INDICATIONS FOR HEART–LUNG TRANSPLANTATION

Over time, with the increased technical success of isolated single- or double-lung transplantation, the indications for combined heart–lung transplantation have narrowed. The primary reason for heart–lung transplantation is irreversible dysfunction of both organ systems. The primary underlying defect could be cardiac in origin, such as congenital heart disease with irreversible end-stage cardiomyopathy and secondary pulmonary hypertension—Eisenmenger’s syndrome. Additionally, the primary defect could be pulmonary dysfunction, leading over time to irreversible heart disease. Generally, the cardiac dysfunction is severe right-sided heart failure secondary to chronically elevated pulmonary arterial pressure—cor pulmonale.

Another group of patients who have combined heart and lung disease have two separate disease processes that may not be related—for example, the patient with a heavy smoking history who has severe emphysema and end-stage ischemic cardiomyopathy. Rarely, these patients are considered for heart–lung transplantation. However, the experience with patients who have separate disease processes, in the lungs and the heart, suggests that combined heart–lung transplantation is not a good treatment option and is associated with poor perioperative results and diminished late survival rates.

Recipient Diagnosis

The diagnostic profile of heart–lung transplant recipients reported to the Registry of the International Society for Heart and Lung Transplantation (ISHLT) through 2007 is depicted in Figure 100-2.⁵ Pulmonary hypertension secondary to congenital heart disease is the most frequent diagnosis, found in 33.9% of individuals who require heart–lung transplantation.⁵ Cardiac lesions that can result in secondary pulmonary hypertension include atrial and ventricular septal defects, patent ductus arteriosus, truncus arteriosus, and other complex congenital anomalies, including univentricular heart with pulmonary atresia and hypoplastic left heart syndrome. Pulmonary hypertension secondary to congenital heart disease varies prognostically when compared with primary pulmonary hypertension (PPH). Despite comparable levels of pulmonary arterial pressures, individuals with Eisenmenger’s syndrome have lower right atrial pressures, better cardiac index, and an overall better prognosis than patients with pulmonary hypertension without congenital heart disease.⁶ Therefore, hemodynamic variables are less reliable in this group than the presence of progressive symptoms as an indicator for transplantation (see later). Patients with significant hemodynamic derangements may be effectively managed with medical therapy, thus delaying transplantation.

Figure 100–2 Indications for heart–lung transplantation from 1990 to 2005. AT def, antitrypsin deficiency; COPD, chronic obstructive pulmonary disease.

(Modified from Trulock EP, Christie JD, Edwards LB, et al. The Registry of the International Society of Heart and Lung Transplantation: twenty-fourth official adult lung and heart-lung transplant report—2007. J Heart Lung Transplant 2007;26:782-95.)

Secondary pulmonary hypertension with complex, irreparable cardiac defects must be treated with heart–lung transplantation. In a recent study, patients with Eisenmenger’s syndrome caused by a ventricular septal defect (VSD) or multiple congenital anomalies had a highly significant survival advantage when a heart–lung transplantation was performed as opposed to cardiac repair combined with lung transplantation.⁷ However, patients with simple cardiac defects, such as atrial septal defects, should be considered for repair of the cardiac defect combined with single or bilateral lung transplantation. Lung transplantation with intracardiac repair has evolved as a viable alternative to heart–lung transplantation for several reasons. First, right ventricular function improves after lung transplantation as a result of normalization of pulmonary vascular resistance.⁸ Also, there is an organ donor shortage, and furthermore the denervation and graft coronary artery disease associated with cardiac transplantation is avoided.

PPH associated with irreversible right ventricular failure is the second most common indication for heart–lung transplantation, with 24% of recipients carrying this diagnosis.⁵ In contrast to secondary pulmonary hypertension from congenital heart disease, abnormal hemodynamic parameters are closely related to increased mortality.⁹ Therefore, patients with PPH should be promptly referred to a transplant pulmonologist for initiation of intravenous pulmonary vasodilators. If severe right ventricular failure persists despite aggressive medical therapy, heart–lung transplantation may be indicated.

