Recipient Selection

Potential candidates for heart transplantation generally undergo a multidisciplinary evaluation including a complete history and physical examination, routine hematology, chemistries (to assess renal and hepatic function), viral serology, electrocardiography, chest radiography, pulmonary function tests, and right- and left-sided heart catheterization. Ambulatory electrocardiography, echocardiography, and nuclear gated scans are performed if necessary. The goals of this evaluation are to confirm a diagnosis of end-stage heart disease that is not amenable to other therapies and that will likely lead to death within 1 to 2 years and to exclude extracardiac organ dysfunction that could lead to death soon after heart transplantation. Patients typically have stage D heart failure, New York Heart Association (NYHA) class IV symptoms, and a left ventricular ejection fraction (LVEF) of less than 20%. Although most centers eschew a strict age cutoff, the candidateshould have a “physiologic” age younger than 60 years. Detecting pulmonary hypertension, and determining whether it is due to a fixed elevation of pulmonary vascular resistance (PVR), is crucial; early mortality due to graft failure is threefold higher in patients with elevated PVR (transpulmonary gradient > 15 mmHg or PVR > 150 dynes•sec•cm⁻⁵). If elevated PVR is detected, a larger donor heart, a heterotopic heart transplant, or a heart-lung transplant may be more appropriate. Active infection and recent pulmonary thromboembolism with pulmonary infarction are additional contraindications to heart transplantation. The results of this extensive evaluation should be tabulated and available to the anesthesia team at all times, because heart transplantation is an emergency procedure.

Donor Selection and Graft Harvest

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

Donors can exhibit major hemodynamic and metabolic derangements that can adversely affect organ retrieval. The vast majority of brain-dead donors will be hemodynamically unstable.² Reasons for such instability include hypovolemia (secondary to diuretics or diabetes insipidus), myocardial injury (possibly a result of “catecholamine storm” during periods of increased intracranial pressure), and inadequate sympathetic tone due to brainstem infarction. Donors often also have abnormalities of neuroendocrine function such as low T₃ and T₄ levels. Donor volume status should be assiduously monitored, and inotropic and vasopressor therapy should be guided by data from invasive monitors.

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

Orthotopic Heart Transplantation

Orthotopic heart transplantation is carried out via a median sternotomy, and the general approach is similar to that used for coronary revascularization or valve replacement. Patients will frequently have undergone a prior median sternotomy; repeat sternotomy is cautiously performed using an oscillating saw. The groin should be prepped and draped to provide a rapid route for cannulation for cardiopulmonary bypass (CPB) if necessary. After the pericardium is opened, the aorta is cannulated as distally as possible, and the IVC and SVC are individually cannulated via the high right atrium (RA). Manipulation of the heart before institution of CPB is limited if thrombus is detected in the heart with transesophageal echocardiography (TEE). After initiation of CPB and cross-clamping of the aorta, the heart is arrested and excised (Fig. 20-1). The aorta and PA are separated and divided just above the level of their respective valves, and the atria are transected at their grooves. A variant of this classic approach totally excises both atria, mandating bicaval anastomoses. This technique may reduce the incidence of atrial arrhythmias, better preserve atrial function by avoiding tricuspid regurgitation, and enhance cardiac output (CO) after transplantation.

Figure 20-1 Mediastinum after excision of the heart but before allograft placement. Venous cannulas are present in the superior and inferior vena cavae, and the arterial cannula is present in the ascending aorta. A, Classic orthotopic technique. B, Bicaval anastomotic technique.

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

Heterotopic Heart Transplantation

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

Donor harvesting for heterotopic placement is performed in the previously described manner, except that the azygos vein is ligated and divided to increase the length of the donor SVC; the PA is extensively dissected to provide the longest possible main and right PA; and the donor IVC and right pulmonary veins are oversewn, with the left pulmonary veins incised to create a single large orifice. The operation is performed via a median sternotomy in the recipient, but the right pleura is entered and excised. The recipient SVC is cannulated via the RA appendage, and the IVC is cannulated via the lower RA. After arrest of the recipient heart, the LA anastomosis is constructed by incising the recipient LA near the right superior pulmonary vein and extending this incision inferiorly and then anastomosing the respective LA. The recipient RA-SVC is then incised and anastomosed to the donor RA-SVC, following which the donor aorta is joined to the recipient aorta in an end-to-side manner. Finally, the donor PA is anastomosed to the recipient main PA in an end-to-side manner if it is sufficiently long; otherwise, they are joined via an interposed vascular graft (Fig. 20-2).

Figure 20-2 Placement of heterotopic graft in the right chest, with anastomoses to the corresponding native left and right atria, ascending aorta, and an interposition graft to the native pulmonary artery. LA = left atrial; LV = left ventricle; RA = right atrium; PA = pulmonary artery; AO = aorta; WVC = superior vena cava; RV = right ventricle.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

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

Special Situations

Mechanical ventricular assist devices have been successfully used to “bridge” patients who would otherwise die of acute heart failure awaiting transplantation.³ The technique of transplantation is virtually identical in such patients to that for ordinary orthotopic transplantation. However, repeat sternotomy is obligatory, and patients will often have been exposed to aprotinin during the assist device placement, increasing the probability of an anaphylactic response to the second aprotinin exposure. Although the incidence of anaphylaxis seems to be low, the team should be in a position to expeditiously initiate CPB before administering aprotinin in this setting. Placement of large-bore intravenous access is prudent because excessive hemorrhage can occur during the transplant procedure.

Rarely, patients will present for cardiac transplantation combined with transplantation of the liver. The cardiac allograft is usually implanted first to better enable the patient to survive potential hemodynamic instability associated with reperfusion of the hepatic allograft. Large-bore intravenous access is mandatory. A venous cannula can be left in the RA at the completion of the heart transplant procedure to serve as a return site for subsequent veno-veno bypass during liver transplantation.

