration, including IV sodium nitroprusside, inhaled nitric oxide (iNO), and inhaled epoprostenol (PGI2). In patients who receive VADs, “fixed” elevated PVR may be reduced and thus improve post-transplant outcome, or qualify a previously excluded patient for heart transplant [18–22]. The only transplant options for patients with severe irreversible pulmonary HTN include heterotopic cardiac or combined heart–lung transplantation (HLT).
Table 16.3 Contraindications to heart transplantation
III. The cardiac transplant donor
A. Donor selection
The primary factor limiting cardiac transplantation is a shortage of donors. Standard criteria for donors, first outlined in the 1980s, resulted in a paucity of donor organs relative to the number of patients who could benefit from heart transplantation. In an attempt to increase donor numbers, the criteria for cardiac organ donation have been relaxed. The so-called “marginal donor” hearts may be transplanted into borderline heart transplant candidates with good results when compared to their expected prognosis without transplantation [18,23–25]. Characteristics of marginal donors include older age (>55 yrs), the presence of CAD, donor–recipient size mismatch, history of donor drug abuse, increased ischemic times, and donor seropositivity for viral hepatitis [18,23–25]. Nonetheless, the risk of failed transplantation increases with donor age and the presence of concomitant disease . Contraindications to heart donation are listed in Table 16.4.
Before a donor heart may be harvested, permission for donation must be obtained, the suitability of the heart for donation must be ascertained, and the diagnosis of brain death must be made. Initial functional and structural evaluation of the potential heart donor is made with electrocardiography and transthoracic echocardiography. Normal LV function is predictive of suitability for heart transplantation, and subsequent management of the donor may be guided by other invasive monitors such as PA catheters or serial echocardiography [24,25]. Coronary angiography may be performed on patients ≥40 yrs . Donor–recipient factors such as size, ABO compatibility, and antihuman leukocyte antigen (HLA)–antibody compatibility are also be assessed. Logistic factors, including ischemic organ time, must be considered. Finally, the harvesting surgeon will directly inspect the donor heart .
Table 16.4 Contraindications to heart donation
B. Determination of brain death
In the United States, The Uniform Determination of Death Act defines death as either (1) the irreversible cessation of circulatory and respiratory functions or (2) irreversible cessation of all functions of the entire brain, including the brain stem. The determination of death must be made in accordance with accepted medical standards. For the diagnosis of brain death to be made, the patient’s core body temperature must be >32.5°C, and no drug with the potential to alter neurologic or neuromuscular function should be present.
C. Pathophysiology of brain death
When brain death results from severe brain injury, increased intracranial pressure results in progressive herniation and ischemia of the brain stem. Subsequent hemodynamic instability, endocrine, and metabolic disturbances disrupt homeostasis, and may render organs unsuitable for transplantation (Table 16.5).
Table 16.5 Incidence of pathophysiologic changes after brain stem death
1. Cardiovascular function
In an attempt to maintain cerebral blood flow to the increasingly ischemic brain stem, blood pressure (BP) and heart rate rise. While usually transient, this adrenergically mediated “sympathetic storm” may precipitate electrocardiographic and echocardiographic findings consistent with myocardial ischemia [27–29]. Occasionally, severe systemic hypertension may persist and require management . Hypotension will affect most brain-dead patients and may be refractory to pressors . Hypotension may result from hypovolemia caused by traumatic blood loss, central diabetes insipidus (DI), or osmotic therapy for management of elevated intracranial pressure. Loss of sympathetic tone resulting in blunted vasomotor reflexes, vasodilatation, and impaired myocardial contractility also contributes to hypotension . Noxious stimuli may induce exaggerated hypertensive responses mediated by intact spinal sympathetic reflexes that are no longer inhibited by descending pathways. Despite optimal donor support, terminal cardiac arrhythmias may occur within 48 to 72 h of brain death.
2. Endocrine dysfunction
Dysfunction of the posterior pituitary gland occurs in a majority of brain-dead organ donors. The loss of antidiuretic hormone (ADH) results in DI, which is manifested by polyuria, hypovolemia, and hypernatremia . Derangements in other electrolytes including potassium, magnesium, and calcium may also occur as a result of DI. Dysfunction of the anterior pituitary has been inconsistently described, with hemodynamic and electrolyte disturbances attributable in part to loss of thyroid-stimulating hormone (TSH), growth hormone (GH), and adrenocorticotropic hormone (ACTH) [28,29]. Plasma concentrations of glucose may become variable (most often elevated) due to changes in serum cortisol levels, the use of catecholamine therapy, progressive insulin resistance, and the administration of glucose-containing fluids .
3. Pulmonary function
Hypoxemia resulting from lung trauma, infection, or pulmonary edema may occur following brain death. Pulmonary edema in this setting may be neurogenic, cardiogenic, or inflammatory in origin .
4. Temperature regulation
Thermoregulation by the hypothalamus is lost after brain death. Increased heat loss occurs as a result of an inability to vasoconstrict, along with a reduction in metabolic activity, puts brain-dead organ donors at risk for hypothermia. Adverse consequences of hypothermia include cardiac dysfunction, arrhythmias, decreased tissue oxygen delivery, coagulopathy, and cold-induced diuresis .
Coagulopathy may result from hypothermia, and dilution of clotting factors following massive transfusion and fluid resuscitation. For reasons that are not fully understood, disseminated intravascular coagulation occurs in approximately 28% of brain dead donors [28,29].
D. Management of the cardiac transplant donor
Post-transplant graft function is in part dependent on donor care prior to organ harvesting. Strategies for managing the brain-dead organ donors seek to stabilize the donor’s physiology so that the functional integrity of potentially transplantable organs is maintained .
1. Cardiovascular function
Donor systemic BP and central venous pressure (CVP) should be monitored continuously using arterial and central venous catheters . Goals include a mean arterial pressure >60 mm Hg, a CVP of 6 to 10 mm Hg, urinary output >1 mL/kg/h, and a left ventricular ejection fraction (LVEF) >45% [28,30]. The initial treatment step in maintaining hemodynamic stability is aggressive replacement of intravascular volume with crystalloids, colloids, and packed red blood cells (PRBCs) if the hemoglobin concentration is less than 10 g/dL or the hematocrit is less than 30% [28,30].
If hemodynamic stability is not restored with fluid resuscitation, placement of a PA catheter, echocardiography, or continuous CO monitoring should be used to assess right- and left-sided intracardiac pressures, CO, and systemic vascular resistance (SVR) [28,30]. Use of inotropes and pressors should be guided by these additional diagnostics. Dopamine, epinephrine, and norepinephrine are commonly used for donor cardiovascular support. However, prolonged use of catecholamines at high doses should be avoided due to potential downregulation of b-receptors on the donor heart, and the negative impact this may have on graft function after cardiac transplant [27,28]. High-dose a-adrenergic receptor agonists should be used cautiously, as peripheral and splanchnic vasoconstriction may result in decreased perfusion of other potential donor organs and metabolic acidosis. An infusion of vasopressin has catecholamine-sparing effects without impairing graft function [28,30].
