Heart-lung transplantation in adults

INTRODUCTION — Heart-lung transplantation is the procedure of choice for selected patients with concomitant end-stage heart failure and end-stage lung disease. Combined heart and lung transplantation is limited to patients in whom it offers the only surgical option for their end-stage cardiac and pulmonary disease. The procedure of choice for pulmonary parenchymal and vascular diseases in the absence of left heart dysfunction is single or double lung transplantation. (See 'Indications' below and "Lung transplantation: General guidelines for recipient selection".)

The first heart-lung transplantation was performed in 1981 in a patient with pulmonary arterial hypertension [1]. The indications for the procedure were subsequently expanded to include patients with severe parenchymal lung disease and congenital heart disease complicated by Eisenmenger syndrome. (See "Pulmonary hypertension in adults with congenital heart disease: Disease-specific management", section on 'Transplantation'.)

Indications, prognosis, and management of isolated heart transplantation and isolated lung transplantation are discussed separately. (See "Heart transplantation in adults: Indications and contraindications" and "Heart transplantation in adults: Prognosis" and "Lung transplantation: An overview".)

RECIPIENT SELECTION

Indications — Patients with concomitant refractory end-stage heart disease and chronic end-stage lung disease should undergo evaluation to determine if they are candidates for heart-lung transplantation. The most common indication for heart-lung transplantation is complex congenital heart disease with Eisenmenger syndrome (systemic-to-pulmonary communication, pulmonary arterial disease causing severe pulmonary hypertension, and cyanosis). Heart-lung transplant is also infrequently indicated in patients with concomitant end-stage pulmonary disease (eg, idiopathic pulmonary arterial hypertension [IPAH] or cystic fibrosis) and either right ventricular failure with objective evidence of right ventricular fibrosis or infarction or refractory left ventricular failure [2]. The 2019 International Heart and Lung Transplantation (ISHLT) Registry report summarized the distribution of diagnoses leading to more than 3000 adult heart-lung transplants from January 1988 to June 2018 [3]. The three overall leading indications were nonidiopathic pulmonary arterial hypertension due to congenital heart disease, cardiomyopathy, or other conditions (37.7 percent), IPAH (28.4 percent), and cystic fibrosis (14.9 percent).

Where possible, isolated lung or heart transplantation is preferred to heart-lung transplantation because of several major disadvantages with the combined procedure. The need to procure a heart–lung block can lead to increased waiting time and increased mortality among patients awaiting combined heart-lung transplantation compared with those waiting for isolated heart or lung transplants. Other disadvantages include exposure of the recipient to risks of both graft coronary artery vasculopathy and chronic lung allograft dysfunction. In addition, heart-lung recipients may be disadvantaged by the obligate requirement for cardiopulmonary bypass during surgery and the physiological effects of a denervated heart. (See "Heart transplantation in adults: Indications and contraindications".)

The availability of new medical therapies for patients with pulmonary arterial hypertension and congenital heart disease with Eisenmenger syndrome has also reduced the need for heart-lung transplantation (see "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy" and "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis"). The magnitude of this effect was shown in the 2015 ISHLT Registry report, which noted a 40 percent decrease in the number of centers that reported performing heart-lung transplants since 1994 [4]. From 2010 to 2016, 62 percent of centers that performed at least one heart-lung transplant performed one to two such transplants, and only six centers performed four or more such transplants. The total number of adult procedures reported has declined from a peak of over 200 per year in the late 1980s and early 1990s to fewer than 60 per year for the last several years, compared with an increasing number of single and double lung transplants (4552 in 2017) [3].

Heart diseases — Combined heart-lung transplantation is the preferred procedure for patients with complex congenital heart disease with Eisenmenger syndrome (including those with single ventricle anatomy), unsuccessfully repaired or uncorrectable lesions, and/or severely depressed left ventricular function.