The role of heart–lung transplantation in the setting of PPH has also evolved over the past several years. Individuals with pulmonary vascular disease and improved right ventricular function after initiation of medical therapy may also be treated effectively with either single-lung transplantation (SLT) or double-lung transplantation (DLT). In the setting of PPH, DLT results in both greater hemodynamic improvement and a shorter duration of postoperative mechanical ventilation than SLT.¹⁰ It is the preferred operation in most transplantation centers. Furthermore, comparable survivals were noted after heart–lung transplantation and DLT in patients with PPH.¹¹ This has led to the recent trend in favor of DLT for patients with PPH because it decreases the use of scarce donor hearts. This trend has resulted in a decrease in the number of heart–lung transplants for PPH over the past 10 years. The subsets of patients who have fixed pulmonary vascular resistance not responsive to vasodilators and who have irreversible right-sided heart dysfunction are still candidates for heart–lung transplantation.

The remainder of heart–lung transplantations are performed for a variety of disorders that result in end-stage pulmonary failure and irreversible cardiac failure. These include individuals with septic lung disease, such as cystic fibrosis and bronchiectasis, ischemic and restrictive cardiomyopathies with intercurrent end-stage lung disease, or acquired pulmonary vascular disease. Primary parenchymal lung disease, such as idiopathic pulmonary fibrosis, desquamative interstitial pneumonitis, and lymphangioleiomyomatosis, may occur with severe right-sided heart failure and also may be a reason for heart–lung transplantation.

The introduction of the “domino” transplantation procedure renewed interest in heart–lung transplantation for septic lung disease. In this procedure, the recipient of a heart–lung transplant served as a heart donor for a second recipient, thus maintaining donor organ allocation.^12,13 Recent studies have demonstrated equivalent survival rates in recipients of domino heart grafts and in recipients of cadaveric heart grafts. However, this procedure is rarely performed, and bilateral lung transplantation remains the procedure of choice for most septic or parenchymal lung disease.

The distribution of preoperative diagnoses managed with heart–lung transplantation at Stanford from 1981 to the present has been as follows: Eisenmenger’s syndrome, 44%; PPH, 23%; cystic fibrosis, 12%; complex congenital heart disease, 12%; α₁-antitrypsin deficiency, 2%; cardiomyopathy with pulmonary hypertension, 2%; failure of SLT, 1%; congenital bronchiectasis, <1%; pulmonary lymphangioleiomyomatosis, <1%; and other diagnoses, 3%.¹⁴

TREATMENT OF PATIENTS AWAITING TRANSPLANTATION

The average waiting period for a heart–lung block is greater than 18 months, so treatment of recipients after listing is a critical aspect of the preoperative plan. Routine medical care, including clinical surveillance, optimization of cardiopulmonary function, and management of disease-specific and age-specific issues, should be addressed during this time. General considerations in the pretransplantation period include appropriate surveillance protocols and screening for malignancies such as prostate, breast, and colon cancer. Other issues that should be addressed include appropriate prophylaxis for thromboembolism with warfarin,³⁴ and aggressive maximization of bone density, because osteoporosis is increasingly recognized as a clinical problem for patients on chronic steroids.³⁵ Nutrition and high-intensity pulmonary rehabilitation should be optimized. Finally, psychosocial issues need to be addressed, with referral for supportive counseling, support groups, and other training means to help each patient cope with the upcoming challenges.