Brain-dead donors with hemodynamic instability refractory to fluids, catecholamines, and vasopressin have higher rates of organ procurement when hormonal therapy is added [28,30]. Thyroid hormone and methylprednisolone are part of the UNOS standard donor management protocol .
2. Fluid and electrolytes
Hypernatremia in the donor has been associated with higher rates of primary graft failure . Aggressive treatment of DI with 1-desamino-8-D-arginine vasopressin (DDAVP) is indicated. IV fluids should be given to replace urinary losses and to maintain urine output . Euglycemia (80 to 150 mg/dL) should be achieved through the use of dextrose-containing fluids or an insulin infusion . Metabolic acidosis and respiratory alkalosis should be corrected, with a goal pH of 7.40 to 7.45 [28,30].
3. Pulmonary function
If lung procurement is also being considered, management of the brain-dead donor may become more complicated. The management from the standpoint of maximizing heart graft viability calls for aggressive fluid resuscitation, whereas a minimal volume strategy improves lung graft function after transplant, and recommendations for precise hemodynamic goals are different . Management described here is from the standpoint of maximizing procurement of the heart.
In the absence of metabolic acidosis or alkalosis, minute ventilation should be adjusted to target a PaCO2 of 30 to 35 mm Hg . The inspired oxygen concentration (FiO2) should be titrated to a PaO2>80 mm Hg . Efforts to prevent pulmonary aspiration, atelectasis, and infection are warranted. Pulmonary edema should be managed with positive end-expiratory pressure (PEEP) and diuresis.
Monitoring of core temperature is mandatory as hypothermia adversely affects coagulation, cardiac rhythm, and oxygen delivery. Use of heated IV fluids, blankets, and humidifiers may prevent hypothermia.
Different transplant centers have individual guidelines for blood component therapy for management of coagulopathy. In general, component therapy should be guided by repeated donor platelet and clotting factor measurements. Generally accepted goals include an international normalized ratio (INR) of <1.5 and a platelet count of >50,000/mm3 . Antifibrinolytics to control donor bleeding are not recommended due to the risk of microvascular thromboses.
E. Anesthetic management of the donor
Anesthetic management of the donor during organ harvesting is an extension of preoperative management. An FiO2 of 1 is optimal for organ viability unless the lungs are to be harvested. To decrease the possibility of oxygen toxicity in the case of donor lung harvest, the minimum FiO2 that will maintain a PaO2/FiO2 gradient of at least 300 mm Hg should be used . Although intact spinal reflexes may result in hypertension, tachycardia, and muscle movement, these signs do not indicate cerebral function or pain perception. Nondepolarizing muscle relaxants may be used to prevent spinal reflex-mediated muscle movement.
F. Organ harvest technique
After initial dissection, the patient is fully heparinized. The perfusion-sensitive organs (i.e., kidneys and liver) are removed prior to cardiectomy. The donor heart is excised en bloc via median sternotomy after dissection of the pericardial attachments. The superior and inferior venae cavae are ligated first, allowing exsanguination. The aorta is cross-clamped and cold cardioplegia administered. The aorta and pulmonary arteries are transected, leaving the native donor arterial segments as long in length as possible. Finally, the pulmonary veins are individually divided after lifting the donor organ out of the thoracic cavity. Most donor hearts are currently preserved with specialized cold colloid solutions (e.g., University of Wisconsin solution) and placed in cold storage at 2°C . When this technique is used, optimal myocardial function after transplantation is achieved when the donor heart ischemic time is less than 4 h .
IV. Surgical techniques for cardiac transplantation
A. Orthotopic cardiac transplantation
Over 98% of cardiac transplants performed are orthotopic. The recipient is placed on standard cardiopulmonary bypass (CPB) and, if present, the PA catheter withdrawn into the superior vena cava. The femoral vessels are often selected for arterial and venous CPB cannulation in patients undergoing repeat sternotomy. Otherwise, the distal ascending aorta is cannulated and bicaval cannulae with snares placed, completely excluding the heart from the native circulation. The aorta and pulmonary arteries are then clamped and divided. Depending on the implantation technique (Fig. 16.3), either both native atria or a single left atrial cuff containing the pulmonary veins is preserved. The native atrial appendages are discarded because of the risk of postoperative thrombus formation.
The donor heart is inspected for the presence of a patent foramen ovale. If patent, it is surgically closed, as right-to-left interatrial shunting and hypoxemia may occur in the presence of elevated right-sided pressures following transplantation. The donor and recipient left atria are anastomosed first, followed by the right atria, or cavae when a bicaval anastomotic technique is chosen. The subsequent order of anastomoses varies depending on the donor heart ischemic time and the experience of the surgeon. The donor and recipient aortas are joined and the aortic cross-clamp removed with the patient in Trendelenburg to decrease air embolism. After completion of the PA anastomosis and placement of temporary epicardial pacing wires, the heart is deaired and the patient weaned from CPB.
Figure 16.3 Surgical techniques for cardiac transplantation. A: Biatrial technique. The donor heart is anastomosed to the main bulk of the recipient’s native right and left atria. B: Bicaval technique. The donor heart left atrium is anastomosed to a single left atrial cuff, including the pulmonary veins, in the recipient. (From Aziz TM, Burgess MI, El Gamel A, et al. Orthotopic cardiac transplantation technique: A survey of current practice. Ann Thorac Surg. 1999;68:1242–1246, with permission.)
1. Biatrial implantation
Biatrial implantation is the technique originally described by Barnard. It preserves portions of the recipient’s native atria to create two atrial anastomoses (Fig. 16.3, Panel A). Biatrial orthotopic heart transplantation has been performed successfully for over four decades and has the advantage of being relatively simple, and possibly faster to perform . It is, however, falling out of favor with a decreasing percentage of heart transplants being performed this way (34.7% in 2007) . The biatrial technique puts the sinoatrial node at risk of injury, redundant atrial tissue may contribute to atrial dysrhythmias, and distortion of the right atrium may contribute to a higher risk for tricuspid regurgitation . Although patients receiving biatrial transplant require a higher incidence of permanent pacemakers, no definitive difference in long-term survival has been demonstrated [31,32].
2. Bicaval implantation
The bicaval implantation technique is a modification of the biatrial technique. Only a single, small left atrial cuff containing the pulmonary veins is preserved in the recipient. Bicaval and left atrial anastomoses are performed (Fig. 16.3, Panel B). The bicaval technique is growing in popularity, particularly at higher volume transplant centers . Demonstrated advantages of the bicaval technique include a higher incidence of postoperative sinus rhythm, lower right atrial pressures, and a reduced need for permanent pacemaker [31,32]. A decreased risk of perioperative mortality may exist [31,32].
