Jessica Spellman, Lauren Sutherland Although many disease states result in severe lung disease, lung transplantation remains the only definitive therapy. Because of heterogeneity in underlying disease states and significant cardiopulmonary manifestations of lung disease, lung transplantation procedures carry significant risk, and careful planning with respect to intraoperative management and postoperative care is required, with attention to hemodynamics, ventilatory parameters, immunosuppression, infection prevention, and graft dysfunction. Extracorporeal membrane oxygenation is increasingly being used to support patients as bridge to lung transplantation, intraoperatively for hemodynamic and ventilatory support, and postlung transplantation in the management of graft dysfunction. lung transplantation; end-stage lung disease; extracorporeal membrane oxygenation; mechanical ventilation; primary graft dysfunction Although many disease states result in severe lung disease, lung transplantation remains the only definitive therapy. Because of heterogeneity in underlying disease states, and significant cardiopulmonary manifestations of lung disease, lung transplantation procedures carry significant risk, and careful planning with respect to intraoperative management and postoperative care is required, with attention to hemodynamics, ventilatory parameters, immunosuppression, infection prevention, and graft dysfunction. Extracorporeal membrane oxygenation (ECMO) is increasingly being used to support patients as a bridge to lung transplantation, intraoperatively for hemodynamic and ventilatory support, and postlung transplantation in the management of graft dysfunction. Lung transplantation is the only definitive therapy for many different causes of end-stage lung disease. Between 2009 and 2016, 170 international centers performed lung transplant procedures, with 66% performed among 48 centers.1 The number of lung transplant procedures has been steadily increasing in the United States, with 2714 lung transplants performed in 2019.2 As with other solid organ transplants, there is inadequate organ availability, and currently more than 1300 people are awaiting lung transplantation in the United States. The median waiting time for candidates listed between 2011 and 2014 in the United States varied by blood type, but ranged from 87 days for type AB to 137 days for type O. For this time period, 58.8% of listed adults were eventually transplanted. Survival for lung transplant recipients varies based on single or double lung transplant procedure (Table 43.1).1 Table 43.1 Reprinted with permission from Chambers DC, Yusen RD, Cherikh WS, et al, International Society for H, Lung T. The Registry of the International Society for Heart and Lung Transplantation: Thirty-Fourth Adult Lung and Heart-Lung Transplantation Report—2017; Focus Theme: Allograft ischemic time. J Heart Lung Transplant. 2017;36:1047–1059. The International Society for Heart and Lung Transplantation (ISHLT) guidelines for recipient selection were updated in 2014.3 Referral for transplant involves initial evaluation of the patient for potential as a transplant candidate; placing the patient on the active waitlist occurs when all other treatment options are exhausted, and the benefits outweigh the risks of the transplant procedure. In general, a patient should be actively listed when he or she has chronic, end-stage lung disease with greater than 50% risk of death from lung disease within 2 years, greater than 80% likelihood of 90-day survival from the transplant surgery, and greater than 80% 5-year survival from a general medical perspective. Contraindications to lung transplantation (Table 43.2) generally include conditions that would likely lead to higher morbidity, mortality, or technical difficulty of the transplant surgery, early graft failure, or inability to manage the postoperative transplant state. Relative contraindications are less well defined, and patients who are initially deemed not to be candidates may be actively listed if medical conditions are treated or improve. For example, patients requiring invasive mechanical ventilation (IMV) or extracorporeal life support (ECLS) may be successfully transplanted if there is no significant evidence of another organ dysfunction. Patients with highly virulent pulmonary infections (e.g., Burkholderia or mycobacterium) if adequately treated and without extrapulmonary involvement may also be candidates for lung transplantation. Elderly patients who are otherwise healthy or patients with controlled medical conditions may also qualify for active listing. Table 43.2 aUnless combined organ transplant can be performed. BMI, Body mass index. Reprinted with permission from Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014–an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015;34:1–15. Many patients listed for lung transplantation have had prior thoracic surgery, ranging from minor thoracoscopic biopsies to large thoracotomies for lung volume reduction surgery (LVRS), to cardiac surgeries with internal mammary arterial harvest. Depending on the extent of scar tissue and adhesions, surgical dissection may be significantly more challenging. Overall, this patient population has higher rates of intraoperative bleeding and phrenic nerve damage, as well as postoperative complications including renal dysfunction, primary graft dysfunction (PGD), chylothorax, and need for reexploration. Specifically, prior pleurodesis is associated with prolonged intensive care unit (ICU) length of stay and causes