Pathophysiology Before Transplantation

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

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

Pathophysiology after Transplantation

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

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

Denervation has important implications in the choice of pharmacologic agents used after cardiac transplantation. Drugs that act indirectly on the heart via either the sympathetic (ephedrine) or parasympathetic (atropine, pancuronium, edrophonium) nervous systems will generally be ineffective. Drugs with a mixture of direct and indirect effects will exhibit only their direct effects (leading to the absence of the normal increase in refractory period of the atrioventricular node with digoxin, tachycardia with norepinephrine infusion, and bradycardia with neostigmine). Thus, agents with direct cardiac effects (e.g., epinephrine or isoproterenol) are the drugs of choice for altering cardiac physiology after transplantation. However, the chronically high catecholamine levels found in cardiac transplant recipients may blunt the effect of α-adrenergic agents, as opposed to normal responses to β-adrenergic agents.⁴

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

Anesthetic Management

Postoperative Management and Complications

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

Early complications after heart transplantation include acute and hyperacute rejection, cardiac failure, systemic and pulmonary hypertension, cardiac arrhythmias, renal failure, and infection. Hyperacute rejection is an extremely rare but devastating syndrome mediated by preformed recipient cytotoxic antibodies against donor heart antigens. The donor heart immediately becomes cyanotic from microvascular thrombosis and ultimately ceases to contract. This syndrome is lethal unless the patient can be supported mechanically until a suitable heart is found. Acute rejection is a constant threat in the early postoperative period and may present in many forms (e.g., low CO, arrhythmias). Acute rejection occurs most frequently during the initial 6 months after transplantation, so its presence is monitored by serial endomyocardial biopsies, with additional biopsies to evaluate any acute changes in clinical status. Detection of rejection mandates an aggressive increase in the level of immunosuppression, usually including pulses of glucocorticoid or a change from cyclosporine to tacrolimus. Low CO after transplantation may reflect a number of causes: hypovolemia, inadequate adrenergic stimulation, myocardial injury during harvesting, acute rejection, tamponade, or sepsis. Therapy should be guided by invasive monitoring, TEE, and endomyocardial biopsy. Systemic hypertension may be due to pain, so adequate analgesia should be obtained before treating blood pressure with a vasodilator. Because fixed pulmonary hypertension will have been excluded during the recipient evaluation, pulmonary hypertension after heart transplantation is usually transient and responsive to vasodilators such as prostaglandin E₁, nitrates, or hydralazine after either orthotopic or heterotopic placement.⁷ Atrial and ventricular tachyarrhythmias are common after heart transplantation; once rejection has been ruled out as a cause, antiarrhythmics are used for conversion or control (except those acting via indirect mechanisms such as digoxin, or those with negative inotropic properties such as β-blockers and calcium channel blockers). Almost all recipients will require either β-adrenergic agonists or pacing to increase heart rate in the immediate perioperative period, but 10% to 25% of recipients will also require permanent pacing.⁸ Renal function often improves immediately after transplantation, but immunosuppressives such as cyclosporine and tacrolimus may impair renal function. Finally, infection is a constant threat to immunosuppressed recipients. Bacterial pneumonia is frequent early in the postoperative period, with opportunistic viral and fungal infections becoming more common after the first several weeks.

History and Epidemiology

Although the first human lung transplant was performed in 1963, surgical technical problems and inadequate preservation and immunosuppression regimens prevented widespread acceptance of this procedure until the mid 1980s (Box 20-2). Advances in these areas have since made lung transplantation a viable option for many patients with end-stage lung disease. The frequency of both single- and double-lung transplants increased exponentially during the period up until 1993, with the sharpest growth in unilateral transplants. According to data collected by UNOS between 2000 and 2002, the annual frequency of lung transplantation remained stagnant, with the total number averaging in the vicinity of 1000. This is unchanged from the time between 1993 and 1995 when the numbers first leveled off. Further growth in lung transplantation is constrained by a shortage of donor organs, with demand for organs still vastly exceeding supply. It is estimated that in excess of a million individuals with end-stage lung disease are potential recipients of lung transplants.⁹ Some had hoped that non−heart-beating donors would provide an alternative source of organs, but this has not been the case. The Organ Procurement and Transplantation Network currently registers approximately 4000 patients for lung transplantation. This number does not accurately reflect the number of organs required as some patients will require bilateral lung transplantation. Average time to transplant increased to as much as 451 days in 1999, but now about one fourth of patients receive a transplant within 251 days. Most of this improvement has been seen with recipients who are 50 years of age and older. One explanation for this may be increasing leniency in organ selection criteria. This seems to have not been associated with increasing mortality rates. Mortality for patients on the waiting list has also continued to decline, from a 1993 high of close to 250 per 1000 patient-years to approximately 140 in 2002. Although some of this improvement may be ascribed to better medical management of patients on the waiting list, it is also likely due to broadened criteria for acceptance for transplantation and subsequent inclusion of patients with less severe illness.

Increased experience with lung transplantation has been accompanied by a decrease in both operative and long-term mortality. For example, 30-day mortality for double-lung transplantation decreased from 44% in 1988 to 13.6% in 1991, whereas that for single-lung transplantation decreased from 22.7% to 12.6%.¹⁰ As of the end of 1995, 3-year actuarial survival for recipients of both single- and double-lung transplants performed in the era 1992 to 1995 was approximately 60%, 10% better than for recipients transplanted in the previous 3-year interval. Even better survival data have been reported from centers with extensive experience with these procedures (1-year survival rates of 82% for double-lung recipients and 90% for single-lung recipients). Infection is the most frequent cause of death in the first year after transplant, but this is superceded in later years by bronchiolitis obliterans.

Some of the most challenging patients are those with cystic fibrosis. The 1-year survival of 79% and 5-year survival of 57% after lung transplantation have shown that despite the high incidence of poor nutrition and the almost ubiquitous colonization by multidrug-resistant organisms, these patients can still successfully undergo lung transplantation with acceptable outcome data.¹¹

It is a sign of the maturity of lung transplantation procedures that survival data for repeat lung transplantation are also becoming available. A late 1991 survey of centers reported that actuarial survival after repeat transplantation was significantly worse than that of first-time recipients (e.g., 35% vs. greater than 75% at 1 year),¹² and subsequent data have confirmed this observation. Infection and multiorgan failure before repeat transplant are associated with an almost uniformly fatal outcome.

Recipient Selection

Because donor lungs are scarce, it is important to select as recipients those most likely to benefit from lung transplantation. In general, candidates should be terminally ill with end-stage lung disease (NYHA class III or IV, with a life expectancy of approximately 2 years), be psychologically stable, and be devoid of serious medical illness (especially extrapulmonary infection) compromising other organ systems. Patients already requiring mechanical ventilation are poor candidates, although lung transplantation can be successful in such a setting. Other factors such as advanced age, previous thoracic surgery or deformity, and corticosteroid dependence may be regarded as relative contraindications by individual transplant centers. Hepatic disease due solely to right-sided heart dysfunction should not preclude candidacy.