B. Heterotopic cardiac transplantation
Heterotopic transplantation accounts for less than 1% to 2% of cardiac transplantation procedures per annum. In this technique, the recipient’s heart is not excised. Instead, the donor heart is placed within the right anterior thorax, and anastomosed to the recipient’s native heart such that a parallel circulation is established. The recipient and donor atria are anastomosed, followed by the aortas. An artificial conduit usually joins the pulmonary arteries, with the native and donor right ventricles ejecting into the native PA. Similarly, both the native and donor left ventricles eject into the native aorta. Thus, the recipient’s RV, which is conditioned to eject against elevated PA pressures, will provide most of the right-sided ventricular output, whereas the healthy donor LV will make the major contribution to left-sided ventricular output. Situations in which heterotopic cardiac transplantation may be advantageous include recipients with severe pulmonary HTN, a small donor-to-recipient size ratio, and a marginal donor heart . Disadvantages of heterotopic cardiac transplantation include relatively high operative mortality, a requirement for continued medical treatment of the failing native heart, the potential for the native heart to be a thromboembolic source, and compromised pulmonary function due to placement of donor heart in the right chest .
V. Preoperative management of the cardiac transplant patient
A. Timing and coordination
Important considerations when planning the timing of the operation include the time required for donor organ transport, and potential for failure to complete recipient cannulation in a timely fashion (e.g., repeat sternotomy) . Since the timing of heart transplants is dictated by donor availability, transplantation can take place at any hour of the day. Ideally, to minimize ischemic time, anesthetic induction of the recipient should be timed so that the recipient is already on CPB when the donor heart arrives. However, since the attendant risks of general anesthesia are magnified in the recipient, who by definition has advanced HF, induction of anesthesia ought to be delayed until a definitive “go” is received from the harvesting team.
B. Preoperative evaluation
The anesthesiologist usually has limited time for preoperative assessment of the cardiac transplant recipient. Furthermore, the use of VADs has increased the number of outpatient recipients, further reducing the available time [2,12]. These recipients will have been under the care of a medical team experienced in the management of HF, and their medical therapy is likely to have already been optimized. When the recipient is already admitted to the intensive care unit (ICU), all aspects of their ongoing care should be reviewed, including pulmonary status and ventilation settings, presence of invasive monitors and existing venous access, use of inotropes and/or pressors, and the use of MCS devices. In any case, the preoperative anesthetic evaluation should include a thorough history, physical examination, and review of the patient’s medical record. The electrocardiogram (ECG), echocardiogram, chest x-ray, and cardiac catheterization results should be noted, and all hematological, renal, and liver function tests reviewed.
1. Concomitant organ dysfunction
Chronic systemic hypoperfusion and venous congestion in the recipient may produce reversible hepatic and renal dysfunction. Mild-to-moderate elevations of hepatic enzymes, bilirubin, and prolongation of prothrombin time are common. Preoperative hepatic dysfunction and anticoagulant medication may also contribute to the abnormal coagulation profile frequently observed in cardiac transplant recipients. Blood urea nitrogen is commonly elevated in patients with end-stage heart disease due to chronic hypoperfusion and the concomitant prerenal effects of high-dose diuretics.
2. Preoperative medications
Preoperative inotropic support should be continued throughout the pre-CPB period. Patients receiving digitalis and diuretics have an increased risk of dysrhythmias in the presence of hypokalemia. Anticoagulants such as coumadin, heparin, and aspirin may increase the need for perioperative blood product administration.
3. Preoperative monitoring
The position, function, and duration of invasive monitoring catheters should be noted. The function and settings of IABPs and VADs should be reviewed. If a CIED is present, it should be interrogated and the antitachyarrhythmia functions suspended in the operating room after external defibrillation pads have been applied . Patients with invasive monitoring and/or MCS require extra personnel and vigilance to ensure safe transport from the ICU to the operating room.
4. The combined heart–lung recipient
The combined heart–lung transplant recipient often requires special preoperative evaluation. Recipients with cystic fibrosis should first have an otolaryngologic evaluation before being placed on a waiting list. Many of these patients will require endoscopic maxillary antrostomies for sinus access and monthly antibiotic irrigation. This measure has decreased the incidence of serious post-transplant bacterial infections in this patient population. Ex-smokers must undergo screening to exclude malignancy. A negative sputum cytology, thoracic computed tomography (CT) scan, bronchoscopy, and otolaryngologic evaluation are required. Additionally, left heart catheterization, coronary angiography, and a carotid duplex scan may be performed in previous smokers.
VI. Anesthetic management of the cardiac transplant recipient
The HF patient has elevated levels of circulating catecholamines and is preload-dependent. Even a small dose of sedative medication may result in vasodilatation and hemodynamic decompensation. Supplemental oxygen should be given, and sedative avoided or carefully titrated.
Patients presenting for cardiac transplantation should be considered as having a “full stomach” as most present with short notice. If oral cyclosporine or azathioprine is started preoperatively, gastric emptying is delayed. Oral sodium citrate and/or IV metoclopramide may be useful in raising gastric pH and reducing gastric volumes.
B. Importance of aseptic technique
Perioperative immunosuppressive therapy places the cardiac transplant recipient at increased risk of infection. All invasive procedures should be done under aseptic or sterile conditions.
Noninvasive monitoring should include a standard five-lead ECG, noninvasive BP measurement, pulse oximetry, capnography, nasopharyngeal temperature, and urinary output. If not already in situ, large-bore peripheral and central venous access should be obtained. Invasive monitoring should include systemic arterial as well as central venous and/or PA pressures. Intraoperative transesophageal echocardiography (TEE) is commonly used. A PA catheter may be helpful in the post-CPB period, allowing monitoring of CO, ventricular filling pressures, and calculation of SVR and PVR. Traditionally, catheterization of the right internal jugular vein has been avoided to preserve this route for the endomyocardial biopsies (EMBs) routinely performed to screen for myocardial rejection. Nonetheless, difficulty with EMB by alternative routes has not been reported in circumstances where the right internal jugular vein was used for central access.
D. Considerations for repeat sternotomy
Many cardiac transplant recipients will have undergone previous cardiac surgery and are at increased risk of inadvertent trauma to the great vessels or pre-existing coronary artery bypass grafts during sternotomy. Patients having repeat sternotomy should have external defibrillation pads placed before induction, and cross-matched, irradiated PRBCs available in the operating room prior to sternotomy. If the recipient has had previous sternotomy, additional time for surgical dissection may be required and should be accounted for in planning the timing for the induction of general anesthesia. Other considerations for repeat sternotomy include the potential for bleeding and the need for femoral or axillary CPB cannulation.
E. Anesthetic induction
1. Hemodynamic goals
Cardiac transplant recipients typically have hypokinetic, noncompliant ventricles sensitive to alterations in myocardial preload and afterload. Hemodynamic goals for anesthetic induction are to maintain HR and contractility, avoid acute changes in preload and afterload, and prevent increases in PVR. Inotropic support is often required during anesthetic induction and throughout the pre-CPB period.
2. Aspiration precautions
Rapid sequence induction with maintenance of cricoid pressure should be considered.