a significantly higher rate of bleeding. Prior LVRS is associated with more bleeding, renal dysfunction, and poorer graft function.3 In well-selected patients with prior thoracic surgeries, there is no difference in outcome with respect to PGD and survival at 30 days, 1 year, and 5 years.4 However, patients with multiple comorbidities and extensive prior surgeries have worse outcomes after lung transplant.4 Lung transplant after coronary artery bypass grafting (CABG) is increasing, and prior CABG is an independent predictor of mortality at 30 days, 1 year, and 5 years in patients receiving bilateral lung transplants; however, mortality is similar to non-CABG patients for single lung transplants.5 Chronic obstructive pulmonary disease (COPD) is the most common indication for lung transplantation worldwide, accounting for 33% of all transplants. The disease is characterized by airflow limitation caused by a mixture of small airway destruction (obstructive bronchiolitis), parenchymal destruction (emphysema), and mucociliary dysfunction. Symptoms include dyspnea, chronic cough, and sputum production, and diagnosis is made through spirometry demonstrating postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) of less than 0.70. Risk factors for COPD include smoking, environmental or occupational exposures, history of asthma or chronic respiratory disease, and the genetic disease alpha-1 antitrypsin deficiency. Chronic disease management includes smoking cessation, pharmacologic therapy with bronchodilators, beta-2 agonists, antimuscarinic drugs, inhaled corticosteroids, phosphodiesterase-4 inhibitors, and antibiotics, oxygen or noninvasive mechanical ventilation therapy, and surgical interventions (e.g., LVRS).6 When compared with other lung transplant indications, the clinical course of COPD often results in poor quality of life but longer pretransplant survival, as well as better survival after lung transplant.7 Transplant evaluation should begin when the disease continues to progress despite maximal medical therapy, oxygen therapy, and pulmonary rehabilitation. In addition, hypoxia, hypercapnia, or FEV1 less than 25% should prompt evaluation.3 The BODE index is a scoring system which uses variables including body-mass index, degree of airway obstruction, dyspnea, and exercise capacity to predict survival in COPD patients. The index is calculated by tallying point values for each index variable. Higher scores indicating greater risk of death, and the hazard ratio of death per one-point increase in the BODE index is 1.34 (95% confidence interval [CI], 1.26–1.42; P < .001).8 When applied to COPD patients undergoing lung transplantation versus medical management, lung transplantation offered a better survival than predicted at 1 year (odds ratio [OR] 0.77; 95% CI, 0.65–0.89), 2 years (OR, 0.71; CI, 0.58–84), 3 years (OR, 0.67; CI, 0.54–0.8), 4 years (OR, 0.65; CI, 0.51–0.79), and 10 years (OR, 0.39; CI, 0.21–0.57)9 with greatest benefit seen in most severe disease (BODE >7).9,10 Patients with a BODE score of 5 to 6 are estimated a 57% 4-year survival and should undergo lung transplant evaluation. Active listing may occur when FEV1 decreases to 15% to 20%, BODE index increases to 7 or higher, with moderate to severe pulmonary hypertension (PH), or when 3 or more major exacerbations occurred within the past year.3 Patients who are candidates for LVRS may be evaluated for transplantation concurrently. Those who fail to improve with LVRS may later be listed for transplantation, and at times, LVRS may improve nutritional and functional status enough to make a patient a candidate for transplant. Interstitial lung disease (ILD) is a heterogeneous group of diseases that are characterized by the presence of cellular proliferation, infiltration, and/or fibrosis of the lung parenchyma which is not caused by infection or neoplasia.11 ILD most often results in a restrictive pattern of pulmonary function, characterized by reduced expansion of lung parenchyma and reduced lung volumes. Causes of ILD include autoimmune and collagen vascular diseases, hypersensitivity pneumonitis because of exposures (e.g., medication, occupational, or environmental), genetic abnormalities, and idiopathic pulmonary fibrosis (IPF). ILD is the second most common indication for lung transplantation but carries the worst prognosis; IPF is the most common and life-threatening form of ILD, carrying greater mortality risk as compared with other classified ILD patients with acute respiratory failure.12 IPF is suspected in the setting of ILD with no other identifiable cause and the following features: bilateral fibrosis on chest imaging, inspiratory crackles, age over 60 years (or, if familial fibrosis, age <60 years), history and serologic testing exclude other causes of ILD, and imaging, lavage, or biopsy exclude usual interstitial pneumonia.13 Patients with ILD should be referred for transplant evaluation early because of poor prognosis and the high likelihood for precipitous decline. Predictors of worse survival include older age, poor or worsening pulmonary function, PH, and concomitant emphysema. Specifically, referral should occur if FVC decreases below 80% or diffusion capacity for carbon monoxide (DLCO) below 40%, or there is development of dyspnea, functional limitation, or oxygen requirement. Active listing should occur with significant decline in FVC or DLCO, worsening 6-minute walk test (6MWT), development of PH, or clinical decompensation.3 Cystic fibrosis (CF) is the most common lethal genetic disease in the Caucasian