Potential recipients undergo a multidisciplinary assessment of their suitability, including pulmonary spirometry, radiography (plain film and chest CT scan), and echocardiography or multiple gated image acquisition (MUGA) scan. Patients older than 40 years of age and those with pulmonary hypertension usually undergo left-sided heart catheterization to exclude significant coronary atherosclerosis or an intracardiac shunt. TEE may yield data (e.g., unanticipated atrial septal defect) that will alter subsequent surgical approach in approximately one fourth of patients with severe pulmonary hypertension. Candidates who are accepted are often placed on a physical conditioning regimen to reverse muscle atrophy and debilitation and to keep them within 20% of their ideal body weight. Because lung transplantation is an emergency procedure (limited by a lung preservation time of 6 to 8 hours), results of this comprehensive evaluation should be readily available to the anesthesia team at all times.

Donor Selection and Graft Harvest

The ongoing shortage of suitable donor organs has led to a liberalization of selection criteria. Prospective lung donors who were cigarette smokers are no longer rejected simply based on a pack-year history. CT has been used to assess the structural integrity of the lung, particularly in donors who have sustained traumatic chest injury. Lungs that have contusion limited to less than 30% of a single lobe can be considered adequate.¹³ Greater use has also been made of organs from older but otherwise healthy donors (55 to 60 years old) especially when the ischemic period will be short. A clear chest radiograph, normal blood gas results, unremarkable findings on bronchoscopy and sputum stain, and direct intraoperative evaluation confirm satisfactory lung function. The lungs are matched to the recipient for ABO blood type and size (oversized lungs can result in severe atelectasis and compromise of venous return in the recipient, especially after double-lung transplantation). Donor serology and tracheal cultures guide subsequent antibacterial and antiviral therapy in the recipient.

Most lung grafts are recovered during a multivisceral donor harvest procedure. The heart is removed as described for heart transplantation, using inflow occlusion and cardioplegic arrest, with division of the IVC and SVC, the aorta, and the main PA. Immediately after cross-clamping, the pulmonary vasculature is flushed with ice-cold preservative solution, which often contains prostaglandin E₁. This is believed to promote pulmonary vasodilation, which aids homogeneous distribution of the preserving solution. Other additives that have been included are nitroglycerin and low-potassium 5% Dextran. The LA is divided so as to leave an adequate LA cuff forboth the heart graft and lung graft(s) with the pulmonary veins. After explanation, the lung may also be flushed to clear all pulmonary veins of any clots. After the lung is inflated, the trachea (or bronchus for an isolated lung) is clamped, divided, and stapled closed. Inflating the lung has been shown to increase cold ischemia tolerance of the donor organ. The lung graft is removed, bagged, and immersed in ice-cold saline for transport.

Surgical Procedures

Because of the relative shortage of lung donors and the finding that recipients can gain significant exercise tolerance even with only one transplanted lung, single-lung transplantation is the procedure of choice for all lung transplant candidates, except when leaving one of the recipient’s lungs in place would predispose to complications. For example, the presence of lung disease associated with chronic infection (cystic fibrosis and severe bronchiectasis) mandates double-lung transplantation to prevent the recipient lung from acting as a reservoir of infection and subsequently cross-contaminating the allograft. Patients with severe air trapping may require double-lung transplantation if uncontrollable ventilation-perfusion mismatching will be likely after transplantation. Lobar transplantation into children and young adults from living-related donors is discussed separately.

Single-Lung Transplant

The choice of which lung to transplant is usually based on multiple factors, including avoidance of a prior operative site, preference for removing the native lung with the worst ventilation-perfusion ratio, and donor lung availability. The recipient is positioned for a posterolateral thoracotomy, with the ipsilateral groin prepped and exposed in case CPB becomes necessary. With the lung deflated, a pneumonectomy is performed, with special care to preserve as long a PA segment as possible. After removal of the diseased native lung, the allograft is positioned in the chest with precautions to maintain its cold tissue temperature. The bronchial anastomosis is performed first. A “telescoping” anastomosis is used if there is significant discrepancy in size between the donor and the recipient. The object of the technique is to minimize the chance of dehiscence. Although it was once common to wrap bronchial anastomoses with omentum, wrapping produces no added benefit when a telescoping anastomosis is performed. The PA is anastomosed next, and finally the pericardium is opened and the allograft LA cuff containing the pulmonary venous orifices is anastomosed to the native LA. The pulmonary circuit is then flushed with blood and de-aired. The initial flush solution is usually cold (4°C) but is followed by a warm (37°C) flush. The warm flush is usually performed during final completion of the vascular anastomoses. The goal of the flushing is to achieve a controlled reperfusion. The contents of this solution are listed in Box 20-3. After glucocorticoid administration, the vascular clamps are removed, reperfusion is begun, and the lung reinflated with a series of ventilations to full functional residual capacity. After achieving adequate hemostasis and satisfactory blood gases, chest tubes are placed, the wound is closed, and the patient is transported to the ICU.

Double-Lung Transplant

Early attempts at double-lung transplantation using an en bloc technique via a median sternotomy were plagued by frequent postoperative airway dehiscence due to poor vascular supply of the tracheal anastomosis; by hemorrhage due to extensive mediastinal dissection (which also resulted in cardiac denervation); by the requirement for complete CPB and cardioplegic arrest (to facilitate pulmonary arterial and venous anastomoses); and by poor access to the posterior mediastinum. The subsequent development of the bilateral sequential lung transplant technique via a “clamshell” thoracosternotomy (essentially two single-lung transplants performed in sequence) has avoided many of the problems inherent in the en bloc technique.¹⁴ An alternative to using a clamshell incision in slender patients is an approach through two individual anterolateral thoracotomies. This results in a particularly pleasing cosmetic result in female patients because the scar falls in the breast crease. Use of CPB is optional, exposure of the posterior mediastinum is enhanced (improving hemostasis), and cardiac denervation can usually be avoided. Pleural scarring is usually extensive in patients with cystic fibrosis, and postoperative hemorrhage and coagulopathy are the rule if CPB is required.

Transplantation of both lungs is performed in the supine position. The groins are prepped and exposed in case CPB is required. If a clamshell incision is used, the arms are padded and suspended over the head on an ether screen. In the slender patient whose anteroposterior chest dimensions are normal, the arms may be tucked at the patient’s sides. Recipient pneumonectomy and implantation of the donor lung are performed sequentially on both lungs in essentially the same manner as described above for a single-lung transplant. The native lung with the worst function should be transplanted first. In patients whose indication for transplantation is suppurative disease, the pleural cavity is pulse-lavaged with antibiotic-containing solution that has been tailored to that patient’s antimicrobial sensitivity profile. In addition to this, the anesthesiologist irrigates the trachea and bronchi with diluted iodophore solution before the donor lung is brought onto the surgical field.