3. Anesthetic agents
Due to the slow circulation time in patients with end-stage HF, a delayed response to administered anesthetic agents on induction is common. IV anesthetics commonly used for anesthetic induction of the cardiac transplant recipient include etomidate (0.2 to 0.3 mg/kg) in combination with fentanyl (5 to 10 μg/kg) or sufentanil (5 to 8 μg/kg). High-dose narcotic regimens have also been used successfully. Bradycardia occurring in response to high-dose narcotics should be treated promptly, as CO in patients with end-stage heart disease is HR-dependent. Small doses of midazolam, ketamine, or scopolamine help ensure amnesia, but should be used cautiously as they may synergistically lower SVR and induce hypotension.
4. Muscle relaxants
Due to its vagolytic and mild sympathomimetic properties, pancuronium is commonly used to counteract narcotic-induced bradycardia. Muscle relaxants with minimal cardiovascular effects (e.g., cisatracurium or vecuronium) may be more appropriate for patients who present with tachycardia secondary to preoperative inotropic support.
F. Anesthetic maintenance
During the pre-CPB period, anesthetic goals include maintenance of hemodynamic stability and end-organ perfusion. Most anesthetic maintenance regimens are narcotic-based, with supplemental inhalational agents and benzodiazepines. Although most inhalational agents have negative inotropic effects, low concentrations of these agents are usually well tolerated and decrease the risk of awareness. Anesthetic depth can be difficult to assess in this patient population as the sympathetic response to light planes of anesthesia is often blunted. The use of narcotic-based anesthetic regimens may also increase the risk of awareness during anesthesia.
Antifibrinolytics such as tranexamic acid, or ε-aminocaproic acid may be administered following anesthetic induction to reduce bleeding.
G. Cardiopulmonary bypass
CPB for cardiac transplantation is similar to that employed for routine cardiac surgical procedures. Femoral venous and arterial cannulation sites are frequently chosen in patients undergoing repeat sternotomy. Moderate hypothermia (28 to 30°C) is commonly used during CPB to improve myocardial protection. Hemofiltration and/or mannitol administration is common during CPB as patients with CHF often have a large intravascular blood volume and coexistent renal impairment. Although immunosuppressive regimens vary amongst transplantation centers, high-dose IV glucocorticoids such as methylprednisolone are frequently administered prior to aortic cross-clamp release to reduce the likelihood of hyperacute rejection. Immunosuppressive induction therapy with an interleukin-2 receptor (IL2R) antagonist, or a polyclonal antilymphocyte antibody, occurred in 54% of heart transplant recipients in 2009 . The availability and timing of immunosuppressive medications should be discussed with the transplant team ahead of time.
VII. Postcardiopulmonary bypass
Prior to CPB termination, the patient should be normothermic and have all electrolyte and acid–base abnormalities corrected. Complete deairing of the heart prior to aortic cross-clamp removal is essential. TEE may be particularly useful for assessing the efficacy of cardiac deairing maneuvers. Inotropic agents should be commenced prior to CPB termination. A HR of 90 to 110 beats/min, a mean systemic arterial BP >65 mm Hg, and ventricular filling pressures of approximately 12 to 16 mm Hg (CVP) and 14 to 18 mm Hg (PCWP) are often required in the immediate post-CPB period. Although inotropic support is usually required for several days, patients are often extubated within 24 h and discharged from the ICU by third postoperative day. Clinical considerations in the immediate postoperative period include the following:
A. Autonomic denervation of the transplanted heart
During orthotopic cardiac transplantation, the cardiac autonomic plexus is transected, leaving the transplanted heart without autonomic innervation. The transplanted heart thus does not respond to direct autonomic nervous system stimulation or to drugs that act indirectly through the autonomic nervous system (e.g., atropine). The denervated, transplanted heart responds to direct-acting agents such as catecholamines. Transient bradycardia and slow nodal rhythms are common following aortic cross-clamp release. An infusion of direct-acting b-adrenergic receptor agonist such as isoproterenol is frequently started prior to CPB termination, and titrated to achieve a HR around 100 beats/min. Newly transplanted hearts unresponsive to pharmacological stimulation may require temporary epicardial pacing. Although most initial dysrhythmias resolve, some cardiac transplant recipients require placement of a permanent pacemaker.
B. RV dysfunction
RV failure is a significant cause of early morbidity and mortality, accounting for nearly 20% of early deaths after heart transplantation . Acute RV failure following cardiac transplantation may be due to prolonged donor heart ischemic time, mechanical obstruction at the level of the PA anastomosis, pre-existing pulmonary HTN, protamine-induced pulmonary HTN, donor–recipient size mismatch, and acute rejection . RV distension and hypokinesis may be diagnosed by TEE or direct observation of the surgical field. Other findings suggesting RV failure include elevations in the CVP, PA pressure, or the transpulmonary gradient (>15 mm Hg).
The goal of managing RV dysfunction is to maintain systemic BP, while minimizing RV dilation. Maintaining atrioventricular synchrony is especially important in optimizing RV preload. Correction of electrolyte and acid–base disturbances, and the use of inotropic support may improve RV function. Minimizing blood transfusions, optimizing ventilator settings, and the use of inhaled pulmonary vasodilators may reduce RV afterload . Useful inotropes include epinephrine, dobutamine, and milrinone, as these may also cause a degree of relaxation in the pulmonary vasculature . Inhaled pulmonary vasodilators include prostacyclin (PGI2), prostaglandin E1 (PGE1), and NO [26,34,35]. NO selectively reduces PVR by activating guanylate cyclase in vascular smooth muscle cells, producing an increase in cGMP and smooth muscle relaxation. Little systemic effect is seen as it is inactivated by hemoglobin and has a 5- to 10-s half-life. NO administration results in the formation of the toxic metabolites nitrogen dioxide and methemoglobin. In the presence of severe LV dysfunction, selective dilation of the pulmonary vasculature by NO may lead to an increase in PCWP and pulmonary edema. PGI2 is an arachidonic acid derivative with a half-life of 3 to 6 min. It binds to a prostanoid receptor and affects an increase in intracellular cAMP and, consequently, vasodilation. PGI2 is equivalent to NO in reducing PA pressures . Relative to NO, PGI2 is less costly, easier to administer, and does not create toxic metabolites. It may, however, cause a degree of systemic hypotension due to its longer half-life, and may be implicated in increased bleeding due to inhibition of platelet function . RV failure refractory to medical treatment may require insertion of a right VAD or institution of extracorporeal circulation.
C. LV dysfunction
Post-CPB LV dysfunction may be a result of a prolonged donor heart ischemic time, inadequate myocardial perfusion, intracoronary embolization of intracavitary air, or surgical manipulation. The incidence of post-CPB LV dysfunction is greater in donors requiring prolonged, high-dose inotropic support prior to organ harvest. Continued postoperative inotropic support with dobutamine, epinephrine, or norepinephrine may be required.
