Charles B. Huddleston and Andrew C. Fiore Saint Louis University School of Medicine, Saint Louis, MO, USA The first reported attempt at lung transplantation was at the University of Mississippi Medical Center in 1963 by Dr. James Hardy and his team [1]. The recipient was a 58‐year‐old convicted felon with unresectable carcinoma of the lung and the donor had died in the emergency room of a myocardial infarction. Needless to say, neither the recipient nor the donor would be acceptable to any lung transplantation program in the twenty‐first century. Nonetheless, the recipient survived for 18 days and died secondary to renal failure. In the two decades that followed, multiple attempts at lung transplantation resulted in only one long‐term survivor – to 10 months [2]. Most of the deaths beyond two weeks were due to disruption of the bronchial anastomosis [3]. Finally, the team in Toronto led by Joel Cooper in 1983 performed the first successful lung transplant; this success was the result of many years of experimental study on bronchial healing [4]. Although the introduction of cyclosporine was a significant factor in this success, most of the failures predating this were related to complications at the bronchial anastomosis. The first attempt at lung transplantation in a child was actually a heart–lung transplant performed by Denton Cooley in 1968 in a 2‐month‐old infant with pulmonary hypertension and a complete atrioventricular canal. This patient survived for less than 12 hours following the procedure [5]. The first successful heart–lung transplant was performed at Stanford in 1981 by Bruce Reitz, assisted by Norman Shumway, on a patient with end‐stage pulmonary hypertension [6]. Lung transplantation in children was firmly established in the early 1990s, although very few centers offered it. Over the past 20 years pediatric lung transplantation has grown to the point that over 100 transplants are performed per year in more than 40 centers throughout the world [7]. It remains the only option for end‐stage lung disease when medical therapy has failed. In contrast, over the past 15 years approximately 10 pediatric heart–lung transplants at 5–10 centers have been performed annually throughout the world [7]. Lung transplantation is indicated in children with end‐stage pulmonary parenchymal or pulmonary vascular disease where life expectancy is less than two years and no alternative therapies are available. One of the challenges for any pulmonologist is predicting this short life expectancy in a patient with chronic lung disease that might drastically worsen during an acute infection or exacerbation. Subjecting a patient to a lung transplant early could actually lessen their life expectancy. On the other hand, waiting until a patient is in critical condition makes it less likely that they will survive the transplant procedure. The specific indications are clearly age related and differ significantly based upon that factor [7]. Pulmonary hypertension (idiopathic and congenital heart disease related) and interstitial lung disease (surfactant protein B deficiency being the most common) are the most frequent diagnoses in small children. Cystic fibrosis is the most common indication in children between the ages of 6 and 18, accounting for approximately 65% of all transplants in this age group (Figure 44.1) [7]. Cystic fibrosis is by far the most common disease for which lung transplantation is performed in children [8]. It accounts for two‐thirds of all teenagers undergoing lung transplantation. Although the overall long‐term prognosis for this disease has improved, some patients who are afflicted with this life‐threatening disorder deteriorate more rapidly than others, resulting in the need for transplantation during childhood. The timing of listing is important and is based largely on the study by Kerem and associates [9], updated by Mayer‐Hamblett and colleagues [10]. Specific indications for listing are forced expiratory volume in one second (FEV1) less than 30% predicted, rising arterial pCO2, oxygen dependence, and increasing frequency of hospitalizations for pulmonary exacerbations. Figure 44.1 The indications for lung transplantation in children vary significantly based upon the age at presentation. Cystic fibrosis predominates in the teenage category, while pulmonary hypertension and surfactant protein anomalies are more common in young children and infants. BPD, bronchopulmonary dysplasia; CF, cystic fibrosis; ILD, interstitial lung disease; OB, obliterative bronchiolitis; PAH, pulmonary arterial hypertension; Re‐Tx, retransplant; Surf Prot Anom, surfactant protein anomalies. Pulmonary vascular disease is the second most common diagnosis for which children require lung transplantation [11]. This diagnosis may be categorized broadly into idiopathic pulmonary hypertension (IPH) and that related to congenital heart disease (PH/CHD). PH/CHD is itself a relatively broad category, including Eisenmenger syndrome, pulmonary vein stenosis, and others. Patients with IPH and PH/CHD generally decline due to progressive right heart failure, but also die suddenly from ventricular arrhythmias or severe hemoptysis. Although the causes of death and the pulmonary histology are the same, IPH and Eisenmenger syndrome have very different