For patients with acquired heart disease, a pulmonary artery systolic pressure >50 mmHg and either elevated pulmonary vascular resistance (PVR; defined as >3 Wood units), or a transpulmonary pressure gradient >15 mmHg on right heart catheterization is a relative contraindication to isolated cardiac transplantation due to the risk of right heart failure and early death in such patients [5]. These patients should be tested with vasodilator challenge and/or treated medically with mechanical adjuncts as needed (eg, intra-aortic balloon pump and/or left ventricular assist device [LVAD]) to achieve acceptable hemodynamics (with testing three to six months after LVAD initiation) [2]. Patients whose PVR can be reduced to <4 Wood units (320 dynes-sec/cm⁵) without a fall in systolic blood pressure <85 mmHg are usually considered acceptable candidates for isolated heart transplantation. If PVR fails to improve despite these measures, pulmonary hypertension is deemed irreversible [5]. Pulmonary hypertension with irreversible PVR ≥4 Wood units is commonly considered a contraindication to isolated heart transplantation and in this setting, heart-lung transplantation may be considered as an alternative. However, some centers have successfully performed heart transplantation in patients with irreversible PVR ≥4 Woods units on a case-by-case basis. (See "Heart transplantation in adults: Indications and contraindications", section on 'Elevated pulmonary vascular resistance' and "Treatment of advanced heart failure with a durable mechanical circulatory support device", section on 'Bridge to transplantation' and "Pulmonary hypertension in adults with congenital heart disease: Disease-specific management", section on 'Transplantation'.)

For patients with end stage lung disease and repairable cardiac diseases (eg, coronary artery disease, valvular disease) without intrinsic myocardial dysfunction, corrective cardiac surgery with concomitant lung transplantation is preferable to heart-lung transplantation. Thus, bilateral lung transplantation with repair of the congenital defect is the recommended procedure in patients with simple congenital heart disease. These lesions include [6]:

●Atrial or ventricular septal defect.

●Scimitar syndrome, which refers to the triad of partial anomalous pulmonary venous return, hypoplasia or aplasia of a lobe of the right lung (most often), and the presence of thoracic aorta to pulmonary artery collaterals to the small lung.

●Pulmonary venous stenosis.

●A functionally inadequate vascular bed as with multiple peripheral pulmonary arterial stenoses or pulmonary arteriovenous malformations.

Orthotopic heart transplantation alone is a potential option for patients with congenital heart disease and a physiologic single lung (eg, unilateral pulmonary venous stenosis, or due to previous aortopulmonary shunt procedure) [7].

Lung diseases — In most patients with pulmonary arterial hypertension and preserved left ventricular function, there is no advantage to heart-lung transplantation compared with isolated bilateral lung transplantation, even in the presence of significant right ventricular dysfunction [8-10]. Such patients should generally be treated with lung transplantation alone, unless there are unusual issues such as massive cardiac enlargement, which would not allow adequate intrathoracic space for lung implantation, or severe pulmonary artery enlargement, which would preclude adequate vascular anastomosis. However, some centers prefer heart-lung transplantation for patients with severe right ventricular dysfunction [10,11].

Patients with pulmonary hypertension represent a heterogenous group not only in terms of mechanism leading to the development of pulmonary hypertension but also in regard to presence and degree of right and/or left ventricular dysfunction. The choice between heart-lung transplantation and bilateral lung transplantation is based upon the clinical setting. As mentioned above, patients with complex congenital heart disease with Eisenmenger syndrome are best served by heart-lung transplantation while patients with pulmonary hypertension and repairable congenital cardiac defect should be treated with bilateral lung transplantation and surgical correction of the cardiac anomaly.

In contrast, great disparity exists among centers in regard to the lowest acceptable right and left ventricular ejection fraction for bilateral lung transplantation (particularly among patients with idiopathic pulmonary arterial hypertension) and some centers prefer combined heart-lung transplantation if severe dysfunction exists. The cut-off values range from approximately 10 to 25 percent for right ventricular ejection fraction and 32 to 50 percent for left ventricular ejection fraction based on published reports; values below these thresholds may trigger consideration of heart-lung transplantation. A recent United States registry analysis showed similar survival after heart-lung or isolated lung transplantation in patients with idiopathic pulmonary arterial hypertension, except for those hospitalized in the intensive care unit at the time of transplant, where survival was worse with isolated lung transplantation (adjusted hazard ratio 1.83, 95% CI 1.02-3.28) [12]

In addition, other factors such as patient age, the degree of tricuspid valve damage, dependence on inotropic support, and the presence of technical limitations (eg, pulmonary artery aneurysm or enlargement) would influence the decision about the type of transplant surgery in individual patients [9-11]. Longer wait time for a suitable donor and potentially increased wait list mortality should always be considered when heart-lung transplantation is selected as the appropriate modality.