Coagulopathy following cardiac transplantation is common, and perioperative bleeding should be treated early and aggressively. Potential etiologies include hepatic dysfunction secondary to chronic hepatic venous congestion, preoperative anticoagulation, CPB-induced platelet dysfunction, hypothermia, and hemodilution of clotting factors. After ruling out surgical bleeding, blood product administration should be guided by repeated measurements of platelet count and clotting factors. Due to an increased risk of infection and graft-versus-host disease, all administered blood products should be cytomegalovirus (CMV)-negative, and irradiated or leukocyte-depleted. RBC and platelets should be administered through leukocyte filters. The efficacy of DDAVP for the treatment of postoperative bleeding has not been proven.
E. Renal dysfunction
Renal dysfunction, as evidenced by increased serum creatinine and oliguria, is common in the immediate postoperative period. Contributing factors include pre-existing renal impairment, cyclosporine-associated renal toxicity, perioperative hypotension, and CPB. Treatment of renal dysfunction includes optimization of CO and systemic BP, and the use of diuretics.
F. Pulmonary dysfunction
Postoperative pulmonary complications such as atelectasis, pleural effusion, and pneumonia are common and may be reduced by PEEP ventilation, regular endobronchial suctioning, and chest physiotherapy. Bronchoscopy to clear pulmonary secretions is often useful. Pulmonary infection in the immunosuppressed recipient should be treated early and aggressively.
G. Hyperacute allograft rejection
Cardiac allograft hyperacute rejection is caused by preformed HLA antibodies present in the recipient . There are several explanations for the pre-existing antibodies that initiate hyperacute rejection. First, prior recipients of blood transfusions may develop antibodies to major histocompatibility complex (MHC) antigens in the transfused blood. Multiple pregnancies may also expose females to fetal paternal antigens, resulting in antibody formation. Finally, prior transplant recipients may have already formed antibodies to other MHC antigens, so that they may be present at the time of a second transplant. Although extremely rare, hyperacute rejection results in severe cardiac dysfunction and death within hours of transplantation. Assisted MCS until cardiac retransplantation is the only therapeutic option.
VIII. The role of intraoperative TEE
Intraoperative TEE is a valuable tool for the evaluation and management of the cardiac transplant recipient. In addition to monitoring ventricular function, TEE in the pre-CPB period may be used to identify intracavitary thrombus, estimate recipient PA pressures, and evaluate the aortic cannulation and cross-clamp sites for the presence of atherosclerotic disease. TEE may also be used in the post-CPB period to evaluate the efficacy of cardiac deairing, cardiac function, and surgical anastomoses. The caval veins, left atrium, and pulmonary vein anastomoses should be evaluated for any evidence of obstruction or distortion . Stenosis of the main PA should also be excluded by continuous-wave Doppler measurement of the pressure gradient across the anastomosis. After orthotopic cardiac transplantation, the long axis of the left atrium often appears larger than usual because of the joining of donor and recipient left atria. Occasionally, excess donor atrial tissue may obstruct the mitral valve orifice resulting in pulmonary HTN and RV failure. TEE findings in the immediate post-CPB period frequently include impaired ventricular contractility, decreased diastolic compliance, septal dyskinesia, and acute mild-to-moderate tricuspid, pulmonic, and mitral valve regurgitation. Although LV size and function are typically normal on long-term echocardiographic follow-up of healthy cardiac transplant recipients, RV enlargement and tricuspid valve regurgitation persists in up to 33% of patients. Persistent tricuspid valve regurgitation may result from geometrical alterations of the right atrium or ventricle, asynchronous contraction of the donor and recipient atria, or valvular damage occurring during EMB.
IX. Cardiac transplantation survival and complications
Survival following cardiac transplantation in the United States in 2008 was 93%, 89%, 75%, and 56% at 3 mos, 1, 5, and 10 yrs, respectively . These figures are consistent across the adult range of ages, except for recipients aged 65 or older (10-yr survival of 46%) . At all time points, survival in women is lower by 2% to 3%, and long-term survival in African-Americans is lower than in other ethnic/racial groups (10-yr survival of 43%) . Overall, however, survival after heart transplantation has continued to improve since 1982 (Fig. 16.4). Important causes of morbidity and mortality are infection, acute rejection, graft failure and cardiac allograft vasculopathy (CAV), renal insufficiency (RI), and malignancy. Other long-term morbidity after transplantation is due to hypertension, diabetes mellitus, and hyperlipidemia (prevalence at 5 yrs of 90%, 39%, and 91%, respectively) .
Figure 16.4 Survival for adult heart transplants performed between January 1982 and June 2008, stratified by era of transplant. (From Stehlik J, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Twenty-seventh official a dult heart transplant report – 2010. J Heart Lung Transplant. 2010;29: 1089–1103.)
Infections in the early postoperative period (<30 days) are mainly nosocomial and bacterial in nature, and account for 11% of deaths [2,3]. With the routine use of bacterial and viral prophylaxis, there has been a significant reduction in pneumocystis pneumonia infection and herpesviridae (including CMV) . Beyond 30 days, infection remains an important cause of mortality, reaching its peak as a primary cause of death (29%) at 31 days to 1 yr post-transplant .
B. Acute rejection
Improvements in management have rendered acute rejection of the transplanted heart as a less common cause of death (<11%) . However, up to 30% of recipients may experience rejection within the first year . Female recipients are at higher risk than males, and the risk of rejection decreases with increasing age of the recipient . EMB remains the gold standard for confirming acute allograft rejection . Repeated EMB is associated with an increased incidence of tricuspid valve regurgitation.
C. Graft failure and Cardiac allograft vasculopathy (CAV)
Graft failure, presumably due to primary graft failure, is the leading cause of death in the first 30 days after transplant (39% of deaths) . After 30 days, chronic processes such as antibody-mediated rejection and CAV are more likely causes of graft failure. Graft failures continue to be a significant cause of death after 1 yr, accounting for 16% to 24% of deaths . Graft failures due to CAV become prominent between 1 and 3 yrs after transplant, and account for 10% to 15% of deaths . The prevalence of CAV is 30% at 5 yrs and >50% at 10 yrs . Significant CAV is defined angiographically by a stenosis of at least 50%. Unlike atherosclerotic CAD, CAV is characterized by a diffuse intimal hyperplasia . Nonimmune risk factors for CAV include hypertension, hyperlipidemia, diabetes mellitus, explosive (e.g., gunshot to the head) cause of donor brain death, hyperhomocysteinemia, and increased donor age . Immune risk factors include HLA donor–recipient mismatch, recurrent cellular rejection, and antibody-mediated rejection . Aggressive management of risk factors is the primary strategy for preventing CAV. The diffuse nature of the vasculopathy defies percutaneous or surgical revascularization strategies .
D. Renal Insufficiency (RI)
RI is a strong predictor of survival after transplant. Defined as a serum creatinine >2.5 mg/dL, or necessitating dialysis or kidney transplant, severe RI is identified as the primary cause of death in a significant number of patients . Risks for early RI, developing within 1 yr of transplant, are increased donor and recipient age, increased recipient serum creatinine at the time of transplant, presence of a VAD, female recipient, rapamycin use at discharge, and IL2R-antagonist induction . Fortunately, the incidence of impaired renal function after heart transplant is decreasing, with 82% of patients transplanted between 2001 and 2008 being free of severe renal dysfunction at 5 yrs .