long‐term prognoses. A retrospective analysis by Hopkins [12] of 100 adults with severe pulmonary hypertension due to either Eisenmenger syndrome or IPH revealed marked differences in survival from the time of diagnosis. The patients with IPH had an actuarial survival of 77%, 69%, and 35% at 1, 2, and 3 years, respectively. In contrast, survival was 97%, 89%, and 77% in those patients with Eisenmenger syndrome over the same intervals [12]. This natural history study predates some of the advanced medical therapies now available for pulmonary hypertension, but the difference in prognosis still holds true. Predicting a life‐threatening arrhythmia or episode of hemoptysis is impossible. However, progressive right heart failure is heralded by clinical signs along with a rising central venous pressure and falling cardiac output. These patients should be evaluated with regularly scheduled cardiac catheterizations while undergoing medical treatment. The prognosis for IPH and PH/CHD has improved over the past decade as advanced drug therapy has been developed [13]. These drugs include prostacyclin and its analogues, endothelin‐1 antagonists, and phosphodiesterase inhibitors. Nonetheless, when the patient develops rising central venous pressure and dropping cardiac output while on maximal medical therapy, it is appropriate to place this patient on the prospective recipient list [14]. Patients with PH/CHD include those with Eisenmenger syndrome, an inadequate pulmonary vascular bed (tetralogy of Fallot with pulmonary atresia and multiple aortopulmonary collaterals), repaired congenital heart disease, persistent pulmonary hypertension, and pulmonary vein stenosis. The timing for transplantation in this rather broad group is the same as with IPH. Patients with pulmonary hypertension and repaired congenital heart disease follow a clinical course more like IPH than those with Eisenmenger syndrome [15]. Most patients undergoing lung transplantation for Eisenmenger syndrome have a relatively straightforward lesion (atrial septal defect, ventricular septal defect, patent arterial duct), but some have more complex lesions such as common arterial trunk and complete atrioventricular septal defect. The transplant options for this group are isolated lung transplant with repair of the congenital cardiac lesion or heart–lung transplant. The advantage of heart–lung transplant is that the operation is simple and there is no need for intracardiac repair with the implicit period of myocardial ischemia. The disadvantages are the longer wait for a suitable donor, the possibility of early cardiac graft failure, the potential for isolated cardiac rejection, and the long‐term risks of transplant coronary artery disease. The advantage of isolated lung transplant with repair of the congenital cardiac lesion is that the patient retains their own heart with no chance of cardiac rejection. There is also easier access to donor organs, resulting in a shorter time on the waitlist, and a more economical allocation of a scarce resource – the heart can be used for another recipient. The disadvantages of isolated lung transplant with cardiac repair are that the cardiopulmonary bypass time is increased and an experienced congenital heart surgeon must be available at the time of the transplant. When a ventricular septal defect (VSD) is the underlying cause of Eisenmenger syndrome, and the patient is undergoing lung transplantation with repair of the VSD, it is nearly always necessary to divide the muscle bundles in the right ventricular outflow tract. The right ventricle is hypertrophied and these muscle bundles become especially hypercontractile with relief of the pulmonary hypertension such that a dynamic obstruction occurs following the repair. Each individual center will have to decide how to approach these patients. For the very straightforward lesions, it seems quite reasonable to repair the cardiac lesion and do an isolated lung transplant. Any added complexity to the cardiac operation would have to be considered a major risk factor. Pulmonary vein stenosis is perhaps one of the most treacherous forms of PH/CHD. It presents as either an isolated congenital lesion or in association with another congenital abnormality, usually total anomalous pulmonary venous return (TAPVR). The incidence of pulmonary vein stenosis following repair of TAPVR is reported to be 15–20% [16]. Some of these patients may be palliated with interventions such as balloon dilatation and stent placement [17], but the recurrence rate is very high. Surgical treatment with the so‐called sutureless technique has had reasonably good results for patients with pulmonary vein stenosis following repair of TAPVR [18]. Results with this technique for primary pulmonary vein stenosis have not been as good [19]. Patients who fail to respond or have recurrent disease will deteriorate rapidly and need urgent listing. Pulmonary vasodilators are of no benefit. Pulmonary fibrosis in children is rare and is often a mix of fibrosis and bronchiolitis obliterans. It may be the result of a pulmonary injury such as a viral infection, radiation, chemotherapy, or following bone marrow transplant with graft‐versus‐host disease. Because of the mixed histology and unusual etiologies, the natural history is unpredictable. That