Heart-lung transplantation may be required in patients with end-stage parenchymal lung disease who have severely compromised left ventricular function (eg, sarcoidosis), or patients with unrelated concomitant severe lung disease and severe acquired heart disease not amenable to corrective surgery [2].

Contraindications — Absolute and relative contraindications to combined heart-lung transplantation are similar to those for isolated heart or lung transplantation. While earlier joint guidelines from the American Thoracic Society/American Society for Transplant Physicians/European Respiratory Society and prior ISHLT guidelines suggest an age limit for heart-lung transplantation of 55 years, newer ISHLT guidelines do not specify an age limit [2]. (See "Heart transplantation in adults: Indications and contraindications", section on 'Contraindications' and "Lung transplantation: General guidelines for recipient selection", section on 'Contraindications and risk factors for poor outcomes'.)

Timing of referral — Among patients for whom heart-lung transplantation appears to be the optimal transplant procedure, referral to evaluate candidacy for heart-lung transplantation should be made if the patient has New York Heart Association (NYHA) functional class III or IV symptoms despite optimal medical and surgical treatment (table 1) [2,9].

In general, indications for transplant listing include evidence of right ventricular failure such as persistent NYHA functional class IV symptoms on maximal medical therapy with cardiac index of <2 liters/min/m² and right atrial pressure >15 mmHg [2]. Earlier listing is required for patients requiring heart-lung transplantation who have certain conditions such as pulmonary venous stenosis, pulmonary venoocclusive disease, or pulmonary capillary hemangiomatosis that respond poorly to medical therapy. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

PROCESS — The process of organ transplantation includes evaluation, registration and wait-listing for transplantation, ranked matching of donor organ with recipient (with matches based on blood type, size of the organ, and distance between the donor and recipient), communication and acceptance of the match, and arrangements for donor organ transport and transplant surgery. (See "Lung transplantation: An overview", section on 'Referral for transplant evaluation'.)

The process of organ transplantation involves regulatory, medical, geographical, and epidemiologic factors. In the United States, the United Network for Organ Sharing (UNOS), a private, nonprofit organization, operates the Organ Procurement and Transplantation Network under a contract with the United States Department of Health and Human Services. (See "Lung transplantation: An overview", section on 'Organizations'.)

Evaluation — Potential candidates for heart-lung transplantation are referred to regional transplant centers for evaluation. The evaluation includes collection of data to determine the need and appropriateness of placement on the transplant waiting list.

Since 2005, 22 percent of heart-lung recipients in Europe and 34 percent of recipients in North America were 50 years or older at the time of transplant, and 8 percent of North American recipients were over age 60 [3].

Donor evaluation — The donor heart and lung organs must meet the same criteria for donation as for isolated heart and lung transplantation. Lung donor evaluation, selection, and management are discussed separately. (See "Lung transplantation: Deceased donor evaluation" and "Lung transplantation: Donor lung procurement and preservation".)

Organ allocation — Heart-lung transplant recipients receive an "en bloc" heart and lung allograft from the same donor. There is no dedicated allocation system for heart-lung transplant candidates within the United States. Instead, heart-lung candidates follow both the lung and heart allocation systems. (See "Lung transplantation: An overview", section on 'Activity' and "Heart transplantation in adults: Donor selection and organ allocation".)

In the United States' six-tier heart allocation system, adult heart-lung transplant candidates with underlying congenital heart disease are usually classified as status 4, and patients listed for heart-lung transplantation for other indications are usually classified as status 5 (table 2). The exceptions to these classifications are heart-lung transplant candidates who require venous-arterial extracorporeal membrane oxygenation or other advanced mechanical circulatory support that meet criteria for a higher status (table 2).