Pathophysiology before Transplantation

Patients with highly compliant lungs and obstruction of expiratory airflow cannot completely exhale the delivered tidal volume, resulting in positive intrapleural pressure throughout the respiratory cycle (“auto-PEEP” [positive end-expiratory pressure] or “intrinsic PEEP”), which decreases venous return and causes hypotension. The presence of auto-PEEP is highly negatively correlated with FEV₁ (percent predicted) and highly positively correlated with pulmonary flow resistance and resting hypercarbia. Hyperinflation is a frequent complication of single-lung ventilation during lung transplantation in patients with obstructive lung disease. Hyperinflation-induced hemodynamic instability can be diagnosed by turning off the ventilator for 30 seconds and opening the breathing circuit to the atmosphere. If the blood pressure returns to its baseline value, hyperinflation is the underlying cause. Hyperinflation can be ameliorated with deliberate hypoventilation (decreasing both the tidal volume and/or rate).¹⁵ Although this may result in profound hypercarbia, high carbon dioxide tensions are well tolerated in the absence of hypoxemia. PEEP may also decrease air trapping because it decreases expiratory resistance during controlled mechanical ventilation. However, the application of PEEP requires close monitoring, because if the level of extrinsic PEEP applied exceeds the level of auto-PEEP, further air trapping may result.

RV failure is frequently encountered in lung transplant recipients with pulmonary hypertension due to chronically elevated RV afterload. The response of the RV to a chronic increase in afterload is to hypertrophy, but eventually this adaptive response is insufficient. As a result, RV volume decreases and chamber dilation results. The following should be kept in mind when caring for patients with severe RV dysfunction (Box 20-4). First, increases in intrathoracic pressure may markedly increase PVR, leading to frank RV failure in patients with chronic RV dysfunction. Changes in RV function may occur immediately after adding PEEP, increasing tidal volume or decreasing expiratory time, and can have devastating consequences. In addition, although intravascular volume expansion in the presence of normal PVR increases CO, overzealous infusion in patients with elevated PVR increases RV end-diastolic pressure and RV wall stress, decreasing CO. Inotropes with vasodilating properties (such as dobutamine or milrinone) are often a better choice than volume for augmenting CO in the setting of elevated PVR. Furthermore, the RV has a higher metabolic demand yet a lower coronary perfusion pressure than normal. RV performance can be augmented by improving RV coronary perfusion pressure with α-adrenergic agents, provided these vasoconstrictors do not disproportionately elevate PVR. This can sometimes be a better choice than augmenting the perfusion pressure with β-adrenergic agents because the oxygen supply is increased without a large increase in oxygen demand. Finally, vasodilators such as nitroprusside or prostaglandin E₁ may be effective in decreasing PVR and improving RV dysfunction early in the disease process, when only mild to moderate pulmonary hypertension is present. However, they are of notably limited value in the presence of severe, end-stage pulmonary hypertension. Systemic vasodilation and exacerbation of shunting often limit their use. Inhaled nitric oxide has shown promise as a means of acutely decreasing PVR without altering systemic hemodynamics both during the explanation phase and after lung transplantation.¹⁶ Nitric oxide decreases both PA pressure and intrapulmonary shunting. Further, the combination of inhaled nitric oxide and aerosolized prostacyclin had a synergistic effect, without causing deleterious effects on the systemic perfusion pressure. The use of nitric oxide with or without inhaled prostacyclin may be helpful in avoiding CPB in patients having lung transplantation.

Pathophysiology after Lung Transplantation

The implantation of the donor lung(s) causes marked alterations in recipient respiratory physiology. In single-lung recipients, the pattern of ventilation-perfusion matching depends on the original disease process. For example, with pulmonary fibrosis, blood flow and ventilation gradually divert to the transplanted lung, whereas in patients transplanted for diseases associated with pulmonary hypertension, blood flow is almost exclusively diverted to the transplanted lung, which still receives only half of the total ventilation. In such patients the native lung represents mostly deadspace ventilation. Transplantation results in obligatory sympathetic and parasympathetic denervation of the donor lung and therefore alters the physiologic responses of airway smooth muscle. Exaggerated bronchoconstrictive responses to the muscarinic agonist methacholine have been noted in some studies of denervated lung recipients. The mechanism of hyperresponsiveness may involve cholinergic synapses, inasmuch as they are the main mediators of bronchoconstriction. For example, electrical stimulation of transplanted bronchi (which activates cholinergic nerves) produces a hypercontractile response. This suggests either enhanced release of acetylcholine from cholinergic nerve endings due to an increased responsiveness of parasympathetic nerves or else loss of inhibitory innervation. Such effects are unlikely to be postsynaptic in origin because the number and affinity of muscarinic cholinergic receptors on transplanted human bronchi are similar to controls. Reinnervation during subsequent weeks to months has been demonstrated in several animal models, but there is no definitive evidence concerning reinnervation of transplanted human lungs. Mucociliary function is transiently severely impaired after lung transplantation and remains depressed for up to 1 year after the procedure. Thus, transplant recipients require particularly aggressive endotracheal suctioning to remove airway secretions.

Lung transplantation also profoundly alters the vascular system. The ischemia and reperfusion that are an obligatory part of the transplantation process damage endothelia. Cold ischemia alone decreases β-adrenergic cyclic adenosine monophosphate (cAMP)-mediated vascular relaxation by approximately 40%, and subsequent reperfusion produces even greater decreases in both cyclic guanosine monophosphate (cGMP)-mediated and β-adrenergic cAMP-mediated pulmonary vascular smooth muscle relaxation. Endothelial damage in the pulmonary allograft also results in “leaky” alveolar capillaries and the development of pulmonary edema. Pulmonary endothelial permeability is approximately three times greater in donor lungs than in healthy volunteers. Regulation of pulmonary vasomotor tone solely by circulating humoral factors is another side effect of denervation. Changes in either the levels of circulating mediators or in the responsiveness of the pulmonary vasculature to such mediators may result in dramatic effects on the pulmonary vasculature. An example of the former is the finding that the potent vasoconstrictor endothelin is present at markedly elevated levels (two to three times normal) immediately after transplantation and remains elevated for up to 1 week thereafter. Alterations in the response of denervated pulmonary vasculature to α₁-adrenergic agents and prostaglandin E₁, as well as a reduction in nitric oxide activity, have also been demonstrated in acutely denervated lung. Dysfunctional responses to mediators may be exaggerated if CPB is required. Pulmonary vascular resistance can be substantially decreased with the administration of inhaled nitric oxide after reperfusion. It remains unclear whether nitric oxide also ameliorates reperfusion injury. Several studies suggest that nitric oxide prevents or modulates reperfusion injury as measured by decreased lung water, lipid peroxidase activity, and neutrophil aggregation in the graft.¹⁷ However, there are a number of studies that suggest that although nitric oxide has an effect on pulmonary hemodynamics, it does not ameliorate reperfusion injury.

