Key Points
- 1.
Cardiac transplant is the definitive treatment of advanced heart failure and has demonstrated improving outcomes and long-term survival.
- 2.
The transplanted heart receives no neural modulatory signal in the posttransplant period and is dependent on filling and humoral catecholamines.
- 3.
Mild restrictive physiology is the norm even with well-functioning grafts, and peak exercise capacity is reduced under even optimal circumstances.
- 4.
The risk of rejection decreases with time after transplant and is associated with a reduction in immunosuppression and surveillance. The diagnosis of rejection is via biopsy with management centered around increased immunosuppression.
- 5.
Cardiac allograft vasculopathy is a late form of diffuse coronary occlusion that causes graft dysfunction, which is difficult to treat by conventional means.
- 6.
Anemia, infection, renal dysfunction, and hypertension are common side effects of immunosuppression. Multiple interactions exist between anesthetic drugs and immunosuppressants.
- 7.
There is no contraindication to any anesthesia technique provided it maintains preload, sinus rhythm, and afterload.
- 8.
There is a higher risk of infection and bleeding complications with regional anesthetic techniques in this patient population.
Heart transplantation (HT) means a new lease on life for people with end-stage heart disease who have failed maximal medical therapy. Since its introduction by Dr. Christiaan Barnard more than 50 years ago, HT has rapidly become a viable and reliable treatment option for advanced heart failure (HF). More than 100,000 transplants have been performed to date, and more than 4000 procedures are being performed yearly. A 5-year survival rate of more than 70% and a median survival of more than 10 years serve as a testament to the vast strides forward in patient selection, surgical technique, and immunosuppression ( Fig. 6.1 ). Noncardiac surgery is required in 15% to 47% of these patients, with a higher mortality risk for emergent procedures. Thus with an increasing number of patients surviving and remaining functional long after HT, it is no longer practical to have specialized teams and centers perform noncardiac procedures on transplant recipients exclusively. Furthermore, a large proportion of these procedures are of an urgent nature, and prolonged evaluation, optimization, or transfer to a major academic center is often not possible.
Given this scenario, it is imperative for anesthesiologists to have a comprehensive knowledge of the physiology of the transplanted heart, the pharmacologic implications of immunosuppressive therapy, the complications of immunosuppressive therapy, and the anesthetic options for this subpopulation. The HT population presents a number of challenges because management of HT recipients is evolving. For example, the standard evaluation tools for risk assessment such as the Revised Cardiac Risk Index or guidelines from American Heart Association do not address risk stratification for this particular subgroup, and there are no clear guidelines for preoperative testing. Therefore the goal of this chapter is to provide a brief overview of the following:
- 1.
Physiologic attributes of the transplanted heart
- 2.
Immunosuppressive medications and their perioperative management
- 3.
Preoperative assessment and optimization
- 4.
Perioperative monitoring and management
Physiologic Attributes of the Transplanted Heart
The Transplanted Heart and the Cardiovascular System
Before transplantation, patients with advanced HF display varying degrees of systolic or diastolic dysfunction (or both). Whereas the former leads to a decrease in ejection fraction and cardiac output, the latter results in higher filling pressures. The reduction in cardiac output results in a reduction of blood, oxygen, and nutrient supply to end organs, which is only compounded by partial venous congestion. After HT cardiac output improves, and end-organ perfusion is largely restored. However, transplantation does not completely restore the patient to a nonpathologic state.
Anatomic Correlates
Despite the advances made in the management of HF, immunosuppression, and postoperative care, the surgical technique remains largely unchanged from the one described in the 1960s. The donor heart is anastomosed to the native circulation primarily in one of two ways. Biatrial anastomosis, which involves suturing of the native atria to the donor atria, was the standard approach originally and is technically simpler because it preserves the connections to the recipient atrium. The risk of sinus node injury is higher with the biatrial technique, as is the chance of hemodynamic problems associated with altered atrial geometry, size, and flow. Of note, with the biatrial technique, dual p-waves may be seen on the electrocardiogram (ECG) because of activation of native atrial tissue and can sometimes mimic atrial flutter. In addition, the sewing cuff can be seen as a ridge in the atria and can be confused for thrombi or endocarditis. Therefore knowledge of the surgical technique can often be beneficial to avoid misdiagnoses. The biatrial technique has been largely replaced by the bicaval technique. The bicaval technique involves anastomoses at the level of the great vessels—the superior and inferior vena cava—and a line of left atrial tissue encircling the pulmonary vessels. This technique has been associated with a reduction in sinus node dysfunction, tricuspid regurgitation, atrial fibrillation, and atrial dilation after transplant. The bicaval technique has also been shown to confer a small but significant survival advantage compared to the biatrial approach ( Box 6.1 ).