Within the United States, a heart-lung transplant match is generally determined by the heart allocation match list rather than the lung allocation match list. This is due to a requirement that if a heart-lung transplant candidate receives a lung match based on the lung Composite Allocation Score (CAS) (see "Lung transplantation: An overview", section on 'Lung allocation'), the heart cannot be allocated to that heart-lung transplant candidate until the heart has been first offered to all heart and heart-lung transplant candidates with a heart classification status of 1 through 4 (see "Lung transplantation: An overview", section on 'Activity' and "Heart transplantation in adults: Donor selection and organ allocation"). Conversely, if a heart-lung transplant candidate receives a heart match based on the heart allocation system, the lungs from the same donor are offered to the candidate without any lung CAS requirement.

Transplantation surgery — The heart-lung transplantation procedure involves procurement of the heart-lung bloc from the donor (and transport to the transplant center where implantation will occur), explant of the heart and lungs of the recipient, and implant of the heart-lung bloc into the recipient. Anastomoses are created at the trachea, aorta, superior vena cava and inferior vena cava [13]. Some recipients with congenital heart disease present particular anatomic challenges (eg, systemic venous anomalies or situs inversus) that require careful management.

POSTOPERATIVE MANAGEMENT — The management of heart-lung transplant recipients is similar to that of double and single lung transplant patients. The majority of the postoperative complications, including acute and chronic rejection and infection, are related to the lung allograft, not the cardiac allograft (see 'Complications' below). Therefore, in most programs, the lung transplant team assumes primary responsibility for management with close coordination and consultation with the heart transplant team.

Prevention of rejection — The level of immunosuppression is similar to that employed in lung transplant recipients, which is more profound than in heart transplant recipients. (See "Induction immunosuppression following lung transplantation".)

Maintenance immunosuppressive therapy in heart-lung transplant recipients follows the recommendations for single and double lung transplantation. (See "Induction immunosuppression following lung transplantation".)

Surveillance studies — Heart-lung transplantation recipients are followed closely with frequent pulmonary function tests, chest radiographs, laboratory testing, and clinic visits. Surveillance bronchoscopy with transbronchial biopsies is performed in many programs to permit the early diagnosis of acute rejection and infection [14-16]. There is no consensus regarding biopsy frequency. Surveillance biopsies are most often performed in the first three months to a year after transplantation when the rates of acute rejection and infection are high, and whenever clinically indicated thereafter [17,18]. Biopsy-proven acute cellular rejection in lung transplant can occur in stable asymptomatic patients who have survived two years, but the frequency after four years appears to be very low [17].

Acute cellular rejection of the heart allograft might occur simultaneously or independently from that of the lung allograft. Isolated acute cellular rejection of the heart, however, is infrequent and much less common than after isolated heart transplantation [19-21]. Most episodes occur early [19,20,22] and asymptomatic episodes detected by surveillance biopsy are rare later than four to six months after transplantation [23]. (See 'Acute cellular rejection' below.)

Based upon these observations, surveillance endomyocardial biopsies to detect asymptomatic heart rejection, which are routinely performed after heart transplantation, are not recommended in most centers after heart-lung transplantation, particularly after four to six months [23]. However, endomyocardial biopsy is indicated at any time in patients who exhibit symptoms consistent with heart failure and/or have left ventricular or biventricular dysfunction on echocardiography. (See "Heart transplantation in adults: Diagnosis of allograft rejection".)

Annual comprehensive evaluation of heart-lung transplant recipients is recommended with pulmonary function testing, chest radiograph, bronchoscopy in some programs, echocardiography, bone density scan, and coronary angiography or dobutamine stress echocardiography to rule out cardiac allograft vasculopathy. Other than yearly coronary angiography or dobutamine stress echocardiography, general health maintenance and surveillance requirements are similar to that of patients with lung transplantation. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".)

COMPLICATIONS

Bleeding — Bleeding in the immediate postoperative period in patients with complex congenital heart disease may arise from chest wall and aortopulmonary collaterals as well as adhesions from previous thoracic surgeries. Another contributing factor may be impaired hepatic function, which is a frequent finding in heart-lung transplant recipients due to longstanding hepatic congestion secondary to poor right ventricular function.

Early graft failure and primary graft dysfunction — Patients undergoing heart-lung transplantation are at risk for primary cardiac graft failure and primary lung allograft dysfunction. Definition, classification, and management of primary graft dysfunction are discussed elsewhere. (See "Primary lung graft dysfunction".)