Given these pathophysiologic derangements, it is not surprising that PVR increases in the transplanted lung. However, what the clinician observes in the lung transplant patient will depend on the severity of pulmonary vascular dysfunction present preoperatively. PA pressures decrease dramatically during lung transplantation in patients who had pulmonary hypertension before transplantation and remain so for weeks to months thereafter. Concomitant with the decrease in PA pressure, there is an immediate decrease in RV size after lung transplantation in those patients with preexisting pulmonary hypertension, as well as a return to a more normal geometry of the interventricular septum. Both of these effects are sustained over several weeks to months. Although echocardiographic indices of RV function (RV fractional area change) have not shown a consistent improvement in the immediate post-transplant period, several other studies have documented improvement in RV function during the first several months after lung transplantation. One striking finding was that persistent depression of RV function (defined as baseline RV fractional area change of less than 30% with failure to increase after transplant by at least 5% or by 20% of baseline) was statistically associated with death in the immediate perioperative period.

Anesthetic Management

Intraoperative Management

Institution of one-lung ventilation (OLV) occurs before hilar dissection and may compromise hemodynamics and/or gas exchange (Box 20-6). Patients with diminished lung compliance can often tolerate OLV with normal tidal volumes and little change in hemodynamics. In contrast, patients with increased lung compliance and airway obstruction will often exhibit marked hemodynamic instability, unless the tidal volume is decreased and the expiratory time is increased. The magnitude of hypoxemia generally peaks about 20 minutes after beginning OLV. Hypoxemia during OLV may be treated with continuous positive airway pressure (CPAP) applied to the nonventilated lung,¹⁸ PEEP to the ventilated lung, or both. CPAP attempts to oxygenate the shunt fraction but may interfere with surgical exposure. PEEP attempts to minimize atelectasis in the ventilated lung but may concomitantly increase shunt through the nonventilated lung. Definitive treatment of shunt in the nonventilated lung is provided by rapid isolation and clamping of the PA of the nonventilated lung. Pneumothorax on the nonoperative side may result during OLV if a large tidal volume is used.

BOX 20-6 Management Principles for One-Lung Ventilation during Lung Transplantation

• Tidal volume and respiratory rate

• Maintain in patients with normal or decreased lung compliance (i.e., primary pulmonary hypertension, fibrosis)

• Decrease both tidal volume and rate in patients with increased compliance (e.g., obstructive lung disease) to avoid hyperinflation (“permissive hypercapnia”)

• Maintain oxygenation by

• 100% Inspired oxygen

• Applying continuous positive airway pressure (5 to 10 cm) to nonventilated lung

• Adding positive end-expiratory pressure (5 to 10 cm) to ventilated lung

• Intermittent lung re-inflation if necessary

• Surgical ligation of the pulmonary artery of the nonventilated lung

• Be alert for development of pneumothorax on nonoperative side

• Sharp drop in oxygen saturation, end-tidal carbon dioxide

• Sharp rise in peak airway pressures

• Increased risk with bullous lung disease

• Therapy

• Relieve tension

• Resume ventilation

• Emergency cardiopulmonary bypass

PA clamping is usually well tolerated, except in the face of pulmonary hypertension with diminished RV reserve. If the degree of RV compromise is uncertain, a 5- to 10-minute trial of PA clamping is attempted, then the RV is evaluated by serial CO, RVEF measurements, and TEE. A significant decrease in CO may predict patients who will require extracorporeal support. Other indications for CPB in lung transplantation are listed in Box 20-7.

BOX 20-7 Indications for Cardiopulmonary Bypass during Lung Transplantation

Cardiac index	<2 L/min/m2
	<60%
Mean arterial pressure	<50 to 60 mm Hg
SaO2	<85% to 90%
pH	<7.00

Patients with severe pulmonary hypertension (greater than two thirds of systemic pressure) will generally be placed on CPB before PA clamping. The intraoperative use of nitric oxide (20 to 40 ppm) may allow some procedures to proceed without the use of CPB.¹⁹

Lung transplantation can usually be performed without the aid of CPB; even during bilateral sequential lung transplantation, experienced teams use CPB for only about one fourth of patients. Although CPB may provide very stable hemodynamics, it is associated with an increased transfusion requirement. In addition, graft function (as reflected by alveolar-arterial oxygen gradient) may be compromised, endothelium-dependent cGMP- and β-adrenergic cAMP-mediated pulmonary vascular relaxation may be impaired to a greater degree, and a longer period of mechanical ventilation may be necessary. Several exceptional circumstances require CPB: the presence of severe pulmonary hypertension, because clamping of the PA will likely result in acute RV failure and “flooding” of the nonclamped lung; the repair of associated cardiac anomalies (e.g., patent foramen ovale, atrial or ventricular septal defects); treatment of severe hemodynamic or gas exchange instabilities; and living-related lobar transplantation. Hypercarbia is generally well tolerated and should not be considered a requirement for CPB per se. Thus, the frequency of CPB will depend on recipient population factors such as prevalence of end-stage pulmonary vascular disease and associated cardiac anomalies.

The use of femoral venous and arterial cannulas for CPB during lung transplantation may lead to poor venous drainage and/or “differential perfusion” of the lower and upper body. Moreover, native pulmonary blood flow continues and may act as an intrapulmonary shunt during CPB. In this case, the cerebral vessels receive this desaturated blood while the lower body is perfused with fully oxygenated blood from the CPB circuit. This effect is detectable by blood gas analysis of samples drawn from suitable arteries or appropriately located pulse oximeter probes. Treatment includes conventional measures to increase venous return and augment bypass flow or placing a venous cannula in the RA if this is feasible. The anesthesiologist should also maximize the inspired oxygen concentration and add PEEP to decrease intrapulmonary shunt. If all other measures fail, ventricular fibrillation can be induced using alternating current.