Disease-specific issues in patients awaiting heart–lung transplantation need to be addressed. These patients require optimal treatment of heart failure with standard therapeutic measures such as sodium restriction, aggressive diuresis, and vasodilators. Afterload reduction with nitrates, hydralazine, and angiotensin-converting enzyme inhibitors prolong survival while awaiting transplantation.³⁶ In patients with PPH, supplemental oxygen is recommended to avoid hypoxic pulmonary vasoconstriction. Indications for outpatient oxygen therapy include an arterial partial pressure of oxygen (PaO₂) of 55 mm Hg or less (or arterial oxygen saturation [SaO₂] less than 88% on room air) at rest, during exertion, or while asleep.³⁷ The prognosis of patients with PPH is determined by hemodynamic variables, and the following parameters are associated with a poor outcome: increased mean pulmonary artery pressure (mPAP > 85 mm Hg; median survival, 12 months), increased mean right atrial pressure (RAP > 20 mm Hg; median survival, 1 month), and decreased cardiac index (CI < 2.0 L/min/m²; median survival, 17 months).⁹ In addition to supplemental oxygen therapy, initiation of pulmonary vasodilator therapy improves the hemodynamics and survival while awaiting transplantation. Epoprostenol is a short-acting prostaglandin, released normally by the endothelium, that vasodilates the pulmonary vascular bed and inhibits platelet aggregation. Continuous infusion of epoprostenol (Flolan) has been demonstrated to significantly improve pulmonary hemodynamics, exercise capacity, and survival in patients with NYHA III and IV heart failure.^38,39 Patients may then wait longer for transplantation. Despite improvements in pulmonary hemodynamics and survival, diseases often progress, or the patients develop tachyphylaxis. Therefore, patients need to be followed closely and returned to the active list if any clinical deterioration is noted. In patients with right ventricular failure awaiting transplantation, creation of an interatrial shunt to decompress the pressure-overloaded ventricle may need to be considered.⁴⁰

Patients with cystic fibrosis awaiting heart–lung transplantation have special needs. Pulmonary hygiene is of critical importance, as more than 80% of patients are chronically colonized with Pseudomonas aeruginosa.⁴¹ Pulmonary clearance techniques, institution of bronchodilators, and initiation of antibiotics in the setting of acute infection are lifelong requirements. Prophylactic antibiotics are not routinely given because of the development of multiresistant organisms.⁴² Sinus disease and lower respiratory tract infections are risks in most patients with cystic fibrosis. Bilateral maxillary sinus antrostomies performed in the pretransplantation period have resulted in fewer infectious complications in the post-transplant period.⁴³ In addition to infectious issues, other associated risk factors such as malnutrition secondary to malabsorption, pancreatic insufficiency, and diabetes mellitus must be properly addressed.

SELECTION AND MANAGEMENT OF DONORS

The satisfactory criteria for heart–lung blocks are similar to those for hearts and lungs separately (Box 100-2). The lungs are the most delicate solid organ, with frequent parenchymal damage and neurogenic edema occurring after brain death, as well as the increased risk for aspiration. These factors result in only 20% to 30% of multiorgan donors having lungs suitable for donation. Preliminary donor evaluation includes a detailed history, review of electrocardiogram and echocardiogram, chest film, and arterial blood gas analysis. A donor age of less than 40 is preferred. However, potential donors aged 40 to 50 years are considered at most transplant centers, provided they have normal cardiopulmonary functioning and a normal coronary arteriogram. Acceptance criteria also include no significant lung contusion or history of aspiration or sepsis. There should be no history of prior cardiac or pulmonary surgery. A donor chest film must be clear with no signs of pathology. An arterial blood gas analysis should reveal an arterial oxygen tension level of greater than 350 mm Hg on a fractional inspired oxygen concentration (FiO₂) of 100%, and 100 mm Hg on an FiO₂ of 30%. Lung compliance is estimated by measuring peak inspiratory pressures, which should not exceed 30 cm H₂O. Tracheobronchial infection must be excluded with chest radiography, Gram stain of sputum, and bronchoscopy.

On arrival at the donor hospital, the retrieval team assesses the chest film, recent arterial blood gas analyses, and hemodynamic parameters to confirm that there has been no deterioration in oxygenation or cardiac function. If possible, the bronchoscopic examination is repeated to ensure that there are no mucopurulent secretions suggestive of infection or aspiration, as in tracheobronchitis. The final assessment includes visual and manual intraoperative assessment of the heart and lungs, confirming normal lung parenchyma with no palpable masses or evidence of contusion.