Early graft failure (EGF) is defined as an intrinsic graft failure resulting in death or retransplantation in the first 30 days following transplantation. EGF occurred in 6.8 percent of the heart-lung recipients as compared with 2.3 percent of primary lung transplant recipients from 2005 to 2013 [4].

Primary cardiac graft failure causes the majority of mortality within the first 30 days after transplantation and may manifest in the operating room or in the first 24 hours after transplantation. It is thought to be caused by heterogeneous etiologies including donor-related factors, preservation injury, transplant-related factors, and recipient-related factors such as unrecognized pulmonary arterial hypertension. (See "Heart transplantation in adults: Prognosis", section on 'Causes of death'.)

Primary lung allograft dysfunction develops in the first 72 hours after transplantation and results from donor lung injury caused by the transplant process, including donor and recipient factors. (See "Primary lung graft dysfunction".)

Acute cellular rejection — Early data suggested less acute cellular rejection in both organs following combined heart-lung transplantation compared with the rate of rejection in lungs or hearts that are transplanted alone [19]. In heart-lung transplant recipients, the rate of lung rejection is higher than the rate of heart rejection [14,19,20,22]. Possible explanations for this finding include the presence of donor bronchus-associated lymphoid tissue, increased immunogenicity of the lungs, and frequent infectious insults with suppressed defense mechanisms. In heart-lung transplant recipients at least four months posttransplantation, asymptomatic acute cellular rejection of the heart allograft appears to be a rare event [23].

These relationships were illustrated in a review of 348 heart transplant recipients, 82 double-lung transplant recipients, and 24 heart-lung transplant recipients who were transplanted between 1990 and 2002 [19].

The following findings were noted:

●With respect to the heart, the probability of acute cellular rejection (defined by endomyocardial biopsy [grade ≥3A] or a clinical episode requiring increased immunosuppression) was significantly lower in heart-lung compared with heart transplant recipients in the first three months (22 versus 81 percent) and, at two years, there were significantly fewer acute rejection episodes in heart-lung transplant recipients (0.3 versus 2.8 episodes).

●With respect to the lung, there were significantly fewer acute cellular rejection episodes in heart-lung transplant compared with lung transplant recipients at two years (1.0 versus 2.4 episodes). Although this observation suggests that combined heart-lung transplantation may have a protective immunologic effect in terms of the development of acute rejection [19,24], this conclusion has been disputed in other studies [25,26].

However, an ISHLT registry report found no difference in the percentage of lung recipients experiencing at least one episode of treated lung rejection in the first year after lung-alone (32 percent) versus heart-lung transplant (34 percent) [27]. Conversely, recipients of lung or heart-lung combined with other organ transplants (eg, liver or kidney) experienced a lower rate of treated rejection in the first year (16.5 percent).

The clinical manifestations, diagnosis, and management of acute lung rejection are discussed separately. (See "Evaluation and treatment of acute cellular lung transplant rejection".)

Acute antibody-mediated rejection — In addition to T cell-mediated cellular rejection, alloantibody reactivity to donor antigens can result in tissue injury and rejection mostly via complement fixation. Acute antibody-mediated rejection (AMR) is now a recognized entity in renal and cardiac transplantation, and a new classification system was developed for lung transplantation [28]. (See "Heart transplantation in adults: Diagnosis of allograft rejection", section on 'Acute antibody-mediated (humoral) rejection'.)

Among heart-lung transplants, AMR can occur early or late in the posttransplant period and it may accompany acute cellular rejection or present independently. AMR can affect both transplanted organs, resulting in graft dysfunction.

The diagnosis of cardiac AMR is usually based upon allograft dysfunction, the presence of circulating donor-specific antibodies (HLA and non-HLA antibodies), and histopathologic evidence of graft injury by capillary endothelial changes, recruitment of macrophages, neutrophils, and complement activation demonstrated by positive C4d, C3d, or C1q immunofluorescence or immunohistochemistry [29]. (See "Heart transplantation in adults: Diagnosis of allograft rejection", section on 'Acute antibody-mediated (humoral) rejection'.)