Extracorporeal membrane oxygenation (ECMO) has also been suggested as an alternative method of CPB during lung transplantation. It has been suggested that the use of ECMO with heparin-bonded circuits might improve the outcome of both single- and double-lung transplants by lessening the amount of pulmonary edema especially in those patients who need CPB due to hemodynamic instability or with primary pulmonary hypertension. An added benefit of this technique is also that it clears the operative field of bypass cannulas making left-sided transplant as unimpeded as right-sided transplant. There is no apparent increase in transfusion requirement. Another added benefit of using ECMO in situ is that reperfusion of the lungs can be more easily controlled since the CO transiting the newly transplanted lung can be precisely controlled. This is especially the case for patients with advanced pulmonary hypertension.²⁰

If CPB is used, weaning from circulatory support occurs when the graft anastomoses are complete. Ventilation is resumed with a lung protection strategy. This technique in patients with decreased compliance related to acute respiratory distress syndrome had a 22% decrease in mortality when applying tidal volumes of 6 mL/kg and a plateau pressure less than 30 cm H₂O. Minimizing the inspired fraction of O₂ may help prevent generation of oxygen free-radicals and modulate reperfusion injury. FIO₂ can be decreased to the minimum necessary to maintain the SpO₂ at greater than 90%. Special attention should be directed to assessing and supporting RV function during this period, inasmuch as RV failure is the most frequent reason for failure to wean. Although the RV can often be seen in the surgical field, TEE is more valuable for visualizing this structure’s functional properties at this juncture. Inotropic support with dobutamine or epinephrine as well as pulmonary vasodilation with nitroglycerin, nitroprusside, milrinone, or nitric oxide may be necessary if RV dysfunction is evident. Milrinone has the advantage of providing both inotropic and vasodilatory effects; however, its administration can be complicated by significant systemic hypotension necessitating the concomitant use of epinephrine or norepinephrine.

Coagulopathy after weaning from CPB is common. The severity of coagulopathy may be worse after double- than single-lung transplantation, probably due to the more extensive dissection, presence of collaterals and scarring, and the longer duration of CPB. Factors under the anesthesiologist’s control include incomplete reversal of heparin’s effects, which should be assayed by the activated coagulation time. Similarly, preexisting deliberate anticoagulation (e.g., due to warfarin) should be aggressively corrected with fresh frozen plasma. Because platelet dysfunction is common after CPB, empirical administration is justified if coagulopathy persists. The thrombotic and fibrinolytic systems are activated during lung transplantation, especially if CPB is used, and aprotinin can reduce this activation and perhaps reduce perioperative hemorrhage. The efficacy of ε-aminocaproic acid, tranexamic acid, and desmopressin (DDAVP) in this setting remains unknown.

Reperfusion without CPB is often accompanied by a mild to moderate decrease in systemic blood pressure and occasionally is complicated by severe hypotension. This is usually the result of profound systemic vasodilation. The etiology is unknown but may be due to ionic loads such as potassium or additives such as prostaglandin E₁ in preservation solutions or vasoactive substances generated during ischemia and reperfusion. This hypotension generally responds well to large doses of α-adrenergic agents and fortunately is short-lived. Agents of greatest use in this setting are norepinephrine and vasopressin. Ventilation is resumed with a lung protection strategy identical to that used when weaning from CPB.

Patients with preexisting increased lung compliance as found in chronic obstructive pulmonary disease can manifest great disparity in lung compliance after single-lung transplant. The donor lung usually exhibits normal to decreased compliance, depending on the presence of reperfusion injury. This will result in relative hyperinflation of the native lung and underinflation with loss of functional residual capacity in the donor lung. Hyperinflation of the native lung may cause hemodynamic instability due to mediastinal shift, especially if PEEP is applied. Therefore, patients exhibiting signs of hyperinflation during OLV, which improves with deliberate hypoventilation, should be treated with independent lung ventilation after reperfusion. To accomplish this, the patient’s postoperative ventilator is brought to the operating room while the donor lung is being implanted. When all anastomoses are completed, the donor lung is ventilated with a normal tidal volume (8 to 10 mL/kg) and rate, with PEEP initially applied at 10 cm H₂O. These settings can be adjusted according to blood gases analysis. The vast majority of gas exchange will take place in the donor lung. The native lung is ventilated with a low tidal volume (2 to 3 mL/kg) and a low rate (2 to 4/min) without PEEP. The objective is to prevent this lung from overinflating or developing a large shunt. Carbon dioxide exchange occurs predominantly in the donor lung.

Although some degree of pulmonary edema is commonly detected by chest radiography postoperatively, it is uncommon to encounter severe pulmonary edema in the operating room immediately after reperfusion of the graft. However, when it does occur, postreperfusion pulmonary edema can be dramatic and life-threatening. Copious pink frothy secretions may require almost constant suctioning to maintain a patent airway and be accompanied by severe gas exchange and compliance abnormalities. Treatment includes high levels of PEEP using selective lung ventilation, diuresis, and volume restriction. Occasionally, patients may require support with ECMO for several days until reperfusion injury resolves; a high percentage of patients so treated ultimately survive.

Adequate analgesia is crucial for these patients to facilitate the earliest possible extubation, ambulation, and participation in spirometric exercises to enhance or preserve pulmonary function. Lumbar or thoracic epidural narcotic analgesia provides excellent analgesia while minimizing sedation. Epidural catheters can be placed prior to the procedure if time permits or after conclusion of the procedure. Placement of epidural catheters in cases where a high expectation exists for the necessity of CPB still remains a controversial topic. If CPB has been used or coagulopathy has developed, placement should be deferred until coagulation tests have normalized.

Postoperative Management and Complications

Routine postoperative management of the lung transplant recipient continues many of the monitoring modes and therapies begun in the operating room. Positive-pressure ventilation is continued for at least several hours; if differential lung ventilation was used intraoperatively, this is continued in the early postoperative period. Because the lung graft is prone to the development of pulmonary edema due to preservation/reperfusion and the loss of lymphatic drainage, fluid administration is minimized and diuresis encouraged when appropriate. When hemorrhage has ceased, the chest radiograph is clear, and the patient meets conventional extubation criteria, the endotracheal tube can be removed. Prophylactic antibacterial, antifungal, and antiviral therapy, as well as the immunosuppressive regimen of choice, is begun after arrival in the ICU.

Surgical technical complications are uncommon immediately after lung transplantation but may be associated with high morbidity. Pulmonary venous obstruction usually presents as acute, persistent pulmonary edema of the transplanted lung. Color-flow and Doppler TEE will show narrowed pulmonary venous orifices with turbulent, high-velocity flow and loss of the normal phasic waveform. PA anastomotic obstruction should be suspected if PA pressures fail to decrease after reperfusion of the lung graft. If the right PA is obstructed, this is usually evident on a TEE examination in the same way as for pulmonary venous obstruction; it is usually much more difficult to adequately inspect the left PA anastomosis with TEE, although some centers have reported a high success rate. The diagnosis can be definitively made by measuring the pressure gradient across the anastomosis either by inserting needles on both sides of the anastomosis to transduce the respective pressures, or by advancing the PA catheter across it. However, care should be taken not to measure this gradient while the contralateral PA is clamped, because the shunting of the entire CO through one lung will exaggerate the gradient present. Angiography and perfusion scanning are also useful for making this diagnosis but are not immediately available in the operating room. Bronchial dehiscence or obstruction is extremely rare in the immediate perioperative period and can be evaluated by fiberoptic bronchoscopy.