Box 6.1- •
Advantages: reduction in sinus node dysfunction, tricuspid regurgitation, atrial fibrillation, and atrial dilation after transplant; also, small significant survival advantage
- •
Disadvantage: more complex technique
Reinnervation
The normal heart is innervated by sympathetic and parasympathetic fibers of the autonomic nervous system. Whereas sympathetic innervation to the heart is from the cervical ganglia and upper thoracic (T1–T4) sympathetic chain, branches of the vagus nerves contribute the parasympathetic input. The cardiac plexus, which contains the postganglionic sympathetic and preganglionic parasympathetic fibers, is located at the base of the heart. The autonomic nervous system is also the conduit by which a supply of visceral sensory fibers is supplied to the pericardium. During transplantation, postganglionic neural axons innervating the heart are transected. Within days, cardiac stores of norepinephrine are exhausted, and autonomic influence over the heart ceases. After a variable period of 6 to 12 months, partial reinnervation of the transplanted heart has been shown to occur (see later). However, it remains incomplete and variable for many years after transplant. Thus in the early postoperative period, the transplanted heart is only subject to manipulation via humoral catecholamines.
As a consequence of efferent denervation, sympathetic stimulation and chronotropic responses to exercise, stress, and hypovolemia are not seen. This also includes blunting of baroreceptor responses (e.g., responses to laryngoscopy and intubation). Afferent denervation, on the other hand, impedes vasoregulatory responses by means of the renin-angiotensin axis, and the perception of pain secondary to ischemia (angina) is lost. Transplanted hearts demonstrate a high resting heart rate (90–100 beats/min) without much variability ( Table 6.1 ). Eventually, nerve sprouting occurs, and reinnervation proceeds along the left ventricle into the sinoatrial node and then to the coronaries, in that chronological order. Parasympathetic reinnervation tends to lag behind sympathetic reinnervation; in theory, there could be a state where the transplanted heart could have “unbalanced” autonomic input with sympathetic predominance. With the passage of time, the resting heart rate slows down, and rate variability reappears (see Table 6.1 ). The clinical implications of this pattern of cessation and gradual restoration of neural input to the transplanted heart are many and are discussed later in the text ( Box 6.2 ).
| Normal | Early Posttransplant | Late Posttransplant | |
|---|---|---|---|
| Heart rate: rest (beats/min) | 60–80 | 100–120 | 80–100 |
| Heart rate: exercise | Early rise | Slow rise | Intermediate |
| Heart rate: peak | +++ | + | ++ |
| Heart rate variability | ++ | Decreased | Variable |
| Systolic BP (mm Hg) | 100–120 | No change | Increased |
| Stroke volume (mL) | Normal | Slightly decreased | Decreased |
| Cardiac output (L/min) | 4–5 | No change | No change |
| Ejection fraction: rest (%) | 60–70 | No change | No change |
| Ejection fraction: exercise | +++ | + | ++ |
| SVR (dynes/sec/cm 5 ) | 700–1600 | + | ++ |
Box 6.2- •
Postganglionic neural axons innervating the heart are transected during transplant.
- •
The newly transplanted heart is only subject to manipulation via humoral catecholamines.
- •
Reinnervation can occur within 6–12 months posttransplant.
Filling Patterns
The filling pressures of an immediate posttransplant heart are significantly elevated. The elevated filling pressures are likely related to ischemic myocardial injury, rejection, volume overload, or a preexisting pulmonary vascular abnormality. Over time, this transitions to a mild rightward shift on the Frank-Starling curve during rest. However, circulating brain natriuretic peptide (BNP) levels are elevated even with normal hemodynamic parameters, suggesting some atrial stretch. The filling pressures, which are significantly elevated immediately after transplant, typically never fully return to normal, suggesting a mild restrictive physiology. Donor recipient size mismatch, increased afterload in the form of hypertension, and rejection are all proposed mechanisms. Often the end result is an abrupt rise in left ventricular filling pressures in response to fluid challenges, which makes these patients prone to pulmonary and systemic venous congestion. Mild rejection does not affect function significantly, although both systolic and diastolic function are adversely affected when rejection reaches severe proportions. Overall, this calls for caution with fluid challenges in the face of hypotension and vigilance toward volume status under anesthesia.