population, with 30,775 patients in the United States living with the disease and 852 newly diagnosed individuals in 2018.14 The disease is caused by a mutation in the CFTR gene, encoding a transmembrane chloride channel. Dysfunction or downregulation of this channel leads to dehydration of airway surfaces and accumulation of thickened secretions, inhibiting normal ciliary function and clearance of mucous. These abnormal airway secretions, as well as an abnormal host response to bacterial pathogens lead to chronic pulmonary infections, bronchiectasis, and eventual gas trapping, hypoxemia, and hypercarbia. Extrapulmonary manifestations of CF include gut malabsorption and dysmotility from impaired biliary and pancreatic secretions, diabetes from chronic pancreatic insufficiency, sinusitis, and infertility.15 Patients with CF have superior long-term survival after lung transplant compared with other indications.1 Patients should be referred for transplant evaluation when frequency or severity of exacerbations increases, including need for noninvasive mechanical ventilation, diagnosis of infections with increasing antibiotic resistance, pneumothorax, life-threatening hemoptysis, or worsening nutritional status. In addition, pulmonary measures, such as an FEV1 less than 30%, 6MWT less than 400 m, or development of PH should trigger referral. FEV1 less than 30% is the most useful predictor of 2-year mortality. Active listing should be considered with development of chronic hypoxia or hypercapnia, PH, a need for invasive or long-term noninvasive mechanical ventilation, or overall clinical decline. Special consideration should be taken in patients with particularly virulent and resistant pulmonary infections.1 All patients should be evaluated for nontuberculous mycobacterium, and in those with progressive pulmonary or extrapulmonary disease despite optimal therapy, lung transplantation is contraindicated. CF patients infected with Burkholderia cenocepacia have a more rapid progression of pulmonary decline, as well as a higher mortality posttransplant because of high risk of recurrent disease.3 Pulmonary vascular disease (PVD) refers to any process that disrupts blood flow between the heart and lungs, including pulmonary arterial hypertension (PAH), pulmonary venoocclusive disease, thromboembolic disease, pulmonary arteriovenous malformations, and pulmonary vasculitis. PVD may present acutely or chronically with signs and symptoms including dyspnea, chest pain, hypoxemia, or right heart failure (e.g., syncope, weight, edema, ascites from hepatic congestion).16 PH is defined as mean pulmonary artery (PA) pressure of 20 mm Hg or more measured by right heart catheterization (RHC) in the supine position at rest.17 PH can be defined by hemodynamics as pre- or postcapillary and classified further into five groups: PAH, PH caused by left heart disease, PH resulting from chronic lung disease or hypoxemia, PH caused by PA obstruction, or PH arising from multifactorial mechanisms (Box 43.1).18 Management of PH is targeted at the underlying pathophysiology and group classification. Patients with PAH should be assessed and risk stratified at expert PAH centers regularly.18 The United States Registry to Evaluate Early and Long-Term PAH disease management (REVEAL) registry data created a risk score which includes the following factors: group 1 subgroup, demographics, comorbidities, functional class, vital signs, 6MWT, brain natriuretic peptide (BNP) level, echocardiogram, pulmonary function tests, and RHC findings. This scoring system was shown to effectively risk stratify and predict clinical worsening and mortality in patients who were followed 1 year or more.19 Pharmacologic management includes prostacyclin pathway agonists (e.g., epoprostenol, trepostinil, iloprost, selexipag), endothelin receptor antagonists (e.g., ambrisentan, bosentan, macitentan), phosphosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil). A small subset of patients with group 1 PAH who respond to short-acting vasodilators with improvement in hemodynamics measured by RHC are deemed to be “vasoreactive” and should receive a trial of calcium channel blocker therapy.18 Patients with PVD with rapidly progressive disease, New York Heart Association (NYHA) functional class III or IV symptoms with escalating therapy, venoocclusive disease or capillary hemangiomatosis, or use of parenteral therapy (e.g., prostanoids, endothelin receptor antagonists, or phosphodiesterase inhibitors) for PAH should be evaluated for transplant. Persistent class III or IV symptoms after a 3-month trial of combination therapy, cardiac index of less than 2 L/min/m2, or central venous pressure of greater than 15 mm Hg, worsening functional capacity, hemoptysis, pericardial effusion, or evidence of progressive right heart failure should warrant active listing.3 Lung retransplantation makes up a small portion of lung transplants, but the proportion is increasing. Candidate selection is similar for that of initial transplant evaluation. Common indications for retransplantation include bronchiolitis obliterans syndrome (BOS), PGD, or airway complications. Survival for retransplant is inferior to original transplants, with 67% survival at 1 year and 40% at 5 years internationally,1 and there is a higher risk of acute rejection. Renal dysfunction in this population increases mortality significantly. Consideration for removal of the prior transplant allograft should be undertaken because this can become a nidus for infection or ongoing immune stimulation. Because of