Pneumothorax must be a constant concern for the anesthesiologist, especially involving the nonoperative side. Diagnosis of pneumothorax on the nonoperative side during a thoracotomy is extremely difficult. A sudden increase in inflation pressures with deterioration of gas exchange and possibly hypotension are characteristic. However, these same findings are possible with hyperinflation, mucus plugging, or malpositioning of the endobronchial tube. Transient cessation of ventilation and immediate fiberoptic bronchoscopy may rule out the former explanations, and the observation of an upward shift of the mediastinum in the surgical field may be observed in the presence of tension pneumothorax. If this diagnosis is strongly suspected, needle thoracostomy on the field may be lifesaving. Alternatively, the surgeon may be able to directly dissect across the mediastinum and decompress the non-operative thorax, facilitating reinflation.

Tension pneumopericardium and postoperative hemothorax with complete ventilation-perfusion mismatch are other rare complications that have been reported after lung transplantation. Patients with pulmonary hypertension and RV hypertrophy may occasionally develop dynamic RV outflow obstruction when transplantation acutely decreases RV afterload; the diagnosis can be confirmed using TEE. Hyperacute rejection of a kind similar to that seen with heart transplantation has not been noted with lung transplantation.

The most common cause of death in the immediate perioperative period is graft dysfunction from reperfusion injury, which usually presents as hypoxemia, pulmonary infiltrates, poor lung compliance, pulmonary hypertension, and RV failure. If there are no technical reasons to account for pulmonary hypertension and RV failure, then graft dysfunction must be suspected. Unfortunately, few treatments will specifically ameliorate graft dysfunction, and therapy is largely supportive. Vasodilator therapy to directly decrease PVR and therefore RV afterload may improve hemodynamics and in some cases may improve gas exchange. Both prostaglandin E₁ and nitrates can reverse severe hypoxemia and pulmonary hypertension after lung transplantation, and the latter attenuate the increase in transcription of vasoconstrictor genes (such as for endothelin and platelet-derived growth factor) induced by hypoxia. Improvement in pulmonary hemodynamics and gas exchange in patients with graft dysfunction has also been reported with the administration of nitric oxide. Compared with historical control patients who developed graft dysfunction before the advent of nitric oxide, inhalation of nitric oxide decreased the duration of mechanical ventilation, frequency of airway complications, and mortality. Improved hemodynamics and gas exchange may reflect the ability of nitric oxide to compensate for the decrease in endothelium-derived relaxant factor activity after transplantation. If nitric oxide has been used to control pulmonary hypertension postoperatively it should be weaned gradually to avoid any rebound pulmonary vasoconstriction. Finally, extracorporeal membrane oxygenation may be employed to support the patient until there is adequate recovery of pulmonary function.

Rejection episodes are common and may occur as early as several days after transplantation. Rejection often presents as new infiltrates on chest radiograph in the setting of deteriorating gas exchange. Bronchoscopy with transbronchial biopsy helps to rule out other causes of deterioration and document acute changes consistent with rejection. Therapy for acute lung rejection consists of large pulses of corticosteroids such as methylprednisolone or changing the immunosuppressive agents (cyclosporine to tacrolimus or vice versa). Expired nitric oxide has been shown to be an indicator of chronic rejection in post–lung transplant patients. Measurements of expired nitric oxide have been shown to fall with the switch of cyclosporine to tacrolimus, reflecting a decrease in the inflammation in the pulmonary mucosa. Expired nitric oxide may be a useful tool to follow patients for the presence or change in chronic graft rejection.

One of the most serious complications of lung transplantation occurs late. Bronchiolitis obliterans is a syndrome characterized by alloimmune injury leading to obstruction of small airways with fibrous scar. Patients with bronchiolitis obliterans present with cough, progressive dyspnea, obstruction on flow spirometry, and interstitial infiltrates on chest radiograph. Therapy for this syndrome includes augmentation of immunosuppression, cytolytic agents (which have been used with varying degrees of success), or retransplantation in refractory cases.

Living-Related Lung Transplantation

The scarcity of suitable donor lungs has resulted in waiting times on transplant lists in excess of 2 years, during which as many as 30% of candidates succumb to their illness. Living-related lung transplantation programs have developed to address the needs of lung transplant candidates with acute deterioration expected to preclude survival. Successful grafting of a single lobe for children with bronchopulmonary dysplasia or Eisenmenger’s syndrome, or two lobes for children and young adults with cystic fibrosis, has encouraged several centers to consider such procedures. The anesthetic management issues related to such undertakings have been reviewed.²¹ Donor candidates will have undergone a rigorous evaluation to ensure that there are no contraindications to lobe donation and that the donation is not coerced. Donor lobectomy is performed via a standard posterolateral thoracotomy. Of special note to the anesthesiologist during such procedures is the requirement for OLV to optimize surgical exposure, the continuous infusion of prostaglandin E₁ to promote pulmonary vasodilation, and the administration of heparin and steroids just before lobe harvest. Anesthetic management of the recipient is identical to that for a standard lung transplant, except that the use of CPB is mandatory for bilateral lobar transplant.

History and Epidemiology

The diminished frequency of heart-lung transplantation over the past decade reflects that it is being supplanted by lung transplantation. The number of heart-lung transplants worldwide peaked at 241 in 1989, and there has been a continual decline in subsequent years to approximately half that number. Approximately only 173 heart-lung transplant candidates were registered with UNOS as of early March 2005, less than 5% of the number on the lung transplant list. The most common recipient indications remain primary pulmonary hypertension, congenital heart disease (including Eisenmenger’s syndrome), and cystic fibrosis.

One-year survival after heart-lung transplantation is 60%, significantly lower than that for isolated heart or lung transplantation. Mortality in subsequent years is approximately 4% per year, similar to that for heart transplantation. Risk factors for increased mortality after heart-lung transplant are recipient ventilator dependence, male recipient gender, and a donor age older than 40 years. Early deaths are most often due to graft failure or hemorrhage, whereas midterm and late deaths are primarily due to infection and bronchiolitis obliterans, respectively. Repeat heart-lung transplant is a rare procedure and likely to remain so because the 1-year survival after repeat heart-lung transplant is dismal (28%).