Similar serologic and histologic changes of AMR can also occur in lung allografts [28,30-32]. Studies examining the specificity of C4d staining in lung biopsies and its association with circulating donor-specific alloantibodies have led to conflicting results [32-35]. Evidence of allograft dysfunction is a prerequisite for lung "clinical AMR" and is broadly defined as alterations in pulmonary physiology, gas exchange, radiologic features, or functional performance. The level of certainty in AMR diagnosis depends on the number of diagnostic criteria present; these criteria are detection of circulating donor-specific anti-HLA antibodies (DSA), histopathologic changes consistent with AMR, and C4d staining of interstitial alveolar capillaries in a linear pattern. Definite AMR requires all three of these factors, while probable AMR requires two of three factors.

Optimal therapy of AMR is not well defined. Treatment may include high-dose glucocorticoid therapy, plasmapheresis, high-dose intravenous immune globulin, rituximab, and bortezomib. (See "Heart transplantation in adults: Treatment of rejection", section on 'Antibody-mediated rejection' and "Evaluation and treatment of antibody-mediated lung transplant rejection".)

Infection — Most infectious complications following heart-lung transplantation occur at rates similar to those seen in lung transplantation alone and primarily affect the lungs. Approaches to treatment of infectious complications and prophylactic measures to prevent them in heart-lung transplant recipients are the same as those employed following lung transplantation. (See "Prevention of cytomegalovirus infection in lung transplant recipients" and "Bacterial infections following lung transplantation" and "Fungal infections following lung transplantation" and "Tuberculosis in solid organ transplant candidates and recipients" and "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients".)

Chronic rejection — Chronic rejection can affect both the heart and lungs. Chronic rejection of the heart is manifested as coronary allograft vasculopathy and is usually diagnosed by surveillance angiographic monitoring before the patient is symptomatic. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".)

Chronic rejection of the lungs is manifested as chronic lung allograft dysfunction (CLAD), which can have an obstructive or a restrictive phenotype [36]. CLAD is most frequently manifested histologically as bronchiolitis obliterans, which is diagnosed via spirometry and known as bronchiolitis obliterans syndrome (BOS) [36]. Characteristic clinical features of BOS include progressive dyspnea, cough, frequently a relatively normal chest radiograph, accentuated airtrapping on expiratory computed tomography images with or without bronchiectasis, and worsening airflow obstruction without other obvious cause. CLAD can also present as restrictive allograft syndrome (also termed "restrictive CLAD"), which is characterized by restrictive changes in pulmonary function, and radiographic and pathologic evidence of fibrosis [37]. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome" and "Chronic lung allograft dysfunction: Restrictive allograft syndrome".)

As with acute rejection, chronic rejection of the heart is less common after heart-lung transplantation compared with heart transplantation alone. Whether chronic rejection of the lungs occurs as often in heart-lung recipients as it does in single or double lung recipients is less clear [4,19,26,27].

These relationships were illustrated in the 2018 International Society for Heart and Lung Transplantation registry report in which the following findings were noted in adult heart-lung transplant recipients transplanted between January 1994 and June 2016 [27]:

●The rate of BOS at five years was higher than that of cardiac allograft vasculopathy (31 versus 7 percent) [27].

●The rate of cardiac allograft vasculopathy at five years was lower with heart-lung compared with heart transplant recipients.

●The crude rate of BOS at five years in heart-lung transplant recipients was lower than that of in lung transplant recipients. This should be interpreted with caution, since the analysis was not adjusted for important confounders such as single versus double lung transplantation. CLAD rates were similar between bilateral lung alone and heart-lung transplant recipients for pulmonary hypertension in a recent single-center analysis [38]

Other — Heart-lung transplantation shares most of the complications of single or double lung transplantation. (See "Noninfectious complications following lung transplantation" and "Infection in the solid organ transplant recipient" and "Malignancy after solid organ transplantation".)

In addition, there are a few complications that appear to be more common following heart-lung transplantation, including phrenic nerve dysfunction, gastroparesis/gastroesophageal reflux disease (GERD), and chylothorax. (See "Noninfectious complications following lung transplantation".)