this, retransplants are often done as double lung transplantations. However, removal of the prior allograft may pose greater technical difficulty surgically owing to the presence of adhesions and lead to greater operative morbidity. If a single retransplant is to be performed, generally a contralateral lung transplant is preferred.20 In most patients with right-sided heart failure from longstanding or severe acute pulmonary disease, lung transplantation improves conditions that allow for myocardial recovery. In end-stage PH, single-center reporting of bilateral lung transplantation as compared with heart-lung transplant is associated with comparable survival.21 However, patients with irreversible myocardial dysfunction or severe congenital defects in addition to end-stage lung disease may be candidates for combined heart-lung transplantation. Patients with intrinsic cardiac disease, such as coronary artery disease, valvular pathology, or septal defects may undergo concomitant cardiac surgery at the same time as lung transplantation rather than combined heart-lung transplant. The number of performed heart-lung transplants has generally downtrended in recent years both nationally and internationally. In the United States, 15 heart-lung transplants were performed in 2015; however, in 2019, 45 were performed, demonstrating a possible resurgence in this procedure. When indices of right ventricular (RV) function begin to decline despite maximal medical therapy, including NYHA functional class IV symptoms or cardiac index less than 2 L/min/m2 with RA pressure over 15 mm Hg, patients should be actively listed for transplant.3 Pediatric lung transplantation is performed much less commonly than in adults. In 2019 of the 2714 total lung transplants, only 50 were in patients under 18 years of age in the United States. Of these, most occurred in the 11 to 17 year age range.2 CF is the most common indication for pediatric lung transplantation overall, but this varies by age. Congenital heart disease is the most common indication in infants, whereas CF and idiopathic PAH are most common between ages 1 and 10. Referral for lung transplant should occur in children with progressive lung disease on maximal medical therapy, a short-life expectancy, a poor quality of life, and when appropriate social support is in place. Nonadherence in adolescents is a common cause of graft failure, so this should be addressed at transplant assessment. Waiting times tend to be longer, especially for smaller children, so referral should occur earlier. Contraindications to transplant are similar to adult patients based on disease process. Living donor lobar transplant is an option in some pediatric cases. All patients on the waiting list should be regularly evaluated to ensure that they remain transplant candidates.3 Patients may be temporarily or permanently delisted if their candidacy changes based on either clinical improvement or deterioration or change in social factors. Examples of causes for delisting include substantial weight loss or debilitation, renal failure, new virulent infection, and medical noncompliance. If a patient clinically improves on medical therapy, he or she may be delisted because of improved quality of life. Patients bridged with IMV or ECLS frequently have clinical changes that may result in significantly higher morbidity and mortality of the transplant procedure. As part of the selection process for lung transplantation, recipient candidates undergo a variety of studies to better define pulmonary disease, assess for decline in function, and exclude other systemic illness. Testing includes pulmonary function tests, chest x-ray, computed tomography (CT) scanning, nuclear medicine ventilation perfusion studies, walk or exercise testing, electrocardiogram, echocardiogram, myocardial stress testing, right and left heart catheterization, and laboratory evaluations of hematologic system, liver, and kidney function. Blood typing and comprehensive recipient human leukocyte antigen (HLA) testing is performed to allow for virtual cross-matching at the time of identification of a potential donor.22 Because of an organ demand that far outnumbers supply, a method of allocation was devised to distribute the available lungs in the most optimal way to both reduce waitlist mortality and improve transplant outcomes.23 The first step in matching a donor with a recipient is based on blood type and lung size as determined by total lung capacity (TLC). Next, either national or regional location determines which recipients are eligible. In the United States, the Donation Service Area (DSA) is now a 250 nautical mile area in determining eligible recipients.24 In the United States, the Organ Procurement and Transplantation Network (OPTN) devised the lung allocation score (LAS) system in 2005 to prioritize recipients based on likelihood of transplant benefit. The LAS uses patient physiologic characteristics and statistical models to calculate a patient’s waiting list urgency and expected posttransplant survival. Parameters incorporated into these calculations were updated in 2015 (Box 43.2).25 A raw score is determined by subtracting the waiting list survival (days) from the transplant survival (days) with higher weight given to waitlist mortality, and this is converted into the LAS by normalizing between 0 and 100; a higher LAS has higher priority. Candidate information must be updated at least once every 6 months, or every 14 days for LAS scores of 50 or higher.26 Pediatric candidates (i.e., <12 years of age) are designated