Recipient Selection

Candidates undergo an evaluation similar to that for lung transplant candidates. As more patients with pulmonary hypertension and cystic fibrosis are treated with isolated lung transplantation, it is likely that the indications for heart-lung transplantation will be limited to congenital heart disease with irreversible pulmonary hypertension that is not amenable to repair during simultaneous lung transplantation or diseases with both pulmonary hypertension and concomitant severe left ventricular dysfunction.

Donor Selection and Graft Harvest

Potential heart-lung donors must meet not only the criteria for heart donors but also those for lung donation, both described earlier in this chapter. Graft harvesting is carried out in a manner similar to that previously described for heart transplantation. After mobilization of the major vessels and trachea, cardiac arrest is induced with inflow occlusion and infusion of cold cardioplegia into the aortic root. After arrest, the pulmonary artery is flushed with a cold preservative solution often containing prostaglandin E₁. The ascending aorta, superior vena cava, and trachea are transected, and the heart-lung bloc is removed after it is dissected free of the esophagus. The trachea is clamped, and the graft is immersed in cold solution before being bagged for transport.

Surgical Procedures

The operation is generally performed through a median sternotomy, but a clamshell thoracosternotomy is also an acceptable approach. Both pleurae are incised. Any pulmonary adhesions are taken down before anticoagulation for bypass. Cannulae for CPB are placed in a manner similar to that for heart transplantation. After the aorta is cross-clamped, the heart is excised in a manner similar to that for orthotopic heart transplant. Each lung is then individually removed, including its pulmonary veins. The airways are divided at the level of the respective main bronchi for bibronchial anastomoses. For a tracheal anastomosis, the trachea is freed to the level of the carina without stripping its blood supply, and an anastomosis is constructed just above the level of the carina. The atrial anastomosis is performed in a manner similar to that for orthotopic heart transplantation, and finally the aorta is joined to the recipient aorta. After de-airing and reperfusion, the patient is weaned from CPB, hemostasis is achieved, and the wound is closed.

Pathophysiology before Transplantation

The pathophysiology of heart-lung transplant recipients combines the elements discussed earlier in this chapter. Patients usually have end-stage biventricular failure with severe pulmonary hypertension. The cardiac anatomy may be characterized by complex congenital malformations. If obstruction of pulmonary airflow is present, there is a danger of hyperinflation after application of positive-pressure ventilation.

Pathophysiology after Transplantation

Like isolated heart recipients, heart-lung transplant recipients’ physiology is characterized by cardiac denervation; transient cardiac ischemic insult during graft harvest, transport, and implantation; and long-term susceptibility to accelerated allograft vasculopathy and rejection. As is the case for lung recipients, heart-lung recipients have denervated pulmonary vascular and airway smooth muscle responses, transient pulmonary ischemic insult, altered pulmonary lymphatic drainage, and impaired mucociliary clearance.

Anesthetic Management

The anesthetic management of heart-lung transplantation more closely resembles that of heart than lung transplantation, because the use of CPB is mandatory. After placement of invasive and noninvasive monitoring similar to that used for heart transplantation, anesthesia can be induced with any of the techniques previously described for heart and lung transplantation. Similar to lung transplantation, avoidance of myocardial depression as well as protection and control of the airway are paramount. Although a double-lumen endotracheal tube is not mandatory, it aids in exposure of the posterior mediastinum for hemostasis after weaning from CPB. Otherwise, anesthetic management before CPB is similar to that for heart transplantation.

A bolus of glucocorticoid (e.g., methylprednisolone, 500 mg) is given when the aortic cross-clamp is removed. After a period of reperfusion, an inotrope infusion is started, and the heart is inspected for adequate de-airing with TEE. Ventilation is resumed with normal tidal volume and rate and the addition of PEEP (5 to 10 cm) before weaning from CPB. After successful weaning from CPB, the pulmonary artery catheter can be advanced into the pulmonary artery again. Protamine is then administered to reverse heparin-induced anticoagulation. The inspired oxygen concentration can often be decreased to less toxic levels based on blood gas analysis.

Problems encountered after weaning from CPB are similar to those encountered after isolated heart or lung transplantation. Lung reperfusion injury and dysfunction may compromise gas exchange, so administration of crystalloid should be minimized. Occasionally, postreperfusion pulmonary edema may require support with high levels of PEEP and inspired oxygen in the operating room. Ventricular failure usually responds to an increase in β-adrenergic support. Unlike isolated heart or lung transplantation, frank right ventricular failure is uncommon immediately after heart-lung transplantation unless lung preservation was grossly inadequate. Coagulopathy is often present after heart-lung transplant and should be aggressively treated with additional protamine (if indicated), platelets, and fresh frozen plasma. Aprotinin can dramatically decrease hemorrhage after heart-lung transplant and reduce transfusion of red blood cells and platelets, and it is associated with a lower alveolar-arterial gradient for oxygen after transplantation.

Postoperative Management and Complications

The principles of the immediate postoperative care of heart-lung transplant recipients are a combination of those for isolated heart and lung recipients. Invasive and noninvasive monitoring done in the operating room is continued. Inotropic support is continued in a manner similar to that for heart transplantation. Ventilatory support is similar to that after lung transplantation; the lowest acceptable inspired oxygen concentration is used to avoid oxygen toxicity, and the patient is weaned from the ventilator after hemodynamics have been stable for several hours, hemorrhage has ceased, and satisfactory gas exchange is present. Diuresis is encouraged. Finally, the immunosuppressive regimen of choice is begun. Barring any complications, the patient can be discharged from the ICU after several days.

Infection is a more frequent and serious complication in heart-lung recipients than in isolated heart recipients. Bacterial and fungal infections are especially common in the first month after transplantation, with viral and other pathogens (Pneumocystis carinii and Nocardia) occurring in subsequent months.

Similar to isolated heart or lung transplants, rejection episodes are common early after heart-lung transplantation. Rejection may occur independently in either the heart or lung. Therapy is similar to that for rejection of isolated heart or lung grafts.

Heart grafts in heart-lung blocks are prone to accelerated coronary vasculopathy in a manner similar to those of isolated heart grafts. As with lung transplantation, a feared late complication of heart-lung transplantation is bronchiolitis obliterans. Clinical presentation is similar to that seen with lung transplant patients. Approximately one third of heart-lung recipients develop this process. Anecdotal reports indicate that most affected patients also have accelerated coronary vasculopathy.