Phrenic nerve dysfunction — Phrenic nerve dysfunction (PND) is thought to result from hypothermia from cold ice slush, pericardial retraction, and electrocautery for dissection during the heart-lung operation. There is a higher prevalence of PND among heart-lung transplant recipients compared with those undergoing lung transplantation alone [39,40]. In one series, for example, the respective rates were 43 and 9 percent.

PND may be associated with more days of mechanical ventilation, prolonged intensive care unit stays, and an increased likelihood of tracheostomy [40]. Only a minority of patients recover diaphragmatic function following injury to the phrenic nerve. In the setting of unilateral diaphragmatic paralysis with evidence of paradoxical movement of the diaphragm during respiration, surgical plication of the diaphragm can be considered. (See "Treatment of bilateral diaphragmatic paralysis in adults".)

Gastroparesis — Surgical manipulation of the posterior mediastinum can injure the vagus nerve and lead to gastroparesis [41,42]. Heart-lung transplant recipients are at higher risk for this complication due to the surgical techniques employed for the tracheal anastomosis. Consequences of gastroparesis include an increased risk of aspiration, GERD, malnutrition, and poor absorption of medications. Recurrent aspiration can result in lung injury leading to graft dysfunction, especially in the early posttransplant period, and both GERD and gastroparesis have been associated with the development of chronic lung rejection [41-43].

The diagnosis and treatment of gastroparesis are discussed separately. Options in heart-lung transplant recipients who do not respond to conventional therapy include gastric pacing and, in an initial report, transcutaneous electrical nerve stimulation [44,45]. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis" and "Treatment of gastroparesis".)

Chylothorax — Chylothorax is caused by the accumulation of chyle in the pleural space after surgical trauma to the thoracic duct or its collaterals. Patients with congenital heart disease frequently have abnormally developed lymphatics that can be susceptible to inadvertent interruption during heart-lung transplantation [46]. Depending upon the level of injury, chylous effusions can be right-sided, left-sided, or bilateral.

The diagnosis and management of chylothorax are discussed separately. (See "Etiology, clinical presentation, and diagnosis of chylothorax".)

PROGNOSIS — Given the relatively low rate of acute and chronic cardiac transplant rejection cited above [4,19], short- and long-term morbidity and mortality relate primarily to lung allograft pathology as they do in lung transplant recipients. (See 'Acute cellular rejection' above and 'Chronic rejection' above.)

Survival — The following findings with respect to patient survival were noted in the 2019 International Society for Heart and Lung Transplantation (ISHLT) registry report of adult patients who underwent primary heart-lung transplantation between January 1992 and June 2017 [3]:

●There is a high rate of early mortality, with overall survival rates of 74 percent at three months and 66 percent at one year for heart-lung transplants from 1992 to June 2017. Overall, survival was 49 percent at five years and 36 percent at 10 years [3]. Early survival rates for heart-lung transplantation remain lower than those seen with adult lung or heart transplantation alone. Five-year survival rates of heart-lung transplant recipients in the latest period are comparable to adult bilateral lung transplantation alone (52 versus 58 percent). In comparison, five-year survival rates are significantly higher following isolated heart transplantation (74 percent in the period of 2009 to 2016) [47].

●The overall median survival improved from 3.7 years for transplants from 1992 to 2001 to 6.5 years in the modern era (2010 to 2017) and it is comparable to primary lung transplantation (6.7 years for transplants from 2010 to 2017) [3]. Overall median survival is significantly better in adult heart transplantation alone (12.5 years for the period of 2002 to 2009) [48].

●Among patients who survived one year, there was a low but steady mortality rate with a conditional median survival (contingent on survival to one year) of 12.8 years in patients transplanted from 2002 to 2009, which compares favorably with the registry-reported 8.8 years for lung transplants [3]. In comparison, the overall conditional median survival in adult heart transplantation alone was 14.8 years [48].

The main causes of death varied with the time after transplantation:

●In the first 30 days, the time of highest risk, graft failure (21.8 percent), technical complications (26.4 percent), and noncytomegalovirus (CMV) infections (15.6 percent) were the leading causes of death.

●From 31 days to one year, non-CMV infections and graft failure together accounted for 33.6 percent and graft failure accounted for 17.6 percent of deaths. Although acute rejection and CMV infection are common, they were together responsible for only 2.3 percent of deaths.