Because of growing waiting lists and increased mortality before a transplant is received, most centers have expanded their donor acceptance criteria with increased use of so-called marginal donors.⁴⁴ Thoracic trauma with a resultant pneumothorax is not a contraindication, provided there is not a continuous air leak. Furthermore, lungs that are mildly contused also can be used, provided ongoing bleeding is not noted on bronchoscopy and/or there is no major atelectasis. Patients with prolonged intubation and ventilation (>70 hours), once thought to be a contraindication, also should be considered. As noted, older donors also are being considered, provided pulmonary functional parameters are normal and there is no significant coronary artery disease. Infection with hepatitis C virus is an evolving area in cardiopulmonary transplantation. Hepatitis C–negative recipients have an increased risk for acquiring hepatitis, but the effect on patient survival remains unclear.⁴⁵ Absolute contraindications include severe coronary or structural heart disease, prolonged cardiac arrest, active malignancy (sometimes excluding primary brain cancers such as astrocytoma and skin cancers), positive smoking history of greater than five pack-years, and positive human immunodeficiency virus (HIV) status.

Donor management after a declaration of brain death is a critical area, with an opportunity for significantly improving the number and quality of potential donors. Aggressive management strategies implemented by organ procurement organizations make “unacceptable” lungs, defined as a PaO₂-to-FiO₂ ratio of less than 150, acceptable for transplant.⁴⁶ These unacceptable donors were treated with invasive monitoring, methylprednisolone, fluid restriction, inotropic agents, bronchoscopy, and diuresis. The resultant “acceptable” organs were successfully transplanted without compromise of either 30-day or 1-year graft survival.⁴⁶ The major goal in the initial management of these donors is the maintenance of hemodynamic stability and pulmonary function. Patients who have suffered an acute brain injury are usually hypovolemic, and appropriate fluid resuscitation is the initial step. Complicating factors include the development of diabetes insipidus, which should be treated with a vasopressin infusion (0.1 to 0.4 U/hr).⁴⁷ Fluid administration is guided by the central venous pressure (CVP), keeping in mind that a CVP of greater than 8 mm Hg has been demonstrated to be an independent risk factor for the development of lung dysfunction.⁴⁸ Inotropic agents such as dopamine or phenylephrine are instituted to maintain perfusion pressure after intravascular volume has been repleted. The donor is not hyperventilated after brain death is declared, and a pH of 7.40 is the goal, thus avoiding pulmonary vasoconstriction. Positive end-expiratory pressure of 5 is maintained to prevent atelectasis, and higher levels are avoided because of their deleterious effect on cardiac output.

The pathophysiology of brain death and its deleterious effect on the cardiovascular system have been well described.⁴⁹ The resultant endocrine and metabolic derangements are a potential area of intervention in the marginal donor with hemodynamic instability. Hormonal therapy, including triiodothyronine (T₃), cortisol, insulin, and vasopressin, has been demonstrated to have beneficial effects on the hemodynamic profile of marginal donors.⁵⁰ Physiologic resuscitation, guided by a better understanding of the pathophysiology of brain death, ultimately leads to increased number and quality of heart–lung donors.

HEART–LUNG PRESERVATION

The goal of optimal heart–lung preservation is to ameliorate the effect of ischemia-reperfusion (IR) injury on the allograft. In the initial heart–lung transplantations, donor transportation to the transplant center with on-site procurement was considered essential because of a lack of confidence in lung-preservation techniques. As with heart transplantation, better preservation techniques would expand the pool of available donors and would make donation more acceptable to referring hospitals and donors’ families.

Minimization of IR injury ultimately results in optimization of allograft function in the post-transplantation period. Nonspecific graft failure, which most likely represents IR injury, remains a significant cause of perioperative morbidity and possibly mortality.⁵¹ Reperfusion injury may predispose to an increased risk for acute rejection secondary to the upregulation of histocompatibility class II antigens.⁵² Understanding the pathophysiology of IR injury allows the implementation of strategies aimed at preserving function, minimizing injury, and prolonging allograft and patient survival.