Exercise Response
Compared with their own pretransplant status, the exercise capacity of HT recipients shows improvement, but it is still reduced compared with that of healthy control participants. In healthy persons, withdrawal of vagal tone at the onset of exercise results in an initial increase in heart rate, which then results in an increased cardiac output. In HT recipients, the heart rate increase is slower, and the maximal heart rate achieved is lower (see Table 6.1 ). During exercise, an initial increase in cardiac output results from an increase in stroke volume and preload, but later during exercise, improved contractility and heart rate augmentation from circulating catecholamines take over. This neurohumoral response is exaggerated in HT recipients and may represent compensation for denervation. In addition, elevated pulmonary resistance and impairment in skeletal muscle function contribute to the reduction in maximal exercise capacity in HT recipients. HF in the pretransplant period, chronic oxygen debt, and steroid use generally lead to muscle fiber atrophy in this patient population. However, exercise training can result in a restoration of muscle mass, strength, and endurance after transplant. In a variety of clinical situations, exercise tolerance has been successfully used as a predictor of a patient’s ability to undergo the stress of anesthesia and surgery. It is no different for a transplant recipient presenting for noncardiac surgery.
Receptors and Drug Response
An increase in the number and the sensitivity of β-adrenergic receptors is present posttransplant. As a consequence, the transplanted heart demonstrates augmented responses to directly acting β-adrenergic antagonists. Resting coronary blood flow increases because of an absence of sympathetic tone. However, serotonin hypersensitivity (likely related to endothelial damage) causes decreased flow reserve in the transplanted heart. Abnormalities of response to endothelium-derived vasodilators such as substance P and acetylcholine have been noted, although the response to non–endothelium-derived vasodilators such as adenosine and dipyridamole is preserved. As previously noted, coronary demand-supply mismatch does not result in ischemic pain or angina in transplanted patients, so surveillance is required to identify coronary vasculopathy, which results in ischemia, even in the absence of symptoms.
Complications After Transplantation
Although rejection, infection, and cancer all come to mind as common complications posttransplant, the total list of complications is fairly long. In fact, surviving recipients have hypertension (97%), severe renal insufficiency (14%), hyperlipidemia (93%), diabetes (39%), and angiographic coronary allograph vasculopathy (CAV) (52%) by 10 years postcardiac transplantation. Many of these have a profound impact on outcomes in the perioperative period and the delivery of an anesthetic.
Rejection
Early success of HT was limited by organ rejection, and the evolution of the procedure has centered around methods to counteract and manage rejection. The risk of allograft rejection is the highest within 3 to 6 months of transplantation and decreases significantly after 1 year. Symptoms from rejection can be insidious and nonspecific, and surveillance biopsies at established intervals posttransplant are often necessary to make the diagnosis. The histologic hallmark of rejection is an inflammatory response directed against the grafted organ. The most feared type of rejection is the hyperacute variety, which manifests soon after restoration of circulation to the transplanted heart and is related to preformed antibodies to human leukocyte antigens (HLAs). This phenomenon has nearly been eliminated thanks to the development of prospective cytotoxic crossmatches. The newer variant of this technique is the “virtual crossmatch,” in which a profile of recipient cytotoxic antibodies against antigens is created. This virtual crossmatch avoids the need for the recipient’s blood to be matched against donor antigens when an organ becomes available.
Cell-mediated immunity has been recognized as the primary offender in rejection, although increasingly, antibody-mediated rejection is being recognized to play an equally important role. Frequently, cell-mediated rejection occurs 3 to 6 months after transplant and generally results in myocyte necrosis. The diagnosis is made by endomyocardial biopsy, and the severity is then graded between 1 and 3, the latter being most severe. Antibody-mediated rejection (AMR) usually results from preformed circulating antibodies. It was previously believed that AMR did not have a significant contribution to rejection that occurred multiple months after transplant. It is now known that humoral responses can occur and do contribute to rejection in the later phases as well. AMR is usually accompanied by early graft dysfunction, allograft vasculopathy, and hemodynamic compromise.