priority 1 or 2 based on their medical condition and do not use the LAS system. Based on OPTN organ allocation, overall lung transplant rates increased from 87.1 per 100 waitlist years in 2009 to 172.3 in 2018.27 Time on the waiting list was stable with 53.4% of patients transplanted after less than 90-days, and median time on the waitlist decreased from 4 to 2.5 months in 2018.27 Patients who acutely decompensate before availability of lungs for transplantation may require bridging with either IMV or ECLS. These interventions intend to extend the interval until transplantation can occur, as well as improve clinical stability. IMV, while extending time to transplantation, may cause new clinical problems to arise, such as ventilator-associated pneumonia, immobility and deconditioning, ventilator-associated lung injury, and hemodynamic instability.3,28 Pretransplant IMV is associated with a higher short-term mortality.1,29 Because of high waiting list mortality and worsened mortality with pretransplant IMV, ECLS has emerged as a method of bridging to transplant to allow longer waiting list times and improved clinical stability.3 ECMO is a form of ECLS that provides support to patients with respiratory, cardiac, or combined failure for days to weeks.30 In 2018 in the United States, 1.6% of patients were bridged to lung transplant with IMV only, 3.3% with ECMO only, and 3.1% with both ECMO and IMV.27 Pretransplant use of IMV and ECMO has in the past been associated with higher mortality compared with nonsupported patients,31 but this may be attributed to higher severity of illness, as well as ventilator and ECMO-related complications and deconditioning. Studies of comparing ECMO-bridged patients to those not requiring ECLS have shown mixed results with a trend toward worse early morbidity and mortality32–34; however, with improvements in technology, patient selection, and management, there is evidence of high overall survival in patients bridged with ECMO,35 especially when avoiding IMV.36,37 The basic ECMO circuit consists of a magnetic levitation pump, conduit tubing with drainage and return cannulas, a membrane oxygenator, and a heat exchanger.30 Deoxygenated blood is removed via the drainage cannula, oxygenated and carbon dioxide removed by the membrane oxygenator, and returned to the body through the reinfusion cannula. ECMO may be venovenous (VV) or venoarterial (VA). VV ECMO both drains and returns blood to a central vein, serving a replacement for lung function in patients with inadequate oxygenation or ventilation and allowing for a reduction in ventilator settings to decrease potential for lung injury.38 VV ECMO places the native lungs in series with the “artificial lung,” so blood enters the pulmonary circulation having already been oxygenated and carbon dioxide removed. VV ECMO provides no cardiac or circulatory support (Fig. 43.1). VA ECMO drains blood from a central vein and returns to a central artery, supplying both cardiac and pulmonary support. The “artificial lung” runs in parallel to the native lung, with a proportion of blood pumped and oxygenated by the circuit whereas the remainder that enters the heart relies on native lung function. VA ECMO cannulation strategies are variable, although can generally be divided into two techniques: central or peripheral (Fig. 43.2). Central VA ECMO involves direct cardiac cannulation through sternotomy or thoracotomy, similar to that of cardiopulmonary bypass (CPB), with venous cannulation of the right atrium and arterial cannulation of the ascending aorta. In peripheral VA ECMO, the drainage cannula enters either the femoral or internal jugular vein (IJV) with advancement to the junction of the inferior or superior vena cava and right atrium; arterial cannulation for reinfusion is to either the descending aorta via the femoral artery or to the subclavian artery (SCA) by way of the axillary artery. There may be combinations of central and peripheral techniques in certain clinical situations. Venoarteriovenous (VAV) ECMO involves drainage from a central vein with reinfusion flow divided between two cannulas, a central venous return and an arterial return. This configuration may be useful in a patient with both cardiac and severe pulmonary dysfunction in which additional circulatory support is required, but blood pumped through the native lungs is inadequately oxygenated and ventilated. Partial clamping of the two reinfusion cannulas allows for titration of the relative contributions of the VV and VA components. Choice of cannulation strategy is based on the clinical indication, patient factors, and available vascular access. Femoral VA ECMO is more easily placed during a cardiopulmonary resuscitation situation because of access of the femoral vessels. VV ECMO cannulation on an intubated patient with acute respiratory distress syndrome (ARDS) may use femoral access; however, in a patient awaiting lung transplantation, upper body cannulation can improve mobility and even allow for ambulation. ECMO cannulation techniques as bridges to lung transplantation will be further discussed later. Although ECMO can normalize hemodynamics, oxygenation, and acid-base status to temporize a patient while awaiting transplant, the benefits must be compared with potential harm of ECMO complications. Frequent complications of ECMO include bleeding from cannula or surgical sites, lower extremity ischemia distal to cannulation sites, stroke or other neurologic complications, infection, and acute kidney injury.30 The most common sites of bleeding are cannula