The result of inadequate preservation is activation of the inflammatory cascade, resulting in pulmonary endothelial injury and increased capillary permeability. The resulting pulmonary interstitial and alveolar edema leads to diminished airway compliance, poor gas exchange, and increased pulmonary vascular resistance. Numerous recent studies have elucidated the role of the neutrophil and its interaction with the pulmonary endothelium in the pathogenesis of IR injury.^53–55 Reperfusion injury is caused in part by a complex interplay between leukocyte activation and subsequent release of inflammatory mediators and cytokines, with a final common pathway of pulmonary endothelial injury.

Since the early 1980s, various methods were developed to provide adequate preservation. These have varied from simple graft excision and cold storage to sophisticated autoperfusion with donor blood and a working heart–lung preparation. Today, only two methods are actively employed: (1) perfusion with pulmonoplegia solutions and cold storage and (2) perfusion with cold donor blood, with both methods using pulmonary vasodilators. Pulmonary artery flush, the most widely adopted method of allograft preservation,⁵⁶ allows rapid cooling of both lungs, with a significant improvement in allograft function noted after both the infusion note (4 minutes) and total volume (60 mL/kg) were increased.⁵⁷ To counteract the reflex pulmonary vasoconstriction arising from preservation solutions, donors are pretreated with prostaglandins. These selective pulmonary vasodilators, alprostadil in North America and epoprostenol in Europe, improve the distribution of the pulmonary arterial flush and thus improve lung preservation. The role of retrograde flush through the left atrium has been advanced recently, because of the improved distribution of the flush in a porcine model.^58,59

The two types of crystalloid pulmonary artery flush solutions, intracellular and extracellular, are both designed to counteract the cellular swelling that results from graft ischemia and hypothermia. The intracellular solutions, Euro-Collins (EC) and University of Wisconsin, are composed of electrolytes that mimic the intracellular environment. The extracellular solutions include the Wallwork solution, which uses donor blood, and low-potassium dextran (Perfadex). The most commonly used preservation solution is EC crystalloid solution, which has been modified with magnesium sulfate and 50% dextrose. A recent study has demonstrated that lung procurement with low-potassium dextran resulted in a significantly decreased incidence and severity of reperfusion injury with improved allograft function, as well as improved survival, when compared with EC.⁶⁰ The addition of a retrograde flush for isolated lung transplantation has resulted in improved post-transplant lung function.⁶¹ This retrograde flush technique can be safely used in combined heart–lung transplantation by making a small left atrial incision, flushing the preservation solution retrograde via the veins, and collecting the effluent in the proximal pulmonary artery, where a separate small incision is made. In contrast, Celsior solution, when used as a lung-preservation solution, resulted in lethal post-transplant outcomes in a porcine model of lung transplantation.⁶²

Recent investigations in the laboratory and clinic have demonstrated improvements in allograft preservation by modification of the pulmonary arterial flush solutions. The focus has been to intervene at the level of the leukocyte–endothelial interaction in an effort to preserve the function of the pulmonary endothelial cell. The impact of toxic inflammatory mediators elaborated by the leukocyte has been reduced by techniques such as leukocyte filtration,⁶³ introduction of monoclonal antibodies directed against anti-intercellular adhesion molecules and selectins,^53,55,64 and vascular immunotargeting strategies.⁵⁴ Furthermore, treatments aimed at preserving pulmonary endothelial function by restoring endothelium-derived mediators such as nitric oxide and prostacyclin have been demonstrated to improve allograft pulmonary function.^65–68 Instead of focusing on the preservation solutions or additives, others have focused their attention of the development of continuous organ perfusion systems. The TransMedics Organ Care System is an organ perfusion system that preserves organs by using a warm blood perfusion of the organ during storage. The system has been approved for use in Europe for donor heart procurement, and in late-stage clinical trial protocol use in the United States.