Presumably as a consequence of the effects of long-term immunosuppression, the risk of malignancy in the solid-organ transplant recipient is elevated compared to the general population . Skin cancer is the most common malignancy in heart transplant recipients, with incidence at 1, 5, 10, and 14 yrs of 1%, 10%, 20%, and 29%, respectively . Lymphoproliferative malignancies occur less frequently than do malignancies of the skin, but their treatments are much less likely to be curative . Incidence at 1, 5, 10, and 14 yrs are 1%, 2%, 4%, and 5%, respectively . Mortality attributed to malignancy depends on time after transplant and is as high as 23% after 10 yrs .
F. Immunosuppressive drug side effects
Cardiac transplant recipients require life-long immunosuppression. Protocols vary among transplant centers; however, most regimens include triple therapy with corticosteroids, a calcineurin inhibitor, and an antiproliferative agent . Immunosuppressants increase the risk of infection and are associated with numerous side effects (Table 16.6) . Furthermore, chronic immunosuppression increases the risk of malignancies including skin cancers, lymphoproliferative malignancies, various adenocarcinomas, cancers of the lung, bladder, renal, breast, and colon, and Kaposis sarcoma.
Table 16.6 Immunosuppressive agents
X. Pediatric cardiac transplantation
In the United States in 2008, cardiac transplantation in children accounted for 17% of cardiac transplants . The primary indications for pediatric cardiac transplantation are complex congenital heart disease and cardiomyopathy . At present, the majority of pediatric heart transplants take place in children >1 yr of age at highly specialized pediatric centers . Survival rates for transplant recipients are lowest in infants, and higher than adults when aged 6 to 17 yrs . Similar to adult programs, pediatric cardiac transplant programs face a severe donor heart shortage. The use of implantable VADs for bridge to transplantation is limited by the small body size of most pediatric transplant candidates .
XI. Combined heart lung transplant (HLT)
During 2007 and 2008, only 58 HLTs were done in the United States . Thirty-three percent carried the diagnosis of Eisenmenger’s syndrome and 24% had idiopathic pulmonary HTN . Approximate survival rates at 3 mos, 1, 5, and 10 yrs were 86%, 81%, 45%, and 29%, respectively. Donor procurement is of critical importance to the success of the operation, especially with respect to lung preservation. However, current techniques have led to safe procurement with ischemic times up to 6 h.
The operation is performed using a double- or single-lumen endotracheal tube with the patient in the supine position. The surgical approach is generally performed through a median sternotomy, with particular emphasis on preservation of the phrenic, vagal, and recurrent laryngeal nerves . After fully heparinizing the recipient, the ascending aorta is cannulated near the base of the innominate artery, and the venae cavae are individually cannulated laterally and snared. CPB with systemic cooling to 28 to 30°C is instituted, and the heart is excised at the midatrial level. The aorta is divided just above the aortic valve, and the PA is divided at its bifurcation. The left atrial remnant is then divided vertically at a point halfway between the right and left pulmonary veins. Following division of the pulmonary ligament, the left lung is moved into the field, allowing full dissection of the posterior aspect of the left hilum, being careful to avoid the vagus nerve posteriorly. After this is completed, the left main PA is divided, and the left main bronchus is stapled and divided. The same technique of hilar dissection and division is repeated on the right side, and both lungs removed from the chest. Meticulous hemostasis of the bronchial vessels is necessary, as this area of the dissection is obscured once graft implantation is completed. Once absolute hemostasis is achieved, the trachea is divided at the carina.
The donor heart–lung block is removed from its transport container, prepared, and then lowered into the chest, passing the right lung beneath the right phrenic nerve pedicle. The left lung is then gently manipulated under the left phrenic nerve pedicle. The tracheal anastomosis is then performed, and the lungs ventilated with room air at half-normal tidal volumes to inflate the lungs and reduce atelectasis. The heart is then anastomosed as previously described. After separation from CPB, the patient is usually ventilated with an FiO2 of 40% and PEEP at 3 to 5 cm H2O, being very careful to avoid high inspiratory pressures that may disrupt the tracheal anastomoses.
XII. Anesthesia for the previously transplanted patient
Many heart transplant recipients will undergo additional surgical procedures in their lifetime . Common surgical procedures following cardiac transplantation are listed in Table 16.7. Many of these subsequent surgical procedures are attributable to sequelae of the transplant surgery itself, atherosclerosis, and immunosuppression. Understanding the physiologic and pharmacologic features of the previously transplanted patient is essential to ensure optimal anesthetic management.
A. Physiology of the previously transplanted patient
During orthotopic cardiac transplantation, the cardiac autonomic plexus is transected, leaving the transplanted heart without autonomic innervation . Due to the absence of parasympathetic innervation of the sinoatrial node, the transplanted heart will exhibit a resting HR of 90 to 110 beats/min. In addition, reflex bradycardia does not occur. Increases in HR and SV in response to stress are blunted as they depend on circulating adrenal hormones. In the normal heart, the immediate response to stress is to increase CO by increasing heart rate through an intact sympathetic nervous system. The transplant patientlacking that response is dependent on maintenance or increase in SV. Thus, any drop in preload during anesthetic interventions, regardless of technique, will not be well tolerated. Although most transplanted hearts have near-normal contractility at rest, stress may reveal a reduction in functional reserve. The Starling volume–pressure relationship, however, tends to remain intact.
A higher rate of dysrhythmia is seen due to the absence of parasympathetic tone coupled with conduction abnormalities. First-degree atrioventricular block is common, and 30% of patients will have right bundle branch block .
Table 16.7 Common surgical procedures following cardiac transplantation
B. Pharmacology of the previously transplanted patient
Autonomic denervation of the transplanted heart alters the pharmacodynamic activity of many drugs (Table 16.8). Drugs that mediate their actions through the autonomic nervous system are ineffective in altering HR and contractility. In contrast, drugs that act directly on the heart are effective. The b-adrenergic response of the transplanted heart to direct-acting catecholamines such as epinephrine is often increased. Reflex bradycardia or tachycardia in response to changes in systemic arterial BP is absent. Narcotic-induced decreases in HR are frequently diminished in the transplanted heart. Drugs with mixed activity (e.g., dopamine and ephedrine) will mediate an effect only through their direct actions. Parasympathomimetics such as atropine and glycopyrrolate will not alter HR, although their peripheral anticholinergic activity remains unaffected. Anticholinergic coadministration with reversal of neuromuscular blockade is still warranted to counteract the noncardiac muscarinic effects.