sites, surgical sites (e.g., mediastinal, thoracic), gastrointestinal, or central nervous system (CNS). Apparent bleeding without a clear source may also represent hemolysis. Thromboembolic complications include limb ischemia, intracardiac thrombus, device thrombosis including pump malfunction, oxygenator failure, or tubing obstruction, ischemic stroke, or deep vein thrombosis and pulmonary embolism. In cases of ischemia of the limb in which a cannula is placed, a distal perfusion cannula may be placed to direct a small amount of blood flow toward the limb. Vascular Doppler assessment of distal arterial vessels may be helpful, as well as vessel caliber assessment at arterial cannulation.39 Other complications may occur with VV and VA ECMO because of competing flow considerations with the circuit or native circulation. VV ECMO support may be ineffective if returned blood is drawn back into the drainage cannula, an issue known as “recirculation” which can be addressed by cannula repositioning. Peripheral VA ECMO specifically results in high left ventricular (LV) end-diastolic pressure because of arterial flow directed up the aorta toward the aortic valve, resulting in LV dilation, dysfunction, or failure in some patients. Failure of the LV to eject volume and resulting LV distension in these cases increase risk of stasis and thrombosis at the LV outflow tract, aortic valve, or ascending aorta. To relieve LV distention, an Impella assist-device, an intraaortic balloon pump, or transseptal left atrial drainage cannula may be placed.38 In addition, it is important to monitor for cerebral and coronary hypoxia in patients with peripheral VA ECMO and lung disease. Especially in states of normal or recovering cardiac function, poorly oxygenated blood, ejected blood from the heart will preferentially supply the proximal aortic vessels (i.e., coronary and carotid arteries). In patients with peripheral VA ECMO, right radial arterial blood gases (ABGs) or saturation monitoring should be monitored as a surrogate for cerebral oxygenation.30 In general, patients awaiting lung transplantation with severe hypercapnia, hypoxemia, or RV failure who are likely not to survive until organ availability may be bridged to lung transplant with ECMO. Those with isolated pulmonary failure benefit from VV ECMO to provide oxygenation and removal of carbon dioxide. For patients with PH or RV failure, VA ECMO provides additional cardiac output, as well as offloads preload to the right ventricle. In some cases, VV ECMO support alone can be sufficient for patients with mild PH and RV dysfunction, as the improvement in systemic oxygenation and respiratory acidosis allows for improvement in hemodynamics and RV function. In patients with PH and a large atrial septal defect (>2 cm) or atrial septostomy, VV ECMO may be effective as a bridge to transplant.40 Candidates with high pretransplant mortality from a pulmonary standpoint but with high likelihood of clinical improvement with cardiopulmonary support should be selected for ECMO bridging to transplantation (BTT). Those with multiorgan dysfunction or poor rehabilitation potential should not be placed on ECMO because this can present an ethical dilemma of “bridging to nowhere” if the patient does not become a transplant candidate. Except in exceptional circumstances, only patients who have been evaluated and deemed appropriate transplant candidates should be placed on ECMO as a bridge to transplant.38 Timing of placement on ECMO support is important and controversial. In one respect, earlier placement of ECMO may prevent development of multiorgan dysfunction and maintain candidacy for transplantation; however, complications of ECMO, such as hemorrhage, thromboembolism, infection, vascular injury, or stroke develop frequently in these patients and may preclude transplantation. Disease- and location-specific factors that result in high waitlist mortality or long waitlist times should be considered in deciding when to place a patient on ECLS while awaiting organ availability. For example, short stature has been associated with higher waitlist mortality and lower rate of transplant, so patients who fall into this category may require earlier initiation of ECMO support.38 Patients who are BTT with ECMO should be continuously reassessed for candidacy for transplantation, as clinical decompensation may occur rapidly, deeming these patients too unstable to undergo the procedure.3 Patients requiring ECMO as a BTT remain good candidates if they have overall good organ function, young age, and good potential for rehabilitation; however, those with evidence of other organ system dysfunction, septic shock, advanced age, obesity, or prior prolonged ventilation are poor candidates. In the earlier years of prelung transplant ECMO use, outcomes of lung transplant for patients BTT with ECMO were poor; however, with the improvements in technology, cannulation strategies, and management, properly selected patients benefit from ECMO support.38 Overall goals in prelung transplant ECMO management include minimizing sedation, avoidance of endotracheal intubation, and early mobilization.38 In many patients, ECMO support can provide sufficient oxygenation and acid-base management to allow for avoidance of or removal of IMV. Patients on ECMO who are not intubated or “awake ECMO” avoid complications related to sedation, IMV, ventilator-associated pneumonia, immobility, and artificial modes of nutrition.38 Awake ECMO is associated with higher posttransplant survival and shorter postoperative IMV.37 Patients