being said, the development of pulmonary hypertension is a poor prognostic sign, as is progression of symptoms on medical therapy. The overall survival at five years for a diffuse group of children with interstitial lung disease is 64% following the onset of symptoms [20]. These diseases are genetic abnormalities that affect surfactant protein production, metabolism, and function. The interstitial lung disease resulting from this is a consequence of mutations in genes that control surfactant protein B, surfactant protein C, ABCA3 transporter protein, and thyroid transcription factor. Infants with surfactant protein B deficiency have the worst clinical outcomes, with severe respiratory insufficiency immediately after birth. There is no medical treatment available. The clinical course of patients with surfactant protein C deficiency and abnormalities in ABCA3 transporter proteins is less predictable. The diagnosis of any of these can be made with genetic testing of a peripheral blood sample and should be suspected in an otherwise normal newborn with interstitial lung disease. Transplantation is the only treatment option for those infants with progressive respiratory failure, but is complicated by multiple issues, including small size of the recipients (infants), ventilator dependence (usually very high settings), unclear neurologic status (often sedated and paralyzed at the time of evaluation), and difficulty with posttransplant surveillance [21]. Other pulmonary diseases seen in the newborn for which transplantation has been applied include alveolar capillary dysplasia and bronchopulmonary dysplasia. Alveolar capillary dysplasia is a disease characterized by malalignment of the pulmonary capillaries with the alveolar sacs, resulting in an inability to provide adequate gas exchange. Most of these infants are critically ill from birth and die within a few days due to hypoxia and pulmonary hypertension. Treatment with nitric oxide and extracorporeal membrane oxygenation (ECMO) provides some degree of stability, but does not result in long‐term survival. The diagnosis is made with lung biopsy only [22, 23]. The only effective treatment for these patients is lung transplantation. The problem is maintaining a stable patient while awaiting a donor. Nearly all of these neonates will require ECMO during their course of treatment. A mechanical alternative to ECMO has been used to successfully bridge an infant with this diagnosis to lung transplantation [24]. Bronchopulmonary dysplasia due to prematurity is the most common pulmonary disease in infants. Despite extreme prematurity and horrific lung disease, only a few of these infants will actually develop end‐stage lung disease, although most will have some degree of pulmonary dysfunction [25]. Many of these infants with progressive pulmonary insufficiency also suffer from a significant neurologic injury and may not be suitable candidates for lung transplantation on that basis [26]. Early graft failure is usually due to severe reperfusion injury and retransplantation may be the only viable option in some of these patients. With the lung allocation score currently in place, it is possible to obtain donor offers in these gravely ill patients in a timely fashion. However, the results of retransplantation for early graft failure are generally poor [27]. One should be very selective when considering a patient for retransplantation in this situation. Late graft failure with respiratory failure is usually due to bronchiolitis obliterans. Retransplantation for these patients is only slightly worse than first‐time transplant recipients [28]. Again, careful patient selection is crucial. As mentioned earlier, the number of heart–lung transplants performed throughout the world has dropped considerably since the 1990s. This was the procedure of choice for cystic fibrosis and pulmonary hypertension in some centers. It is clear that isolated lung transplantation is just as effective. Some centers continue to advocate for this procedure for pulmonary hypertension in children, but its primary indication is for congenital heart disease with pulmonary vascular disease wherein the cardiac problem is not reparable. Some patients with pulmonary fibrosis will also have some degree of myocardial fibrosis or dysfunction, which will dictate the need for heart–lung transplantation. The congenital heart disease that would seem most appropriate would be patients with single‐ventricle anomalies and pulmonary hypertension. In reality, the indications for heart–lung transplantation are very few, as reflected in the paucity of such transplants performed in the past 10 years. In the current era heart–lung transplantation is rarely performed. Table 44.1 lists the absolute and relative contraindications to lung transplantation in children. Although there is some variability among centers, most would agree that active malignancy, autoimmune disease, neuromuscular disease, and human immunodeficiency virus (HIV) infection are absolute contraindications. Absolute is in quotation marks for a reason. The length of time in remission for a patient with a history of malignancy is an important consideration when evaluating a patient with end‐stage lung disease due to chemotherapeutic agents or graft‐versus‐host disease [29]. There have been a few patients with positive serology for HIV who have undergone lung transplantation; in this small cohort the outcomes have been satisfactory [30]. The presence of multisystem organ failure can be altered with adequate medical support, including the use of mechanical respiratory assistance, such as ECMO. However, one should be committed to extended support for adequate rehabilitation. Isolated dysfunction of the liver or kidneys is another issue to consider. The liver disease associated with cystic fibrosis may result in significant derangements of synthetic liver function concomitant with respiratory failure. The combination of liver–lung transplantation may be considered and the results with this procedure have generally been good [31]. The acceptable degree of renal dysfunction is open to some discussion. Given that nephrotoxic drugs will likely be necessary posttransplant, a serum creatinine of greater than 2.0 mg/dL or a glomerular filtration rate of less than 50 mL/min should give one pause. Active autoimmune diseases pose a risk to the transplanted lungs by causing vasculitis and other inflammatory changes. Table 44.1 Contraindications to lung transplantation. By the time transplantation is being considered, the lower respiratory tract as well as the sinuses of patients with cystic fibrosis are often colonized with highly resistant organisms. The organisms of concern include Pseudomonas aeruginosa, Burkholderia cenocepacia, and atypical mycobacterial species. In general, the outcomes for patients with multidrug‐resistant Pseudomonas organisms are no different than other diagnostic groups [32]. However, infection with Burkholderia cenocepacia (genomovar III) is associated with a very poor outcome; in one series there was 75% mortality in the first posttransplant year [33]. Atypical mycobacterium species colonize the airways in approximately 10–15% of patients with cystic fibrosis evaluated for transplantation. Mycobacterium avium complex is the most common of these. Its presence does not appear to worsen outcomes and therefore is not a contraindication to transplantation [34]. Mycobacterium abscessus, however, is a much more difficult organism to treat and if not eradicated with aggressive therapy should be considered a contraindication [35]. At one time, the need for mechanical ventilation was considered a contraindication. It is clearly a risk factor for early and late failure [7]. However, it is no longer considered a contraindication in most centers. Mechanical support with ECMO or some other lung assist device also places the patient at some added risk, but most surgeons do not consider this a contraindication presently. Prior thoracotomies in patients with parenchymal lung disease make the transplant procedure longer and more tedious, but are not a contraindication. A prior thoracotomy in a patient with cyanotic heart disease, however, increases the risk of serious bleeding significantly. The collateral vessels traversing the adhesions are usually large and numerous. These can lead to life‐threatening hemorrhage. A previous pneumonectomy often leads to significant distortion of the chest, with the heart shifted over to the ipsilateral side. This distortion creates some headaches in the technical aspects of lung transplantation. Severe malnutrition is not unusual in these patients, particularly the cystic fibrosis group. This can have a significant impact on outcomes and should be addressed with an aggressive program to establish a positive nitrogen balance. Lung transplantation requires significant commitment on the part of the patient and their caregivers. Psychosocial factors, particularly when accompanied by a history of poor compliance, should raise red flags and prompt thorough evaluation. Poor compliance posttransplant will universally result in a poor outcome. The contraindications for heart–lung transplantation are the same as for isolated lung transplantation, with the exception that poor left ventricular function is obviously not a concern. As mentioned above, patients with congenital heart disease and cyanosis are at particularly high risk if prior thoracotomies were performed as part of the reconstructive process due to the vascularity of the adhesions. This is not true when only sternotomies have been performed. Beginning in 2005, a lung allocation score was assigned to all patients over the age of 12 years. This was developed as an alternative to the “first‐come, first‐served” method previously in place that was based only on time accrued on the waiting list. Critically ill patients are now given priority, resulting in a reduction in waitlist mortality in adults; a similar trend has not yet been noted in children [36]. The risk inherent in this allocation system is that the outcome posttransplant will be worse due to sicker candidates being transplanted. Thus far this has not been noted. Donors are matched on the basis of ABO blood typing and size. Using height as a surrogate of chest size is typically more accurate than weight for size matching; 20% above and below the recipient will provide a reasonable size match. For heart–lung transplantation, matching the donor height is also the most accurate method for organ size fit for the chest. Larger lungs can be trimmed