Treatment for AMR is initiated in patients with the clinical features of HF or ventricular dysfunction, irrespective of histologic evidence of cellular infiltrates. Symptoms of AMR can be nonspecific and include fatigue, unexplained weight gain, edema, or atrial fibrillation. This requires a high index of suspicion on the part of the treating physician. Endomyocardial biopsy via the internal jugular or femoral vein remains the gold standard for diagnosis. It is performed with decreasing frequency after the transplant (i.e., weekly for the first month, twice in the second month, and monthly for the next 4 months) per guidelines from the International Society of Heart and Lung Transplantation. Biopsy results can help differentiate between cell- and antibody-mediated rejection. However, it has the disadvantage of being invasive and sometimes requires general anesthesia. In addition, patchy inflammatory infiltrates may be missed on random biopsy sampling, and a histologic diagnosis may signal that significant myocardial damage has already occurred. Diastolic dysfunction and tissue Doppler imaging, using echocardiography, has shown some promise with a high negative predictive value when no abnormalities are detected. However, these echocardiographic modalities are nonspecific and have limited utility in the early detection of rejection. Cardiac magnetic resonance imaging has also shown some promise as a noninvasive test to detect rejection relatively early by using myocardial contrast enhancement. Serum markers such as troponins and BNP are nonspecific in the low-positive range and are not elevated until late in the disease process. The only Food and Drug Administration–approved noninvasive test used in routine clinical practice involves the creation of a genetic profile and identification of genetic markers that are suggestive of susceptibility to rejection. In a recent trial, this technique was shown to be comparable with endomyocardial biopsy in monitoring for rejection.
Treatment of rejection is guided by the severity and the nature of rejection as seen on biopsy. For asymptomatic patients with cellular rejection, it may suffice to increase the therapeutic levels of therapy. For coexisting cardiac dysfunction, pulse steroid therapy is used, and patients taking cyclosporine are switched to tacrolimus. It is important to remember that patients with asymptomatic humoral rejection are at a higher risk for allograft vasculopathy. Patients with AMR who are symptomatic are more aggressively managed with pulse steroids and occasionally intravenous (IV) γ-globulin. A detailed description of the therapy is beyond the scope of this text, but the principles are summarized in Table 6.2 . Support with inotropes, intraaortic balloon pump counterpulsation, or extracorporeal membrane oxygenation may be required in patients with cardiogenic shock.
| Immune Response | No Symptoms | Reduced Ejection Fraction | Failure or Shock |
|---|---|---|---|
| Cellular | Increase CNI; oral steroid bolus with taper | Oral steroid bolus with taper or IV pulse steroid | IV pulse steroid; cytolytic therapy; plasmapheresis; IVIG; inotropic support; IABP or ECMO; retransplantation |
| Humoral | No treatment (?) | Oral steroid bolus with taper or IV pulse steroid ± IVIG |
When transplant recipients present for noncardiac surgery, it is important to review their transplant and follow-up records to note the incidence, timing, and nature of rejection as well its management. Graft dysfunction is an ominous feature and should be discussed with the primary treatment team. As noted, patients with humoral rejection are at a higher risk of allograft vasculopathy (discussed later). The chronic administration or multiple courses of steroids can result in adrenal suppression and should be considered if this patient population is hemodynamically unstable in the perioperative period. Finally, the management of any circulatory support devices (e.g., ECMO) and associated anticoagulation must be considered.
Cardiac Allograft Vasculopathy
Coronary allograft vasculopathy (CAV) has been a major impediment to the long-term survival of HT recipients, with one-third of the HT patients developing CAV after 5 years. Little advancement has been made in prevention, and the incidence of CAV has not decreased dramatically in the past 20 years. It remains one of the major long-term (i.e., >1 year posttransplant) causes of mortality. CAV begins with a complex interaction between immune and nonimmune factors that eventually results in endothelial injury and subsequently an excessive fibroproliferative response. CAV is characterized by diffuse, concentric, hyperplastic lesions that affect the entire coronary tree. This is in contrast to native coronary atherosclerosis, in which the lesions are eccentric and distributed in a patchy, focal manner in the proximal epicardial vessels.
Endothelial injury is the final common pathway for this complex process, and it results in an excessive tissue repair response characterized by cell proliferation, fibrosis, and luminal narrowing. The previously mentioned nonimmune factors include not only general cardiac risk factors such as obesity, hypertension, smoking, and diabetes but also some modifiers unique to HT such as reperfusion injury and organ preservation. Growing evidence points to HLA compatibility, rejection, and CMV infection having roles in the pathogenesis as well. Calcification on imaging, which is common with native disease, is uncommon with CAV. Because angina is uncommon due to denervation at transplant, CAV manifests in much more sinister forms such as congestive HF, arrhythmias, or sudden cardiac death. This makes routine surveillance essential for diagnosis, which is difficult even when CAV is suspected. Myocardial perfusion imaging and stress echocardiography have limited diagnostic accuracy, though their prognostic utility is better. Coronary angiography combined with intravascular ultrasound is currently the standard for diagnosis, with an increase of 0.5 mm or more in intimal thickness within the first year after transplantation a powerful predictor of all-cause mortality, myocardial infarction, and angiographic abnormalities ( Box 6.3 ).
Box 6.3