with an ongoing need for IMV may undergo early tracheostomy to maximize patient comfort while minimizing sedation, allow for participation with physical therapy, and aid in clearance of respiratory secretions.38 Early mobilization, both in patients requiring IMV and/or ECMO, allows for improvement in physical strength and avoidance of complications related to immobility and deconditioning. This may improve physiologic reserve to tolerate the transplant procedure, as well as rehabilitation potential after surgery. Mobilization in ECMO patients as BTT has been associated with higher survival to transplant.40 Ambulation while on ECMO is not only possible but can be done safely in properly selected patients41,42; a multidisciplinary team should be coordinated and guidelines or protocols developed to ensure patient safety.43 Risk of mobilization should be weighed against potential benefit in patients with hemodynamic instability, and patients may require increased level of ECLS or medication support for ambulation.43 Although traditional VA or VV ECMO require peripheral femoral cannulation, newer cannulation strategies have evolved to allow for maximal patient mobility and early ambulation. It is important to note that emergent VV or VA ECMO cannulation should adhere to traditional approaches because of ease of placement and avoidance of the lengthy procedure required for an open, surgical approach. Configurations for early mobilization generally use single-site dual lumen cannulas, upper body cannulation, or minimally invasive central approaches. The single-site dual lumen VV ECMO cannula (Fig. 43.3) is traditionally placed into the right IJV; bicaval drainage ports are positioned into the superior and inferior vena cava and the reinfusion port lies in the right atrium, with the jet directed toward the tricuspid valve.38 Proper placement of this device is confirmed with fluoroscopy or transesophageal echocardiography (TEE). This device not only allows for improved mobility, but also decreased recirculation given the fixed cannula port distances. For patients who require additional cardiac support, novel VA ECMO upper body configurations are more variable but all aim to improve upper body oxygenation in addition to maximizing patient mobility. The “sport model” approach involves IJV drainage to right SCA reinfusion44 (Fig. 43.4). An end-to-side graft is anastomosed to the right SCA to avoid limb ischemia, and blood is reinfused down the right SCA. Unlike femoral VA ECMO where blood is directed retrograde from the femoral artery toward the aortic arch, the sport model approach ensures well-oxygenated blood flow to the carotid arteries. In patients with small or inaccessible SCAs, the innominate artery can be accessed via a miniature upper sternotomy incision for reinfusion, also known as “central sport model” ECMO.45 In patients with PH and a preexisting atrial septal defect or atrial septostomy, a dual-lumen VV ECMO cannula can be positioned with the reinfusion port directed over the defect, allowing oxygenated blood to shunt to the left heart and offloading the right ventricle.38 “Arteriovenous” ECMO using flow supported by the patient’s cardiac output through a low resistance extracorporeal lung assist device (LAD) membrane ventilator circuit is also an option. This can be placed peripherally via the femoral artery to the femoral vein to support mechanical ventilation, or centrally from the PA to the left atrium.46 Arteriovenous ECMO can also be used to gradually increase flow to the previously underfilled left heart, potentially preventing the complication of LV failure which can be seen immediately after lung transplant reperfusion in patients with severe PH. Allosensitization to donor antigens from blood product transfusions can limit organ availability to patients awaiting transplant. Because of this, a more conservative transfusion strategy is preferred, targeting lower acceptable hematocrit values than in general critically ill populations.38 In addition, although some degree of anticoagulation is required to maintain ECMO circuit patency and prevent thromboembolic complications, this must be weighed against the risk of bleeding, as well as the need for blood product transfusions. Typically, anticoagulation targets are lower in this population and short-acting, reversible anticoagulation (i.e., heparin) is preferred. Lung transplant donors may be deceased or living lobar. Deceased donors include donation after brain death (DBD) and donation after circulatory determination of death (DCDD), also known as “donation after cardiac death” or “nonbeating-heart donation”. Living lobar donation represents a small proportion of total lung transplantations, especially in the United States and Europe, because of high morbidity to the donors47; thus these procedures are most commonly performed in countries with limited deceased donor availability. DCDD donation may be considered in patients whose life-sustaining treatment is planned for withdrawal but criteria for brain death are not met. Eligible conditions include irreversible brain injury, high spinal cord injury, and end-stage musculoskeletal disease.48 In addition, DCDD may occur in certain unplanned situations, such as when patients unexpectedly suffer cardiac arrest from which they do not survive. For DCDD to be allowed, death must clearly precede donation, defined as cessation of all cardiopulmonary functions and irreversibility.48 A time limit for circulatory death of up to 2 hours following withdrawal of life support is generally set to