to fit if necessary using a stapling device to go around the edges. Donor lobectomy may be required in some instances. Donors are excluded if there is a history of positive HIV serology, malignancy, active hepatitis, asthma, tuberculosis, or other significant pulmonary disease. A history of limited cigarette smoking is probably acceptable if other parameters of the evaluation fall within the guidelines. The upper age limit for donors is generally 55 years, but successful lung transplants in teenagers have been performed using donors older than 60. Events resulting in brain death and brain death itself cause significant pulmonary injury. Donor lung function is evaluated with chest radiograph, arterial blood gas on 100% oxygen, and flexible bronchoscopy. The chest film should be free of infiltrates. Any atelectasis should be aggressively treated with chest physiotherapy. The arterial blood gas should have a pO2 of greater than 300 mmHg, with an inspiratory FiO2 of 1.0. Bronchoscopy is performed looking for purulent secretions or evidence of aspiration. When the cause of death is a “pulmonary event” such as asphyxia or drowning, one should be very cautious. Similarly, a donor history of asthma is relatively common. Neither of these would absolutely exclude the donor, but careful selection is imperative [37, 38]. Evaluation of the donor heart function for a potential heart–lung recipient is as described in Chapter 44. It is preferred that the estimated ejection fraction is greater than 40% while on minimal inotropic support. The approach for lung donor retrieval is via a median sternotomy. Both pleural spaces are opened for visual inspection and palpation. The trachea is dissected out between the superior caval vein and the ascending aorta. It may be helpful to develop the interatrial groove to allow for better division of the left atrial tissue anterior to the right pulmonary veins, an area that must be shared with the cardiac retrieval team. The steps to the procurement beyond this are (i) anticoagulation with high‐dose intravenous heparin (300 U/kg), (ii) bolus injection of prostaglandin E1 (50–70 μg/kg) into the main pulmonary artery (MPA); (iii) decompression of the right and left sides of the heart by dividing the inferior caval vein and left atrial appendage; (iv) cross‐clamping the aorta; (v) high‐volume (50 mL/kg) low‐pressure flush of cold pulmonary preservation solution via a cannula in the MPA; (vi) topical application of cold saline and slush to the lungs; and (vii) continued ventilation of the lung with low volumes and low pressures using an FiO2 of 0.4. The cardiac harvest should be performed in such a manner as to leave the back wall of the left atrium and a reasonable cuff of tissue around the orifices of the pulmonary veins. The MPA is divided at the bifurcation. After the cardiac retrieval team has removed the heart, retrograde pulmoplegia should be given via all four pulmonary veins; this serves to flush out any pulmonary emboli that might have occurred in the donor while in the intensive care unit (ICU). It is not at all uncommon to see this. The lungs are removed en bloc with the mediastinal tissue, including the esophagus and descending thoracic aorta. The esophagus is isolated with a stapling device to avoid contamination. The trachea is stapled while the lungs are gently inflated at a low inflation pressure (15–20 cm H2O) with an FiO2 of 0.4. The lungs are then explanted and placed into a container of the preservative solution, which is then put into sterile bags of cold saline and ice. This is then placed into a cooler for transport. A number of preservative solutions are available, including a modified Euro‐Collins solution (EC; Frusten, Hamburg, Germany), University of Wisconsin solution (Belzer UW®, Bridge to Life, Northbrook, IL, USA), Perfadex® (Medisan, Uppsala, Sweden), and Celsior® (Genzyme Corp., Boston, MA, USA). None of these solutions has clear superiority over another. For heart–lung bloc retrieval, all of the above steps are carried out, but there are obviously other factors that come into play. Once the preservative solutions have been given, the aorta, inferior caval vein, and superior caval vein are divided. The trachea is divided, with the lungs gently inflated with an FiO2
CHAPTER 44
Lung and Heart–Lung Transplantation
Lung Transplantation
Indications
Cystic Fibrosis
Pulmonary Hypertension
Pulmonary Fibrosis
Surfactant Genetic Anomalies
Retransplantation
Heart–Lung Transplantation
Indications
Contraindications
“Absolute” contraindications
Active malignancy
Active autoimmune disease
Human immunodeficiency virus infection
Infection/colonization with Burkholderia cenocepacia and Mycobacterium abscessus
Severe neuromuscular disease
Multisystem organ failure
Poor left ventricular function
Relative contraindications
Renal dysfunction
Liver dysfunction
Severe malnutrition
Colonization with multiresistant organisms
Poorly controlled diabetes mellitus
Osteopenia
Multiple prior thoracotomies, especially with cyanotic congenital heart disease
Prior pneumonectomy with mediastinal shift
Extreme prematurity
Poor compliance with medical care
Inadequate psychosocial support system
Listing and Donor Evaluation
Surgical Technique
Organ Harvest
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