●After the first year, bronchiolitis obliterans syndrome accounted for 20 to 23 percent of deaths and late graft failure for 14 to 21 percent of deaths; non-CMV infection caused 21 to 26 percent of deaths.

●Across time periods, cardiovascular disease accounted for 5.6 to 11.2 percent of deaths.

Large case series have shown better overall actuarial survival for heart-lung transplantation than the ISHLT registry [25,26,49,50]. In two reports, for example, one-year survival was 87 and 78 percent compared with 64 percent in the registry [26,49]. In addition, survival following heart-lung transplantation in all the case series was comparable to that following double or single lung transplantation in contrast to the better outcomes cited above with lung transplantation in the ISHLT registry. A multivariate analysis of the US Scientific Registry of Transplant Recipients (SRTR) database including recipients of heart-lung or bilateral lung transplants for IPAH showed no differences in survival between the two groups, except for patients who were critically ill at the time of transplant [12]

Morbidity — In a study of patients who received a heart-lung transplant and who were followed for at least one year after transplantation, common complications included new onset of severe renal dysfunction (7.1 percent), diabetes (17 percent), and malignancy (5.3 percent) [4].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lung transplantation".)

SUMMARY AND RECOMMENDATIONS

●Patients with concomitant refractory end-stage heart disease and chronic end-stage lung disease should undergo evaluation to determine if they are candidates for heart-lung transplantation. The most common indication for heart-lung transplantation is congenital heart disease with Eisenmenger syndrome. Heart-lung transplant is also indicated in patients with concomitant end-stage pulmonary disease (eg, idiopathic pulmonary arterial hypertension or cystic fibrosis) and either right ventricular failure with objective evidence of right ventricular fibrosis or infarction or refractory left ventricular failure [2]. (See 'Indications' above.)

●For patients with heart disease, pulmonary hypertension with irreversible pulmonary vascular resistance (PVR) ≥4 Wood units is commonly considered a contraindication to isolated heart transplantation and in this setting, heart-lung transplantation may be considered as an alternative. However, some centers have successfully performed heart transplantation in patients with irreversible PVR ≥4 Woods units on a case-by-case basis. (See 'Heart diseases' above.)

●For patients with repairable cardiac defects (eg, coronary artery disease, valvular disease, or septal defects) without intrinsic myocardial dysfunction, corrective cardiac surgery with concomitant lung transplantation is preferable to heart-lung transplantation. (See 'Heart diseases' above.)

●Most patients with pulmonary arterial hypertension and preserved left ventricular function should be treated with bilateral lung transplantation rather than heart-lung transplantation. Exceptions include patients with anatomic challenges such as massive cardiac enlargement or severe pulmonary artery enlargement. (See 'Lung diseases' above.)

●Postoperative management of heart-lung transplant recipients is similar to that for patients who have undergone single or double lung transplantation, including monitoring of lung function using pulmonary function tests, chest radiographs, and bronchoscopy with transbronchial lung biopsies. (See 'Surveillance studies' above.)

●In heart-lung transplant recipients, acute rejection occurs infrequently in the cardiac allograft; as a result, surveillance endomyocardial biopsy is not routinely recommended (particularly after four to six months). (See 'Surveillance studies' above and 'Complications' above.)

●Chronic rejection of the heart allograft (cardiac allograft vasculopathy) is diagnosed in only about 10 percent of heart-lung transplant recipients; this is generally diagnosed by annual surveillance coronary angiography. (See 'Chronic rejection' above.)

●Chronic rejection in the lungs, manifested as chronic lung allograft dysfunction (bronchiolitis obliterans syndrome or restrictive allograft syndrome subtypes) occurs in almost one-half of heart-lung transplant recipients by five years and represents the most important obstacle to improved long-term survival. (See 'Chronic rejection' above.)

●Heart-lung recipients have reduced early survival but similar long-term survival to bilateral lung transplant recipients. Survival after heart-lung transplantation is inferior to survival after heart transplantation. (See 'Survival' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dale Lien, MD, and Roland G Nador, MD, who contributed to earlier versions of this topic review.