ensure viability of organs for transplantation. In selecting a patient as an appropriate donor for DCDD, clinical assessment for likelihood of circulatory death within 2 hours of withdrawal of life support should be used. Scoring systems to predict likelihood of circulatory death may be helpful. Once the diagnosis of brain death is made or a potential DCDD donor is identified, the local procurement organization evaluates the potential donor. This organization also provides family support, obtains consent, and communicates with the United Network for Organ Sharing (UNOS) to match the donor with a recipient. Once a potential lung donor is identified, a rigorous process is undertaken to ensure graft acceptability.49 Empiric criteria are used to identify ideal lung donors.49 Most potential grafts are declined because of issues with donor history, chest trauma, pneumonia, aspiration, or various ICU complications.50 Extended donor criteria, or donor organs that do not meet this ideal donor criteria, may help increase the pool of suitable donors, while maintaining transplant outcomes in adult and pediatric lung transplantation.51 This would include evaluation of donors of greater age range, smoking or asthma history, and certain causes of death, or other high-risk donors, if there is a continued positive trend in imaging studies and arterial partial pressure of oxygen (PaO2):fraction of inspired oxygen (FiO2) (P/F ratio).52 The U.S. Center for Disease Control and Prevention (CDC) labels high-risk donors as: those with exposure to human immunodeficiency virus (HIV), prison inmates, intravenous (IV) drug users, prostitution history, high-risk sexual history, and hemophiliacs. In the period of 2004 to 2010, 7% of lung transplant recipients received high-risk organs, and there was no difference in 1-year mortality as compared with nonhigh-risk organs.53 With respect to donor age, donor graft outcome data are similar for donor ages 18 to 64 years54; however at the extremes of donor age, recipient pathology may play an important role in outcomes.55 To reduce the risk of viral transmission of SARS-CoV-2 virus (which causes COVID-19) from donor to recipient, donors are screened by polymerase chain reaction (PCR)-based testing of a nasopharyngeal or oropharyngeal swab, tracheal aspirate, or bronchoalveolar lavage (BAL), and CT scan is considered to evaluate for viral pneumonitis. It is recommended to avoid donors with positive test or CT scan results, as well as donors with exposure to confirmed or suspected SARS-CoV-2 cases in the past 14 days.56 Recommendations for donor and recipient size matching are based retrospective analysis and may vary based on disease state. In general, larger donor organs are preferred for recipients with hyperinflation and associated enlarged thoracic cavities and smaller organs for recipients with restrictive disease.57 For example, it is recommended for patients with emphysema to be matched with donor lungs with 67% to 100% of the recipient actual TLC, whereas for patients with PH or CF it is recommended to match donor lungs up to 120% of the recipient predicted TLC,58 based on height, weight, and gender. Undersized donor allografts based on of height and weight are associated with inferior posttransplant survival, with the exception of ILD in which undersized allografts experience similar survival to those that are well-matched or oversized.59 Newer methods of three-dimensional CT lung volumetry may also provide information for size matching in lung transplantation.60
Lung Transplantation
Abstract
Keywords
Introduction
Epidemiology
1-Year Survival
5-Year Survival
Single
Double
Single
Double
United States
85%
87%
46%
56%
International
78%
82%
48%
59%
Recipient Selection
Absolute Contraindications
Relative Contraindications
Untreatable, significant dysfunction of another organ system,a including atherosclerotic disease, coronary disease not amenable to revascularization, and uncorrectable bleeding diathesis
Severe systemic illness
Recent history of malignancy
Age >75 years (or >65 years with low physiologic reserve)
Acute medical instability (e.g., bleeding, sepsis, myocardial infarction, or liver failure)
Medical conditions likely to result in end-stage organ damage
Chronic infection with highly virulent or resistant microbes (e.g., Mycobacterium tuberculosis)
Colonization or infection with highly resistant or highly virulent organisms
Severely limited functional status with poor rehabilitation potential
Severe malnutrition or osteoporosis
BMI ≥35.0 kg/m2
BMI 30–34.9 kg/m2
Significant chest wall or spinal deformity
Extensive prior thoracic surgery
Nonadherence to medical therapy
Psychiatric conditions associated with the inability to cooperate with complex medical therapy
Substance abuse or dependence
Absence of an adequate social support system
Disease-Specific Selection
Chronic Obstructive Pulmonary Disease
Interstitial Lung Disease
Cystic Fibrosis (See Chapter 50)
Pulmonary Vascular Disease
Special Populations
Retransplantation
Combined Heart-Lung Transplant
Pediatric Lung Transplantation
Removal From the Waiting List
Recipient Preparation
Organ Allocation
Bridging to Transplantation
Invasive Mechanical Ventilation
Extracorporeal Membrane Oxygenation (See Chapter 28)
Basics
Complications
Patient Selection
Prelung Transplant Extracorporeal Membrane Oxygenation Management
Cannulation Techniques
Transfusions and Anticoagulation
Organ Selection, Transport, and Preparation
Donor Evaluation
Organ Selection
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Lung Transplantation