Table 16.8 Drug effects on the denervated heart
C. Preoperative evaluation
A thorough medical history, physical examination, and review of the medical record should be undertaken. Current medications should be noted. Particular attention should be paid to determining cardiac allograft function, evidence of rejection or infection, complications of immunosuppression, and end-organ disease. Systemic HTN is common and a significant proportion of patients will have CAV within 1 yr of cardiac transplantation. The absence of angina pectoris does not exclude significant CAD, because the transplanted heart is denervated. The patient’s activity level and exercise tolerance are good indicators of allograft function. Symptoms of dyspnea and CHF suggest significant CAD or myocardial rejection. The presentation of infection may be atypical in immunosuppressed patients, with fever and leukocytosis often absent. Soft tissue changes in the patient’s airway may occur due to lymphoproliferative disease and corticosteroid administration. Cyclosporine may cause gingival hyperplasia and friability. Hematocrit, coagulation profile, electrolytes, and creatinine should be checked, because immunosuppressive therapy is commonly associated with anemia, thrombocytopenia, electrolyte disturbances, and renal dysfunction. Recent chest x-rays, ECGs, and coronary angiograms should be reviewed. More than one P wave may be seen on the ECG in patients in whom cardiac transplantation was performed using a biatrial technique (Fig. 16.5). Although seen on the ECG, the P wave originating in the native atria does not conduct impulses across the anastomotic line.
Figure 16.5 Transplanted heart ECG. The transplanted heart ECG is commonly characterized by two sets of P waves, right-axis deviation, and incomplete right bundle branch block. The donor heart P waves are small and precede the QRS complex, whereas P waves originating from the recipient’s atria (labeled as p) are unrelated to the QRS complex. (From Fowler NO. Clinical Electrocardiographic Diagnosis. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:225, with permission.)
D. Anesthesia management
1. Clinical implications of immunosuppressive therapy
All cardiac transplant patients are immunosuppressed and consequently at higher risk of infection. All vascular access procedures should be carried out using aseptic or sterile technique. Antibiotic prophylaxis should be considered for any procedure with the potential to produce bacteremia. Oral immunosuppressive medication should be continued without interruption or given intravenously to maintain blood levels within the therapeutic range. IV and oral doses of azathioprine are approximately equivalent. Administration of large volumes of IV fluids will decrease blood levels of immunosuppressants, and therefore levels should be checked daily. Immunosuppressant nephrotoxicity may be exacerbated by coadministration of other potentially renal toxic medications such as nonsteroidal anti-inflammatory agents or gentamicin. Chronic corticosteroid therapy to prevent allograft rejection may result in adrenal suppression. Supplemental “stress” steroids should thus be administered to critically ill patients or patients undergoing major surgical procedures.
Standard anesthetic monitors should be used, including five-lead ECG to detect ischemia and dysrhythmias. Cardiac transplant patients frequently have fragile skin and osteoporotic bones secondary to chronic corticosteroid administration. Care with tape, automated BP cuffs, and patient positioning is essential to avoid skin and musculoskeletal trauma. As for all patients undergoing anesthesia, invasive monitoring should only be considered for situations in which the benefits outweigh the risks. Importantly, cardiac transplant patients have an increased risk of developing catheter-related infections with a high associated morbidity and mortality. Intraoperative TEE permits rapid evaluation of volume status, cardiac function, and ischemia, and may be a useful substitute for invasive monitoring. Should central venous access be required, alternatives to the right internal jugular vein should be considered to preserve its use for EMB. Careful monitoring of neuromuscular blockade with a peripheral nerve stimulator is recommended in the previously transplanted patient as cyclosporine may prolong neuromuscular blockade following administration of nondepolarizing neuromuscular blocking agents. In contrast, an attenuated response to nondepolarizing muscle relaxants may be seen in patients receiving azathioprine.
3. Anesthesia techniques
Both general and regional anesthesia techniques have been used safely in cardiac transplant patients. In the absence of significant cardiorespiratory, renal, or hepatic dysfunction, there is no absolute contraindication to any anesthetic technique. For any selected anesthetic technique, maintenance of ventricular filling pressures is essential as the transplanted heart increases CO primarily by increasing SV.
a. General anesthesia
General anesthesia is frequently preferred over regional anesthesia for cardiac transplant patients as alterations in myocardial preload and afterload may be more predictable. Cyclosporine and tacrolimus decrease renal blood flow and glomerular filtration via thromboxane-mediated renal vasoconstriction. Thus, renally excreted anesthetics and muscle relaxants should be used with caution in patients receiving these medications. Cyclosporine and tacrolimus also lower the seizure threshold, and hyperventilation should be avoided. Elevations in the resting HR and a delayed sympathetic response to noxious stimuli in cardiac transplant recipients may make anesthetic depth difficult to assess.
b. Regional anesthesia
Many immunosuppressants cause thrombocytopenia and alter the coagulation profile. Both the platelet count and coagulation profile should be within normal limits if spinal or epidural regional anesthesia is planned. Ventricular filling pressures should be maintained following induction of central neural axis blockade to prevent hypotension caused by the delayed response of the denervated, transplanted heart to a rapid decrease in sympathetic tone. Volume loading, ventricular filling pressure monitoring, and careful titration of local anesthetic agents may avoid hemodynamic instability. Hypotension should be treated with vasopressors that directly stimulate their target receptors.
4. Blood transfusion
The cardiac transplant recipient is at increased risk for blood product transfusion complications. Adverse reactions include infection, graft-versus-host disease, and immunomodulation. Use of irradiated, leukocyte-depleted, CMV-negative blood products, and white blood cell filters for blood product administration reduces the incidence of adverse transfusion reactions. The blood bank should receive early notification if the use of blood products is anticipated, because the presence of reactive antibodies delaying cross-match is not infrequent.
E. Pregnancy following cardiac transplantation
Despite an increased incidence of pre-eclampsia and preterm labor, increasing numbers of cardiac transplant recipients are successfully carrying pregnancies to term. In general, the transplanted heart is able to adapt to the physiological changes of pregnancy. Due to an increased sensitivity to the b-adrenergic effects of tocolytics such as terbutaline and ritodrine, use of alternative drugs such as magnesium and nifedipine may be considered. Although pregnancy does not adversely affect cardiac allografts, the risk of acute cardiac allograft rejection may be increased postpartum. All immunosuppressive drugs used to prevent cardiac allograft rejection cross the placenta, though most are not thought to be teratogenic.
XIII. Future directions
As medical management of HF continues to improve, a patient’s need for definitive therapy with heart transplantation may become delayed or diminished. On the basis of trends over the previous decade, it is to be expected that patients who do present for heart transplant will have an increasing number and severity of comorbidities . The emerging role of MCS devices for destination therapy will also affect future developments in heart transplantation . Intensive investigation into the use of stem cells and bioengineered organs may someday obviate the current organ shortage. Continuing advances in our understanding of mechanisms of rejection are likely to improve immunomodulation and delay graft failure. Improvements in surveillance, such as intravascular ultrasound, may eliminate the need for routine EMB. For the immediate future, however, heart transplantation continues to offer patients with advanced HF their best opportunity for a better quality and length of life.
1. Lietz K. Destination therapy: Patient selection and current outcomes. J Card Surg. 2010;25:462–471.
2. Stehlik J, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: Twenty-seventh official adult heart transplant report – 2010. J Heart Lung Transplant.2010;29:1089–1103.
3. Hunt SA, Haddad F. The changing face of heart transplantation. J Am Coll Cardiol. 2008;52:587–598.
4. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics – 2011 update: A report from the American Heart Association. Circulation. 2011;123:e18–e209.
5. Jessup M, Abraham WT, Casey DE, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults. Circulation.2009;119:e391–e479.
6. Mann DL, Bristow MR. Mechanisms and models in heart failure, the biomechanical model and beyond. Circulation. 2005;111:2837–2849.
7. Neubauer S. The failing heart – An engine out of fuel. N Engl J Med. 2007;356:1140–1151.
8. Sinha AM, Breithardt OA, Schmid M, et al. Brain natriuretic peptide release in cardiac surgery patients. Thorac Cardiovasc Surg. 2005;53:138–143.
9. Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med. 2000;343:246–253.
10. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;51:e1–e62.
11. American Society of Anesthesiologists. Practice advisory for the perioperative management of patients with cardiac implantable electronic devices: Pacemakers and implantable cardioverter-defibrillators. An updated report by the American Society of Anesthesiologists Task Force on perioperative management of patients with cardiac implantable electronic devices. Anesthesiology.2011;114:247–261.
12. Johnson MR, Meyer KH, Haft J, et al. Heart transplantation in the United States, 1999–2008. Am J Transplant. 2010;10: 1035–1046.
13. Kirlin JK, Naftel DC. Mechanical circulatory support, registering a therapy in evolution. Circ Heart Fail. 2008;1:200–205.
14. Patlolla V, Patten RD, DeNofrio D, et al. The effect of ventricular assist devices on post-transplant mortality, an analysis of the United network for organ sharing thoracic registry. J Am Coll Cardiol.2009;53:264–271.
15. Shuhaiber JH, Hur K, Gibbons R. The influence of preoperative use of ventricular assist devices on survival after heart transplantation: Propensity score matched analysis. BMJ. 2010;340:c392.
16. John R, Pagani FD, Naka Y, et al. Post-cardiac transplant survival after support with a continuous-flow left ventricular assist device: Impact of duration of left ventricular device support and other variables. J Thorac Cardiovasc Surg. 2010;140:174–181.
17. Shah KB, Parameshwar J. Advances in heart transplantation: The year in review. J Heart Lung Transplant. 2011;30:241–246.
18. Mancini D, Lietz K. Selection of cardiac transplantation candidates in 2010. Circulation. 2010;122:173–183.
19. Zimpfer D, Zrunek P, Roethy W, et al. Left ventricular assist devices decrease fixed pulmonary hypertension in cardiac transplant candidates. J Thorac Cardiovasc Surg. 2007;133:689–695.
20. Etz CD, Welp HA, Tjan TD, et al. Medically refractory pulmonary hypertension: Treatment with nonpulsatile left ventricular assist devices. Ann Thorac Surg. 2007;83:1697–1706.
21. Beyersdorf F, Schlensak C, Berchtold-Herz M, et al. Regression of “fixed” pulmonary vascular resistance in heart transplant candidates after unloading with ventricular assist devices. J Thorac Cardiovasc Surg.2010;140:747–749.
22. Alba AC, Rao V, Ross HJ, et al. Impact of fixed pulmonary hypertension on post-heart transplant outcomes in bridge-to-transplant patients. J Heart Lung Transplant. 2010;29:1253–1258.
23. Wittwer T, Wahlers T. Marginal donor grafts in heart transplantation: Lessons learned from 25 years of experience. Transpl Int. 2008;21:113–125.
24. Russo MJ, Davies RR, Hong KN, et al. Matching high-risk recipients with marginal donor hearts is a clinically effective strategy. Ann Thorac Surg. 2009;87:1066–1071.
25. Venkateswaran RV, Townend JN, Wilson IC, et al. Echocardiography in the potential heart donor. Transplantation. 2010;89:894–901.
26. Daneshmand MA, Milano CA. Surgical treatments for advanced heart failure. Surg Clin North Am. 2009;89:967–999.
27. Apostolakis E, Parissis H, Dougenis D. Brain death and donor heart dysfunction: Implications in cardiac transplantation. J Card Surg. 2010;25:98–106.
28. Dictus C, Vienenkoetter B, Esmaeilzadeh M. Critical care management of potential organ donors: Our current standard. Clin Transplant. 2009;23(suppl 21):2–9.
29. Smith M. Physiologic changes during brain stem death – Lessons for management of the organ donor. J Heart Lung Transplant. 2004;23:S217–S222.
30. Zaroff JF, Rosengard BR, Armstrong WF, et al. Consensus conference report: Maximizing use of organs recovered from the cadaveric donor: Cardiac recommendations: March 28–29, 2001, Crystal City, VA. Circulation.2002;106:836–841.
31. Davis RR, Russo MJ, Morgan JA, et al. Standard versus bicaval techniques for orthotopic heart transplantation: An analysis of the United Network for Organ Sharing database. J Thorac Cardiovasc Surg. 2010;140:700–708.
32. Schnoor M, Schäfer T, Lühmann D, et al. Bicaval versus standard technique in orthotopic heart transplantation: A systematic review and meta-analysis. J Thorac Cardiovasc Surg. 2007;134:1322–1331.
33. Newcomb AE, Esmore DS, Rosenfeldt FL, et al. Heterotopic heart transplantation: An expanding role in the twenty-first century? Ann Thorac Surg. 2004;78;1345–1351.
34. Shanwise J. Cardiac transplantation. Anesthesiol Clin North America. 2004;22:753–765.
35. Haddad F, Couture P, Tousignant C, et al. The right ventricle in cardiac surgery, a perioperative perspective: II. pathophysiology, clinical importance, and management. Anesth Analg. 2009;108:422–433.
36. Khan TA, Schnickel G, Ross D, et al. A prospective, randomized, crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients. J Thorac Cardiovasc Surg.2009;138:1417–1427.
37. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant.2005;24:1710–1720.
38. Asante-Korang A. Echocardiographic evaluation before and after cardiac transplantation. Cardiol Young. 2004;14:88–92.
39. Page RL, Miller GG, Lindenfeld J. Drug therapy in the heart transplant recipient: Part IV: Drug-drug interactions. Circulation. 2005;111:230–239.
40. Roselli EE, Smedira NG. Surgical advances in heart and lung transplantation. Anesthesiol Clin North America. 2004;22: 789–807.
41. Rothenburger M, Hulsken G, Stypmann J, et al. Cardiothoracic surgery after heart and heart-lung transplantation. Thorac Cardiovasc Surg. 2005;53:85–92.
42. Blasco LM, Parameshwar J, Vuylsteke A. Anaesthesia for noncardiac surgery in the heart transplant recipient. Curr Opin Anaesthesiol. 2009;22:109–113.