Pulmonary Medicine

Lung Transplantation (include selection, evaluation, process of organ acquisition, etc.)

General description of procedure, equipment, technique

Lung transplantation has been performed successfully for nearly three decades, and more than 32,000 procedures have been performed worldwide. Lung transplantation offers patients with advanced, debilitating, and often life-threatening lung disease the possibility of extended survival, improved functional status, and enhanced quality of life.

Indications and patient selection

Indications for lung transplantation include a broad spectrum of pulmonary disorders of the lung parenchyma, airways, and vasculature. Chronic obstructive pulmonary disease (COPD) was historically the most common indication for lung transplantation worldwide, but it has now been eclipsed by idiopathic pulmonary fibrosis. Cystic fibrosis (CF) is the third leading indication.

Other, less common indications include alpha-1antitrypsin deficiency-associated emphysema, sarcoidosis, non-CF bronchiectasis, Eisenmenger's syndrome, and lymphangioleiomyomatosis. Idiopathic pulmonary arterial hypertension (IPAH) was once a leading indication for transplant, but in the current era of successful vasodilator therapy, it accounts for only 2 percent of transplant procedures. Patients for whom collagen vascular disease is the underlying cause for their lung disease are usually considered suitable for transplantation if they do not have significant extrapulmonary involvement that could compromise the outcome of transplantation.

Given the considerable risks associated with lung transplantation, including a mortality rate that approaches 50 percent at five years, this option should be reserved for patients whose lung disease poses a significant risk of short-term mortality. Disease-specific guidelines for referral of patients, based on available prognostic indices, are shown in Table 1 (Figure 1)}. In addition to prognosis, other factors that should be considered include the clinical trajectory of the patient's disease (i.e., stable vs. deteriorating), functional status, quality of life, and the patient's willingness to accept the risks, uncertainties, and commitments of transplantation.

Table 1

Historically, most programs had an age cutoff, typically age 65, for eligible candidates, but there has been an increasing willingness to accept older candidates, focusing more on their functional, rather than chronological, age. Patients 65 years and older now account for approximately 20 percent of the recipient pool in the U.S.

Candidates should be functionally limited (New York Heart Association functional class III or IV) but, ideally, still ambulatory. Many programs use the six-minute walk test to assess functional status and set a minimum distance (commonly 600 feet) for eligibility.

Contraindications

Absolute contraindications to lung transplantation are:

  • recent malignancy other than non-melanoma skin cancer

  • active infection with hepatitis B or C virus in association with histological evidence of significant liver damage on biopsy

  • infection with human immunodeficiency virus

  • active or recent cigarette smoking, alcohol abuse, or drug abuse

  • severe psychiatric illness

  • recurrent medical noncompliance

  • absence of a consistent and reliable social support network

Extremes of weight are also often viewed as absolute contraindications, but cutoffs vary from center to center. The presence of significant extrapulmonary vital organ dysfunction, while a contraindication to lung transplantation alone, can sometimes be addressed with multi-organ procedures (e.g., heart-lung, liver-lung) in select candidates. Severe esophageal dysmotility associated with scleroderma is viewed as an absolute contraindication by many centers (but not all) because of concerns that it would predispose to post-transplant aspiration and accelerated graft loss.

Medical comorbidities like diabetes mellitus, osteoporosis, gastroesophageal reflux disease, and coronary artery disease are often present in patients with advanced lung disease. The extent to which these conditions increase the risk of or contraindicate transplantation depends on the severity of the disease, the presence of significant end-organ damage, and ease of control with standard therapies.

Respiratory failure that requires intubation and mechanical ventilation prior to transplantation is a risk factor for increased short-term post-transplant mortality, but it does not significantly impact long-term outcomes. Under the new lung allocation system in the U.S., mechanically ventilated candidates are assigned high allocation scores and often receive organs in expedited fashion. Most transplant centers no longer view short-term pre-transplant mechanical ventilation as a contraindication to transplantation as long as the candidate is otherwise suitable.

However, the development of serious intercurrent complications (e.g., infection) or progressive debility typically leads to removal of the candidate from the active waiting list. Transplantation of patients on extracorporeal membrane oxygenation (ECMO) support is more controversial and is associated with a one-year survival rate of only 50 percent. The recent introduction of ambulatory ECMO devices may increase the level of willingness to transplant these patients in the future.

Selection of patients with CF has always raised unique concerns about the risk that chronic airways infection poses on post-transplant outcomes. Experience has demonstrated that the risk of post-transplant pneumonia is no greater among CF patients than among other patient populations. However, CF patients who are infected with pan-resistant Pseudomonas aeruginosa experience slightly inferior post-transplant survival rates compared to those of CF patients with sensitive organisms (86% vs. 97% five-year survival, respectively). Since these outcomes are still favorable, the presence of pan-resistant P. aeruginosa should not contraindicate transplantation.

In contrast, infection with certain species of Burkholderia cepacia complex (especially B. cenocepacia) has been associated with excessive post-transplant mortality as a direct consequence of lethal infections with these organisms. As a result, the majority of lung transplant centers exclude patients with B. cenocepacia.

Prior pleurodesis is associated with an increased risk of intraoperative bleeding, particularly when cardiopulmonary bypass is used, but it is not a contraindication to transplantation. Pleural thickening associated with aspergillomas, a common issue among sarcoidosis patients, similarly complicates explantation of the native lung and carries the additional risk of soiling the pleural space with fungal organisms if the cavity ruptures during removal. Some patients with extensive pleural reaction and/or cavities abutting the pleural surface may be excluded from consideration for this reason.

Donor selection

Lungs have been the most challenging of all the vital organs to successfully harvest for transplantation because of a variety of insults that occur with or leading up to brain death--aspiration, ventilator-associated pneumonia, chest trauma, volume overload, and neurogenic pulmonary edema--as well as the potential consequences of prior smoking. In order to avoid use of impaired lungs, standard selection criteria have been established (Table 2 ) (Figure 2).

Table 2

Use of these criteria has resulted in lung harvest rates of only around 15 percent from donors who are otherwise suitable for donation of other vital organs. However, it has become clear that these criteria are far too stringent, and lung harvest rates have increased by liberalizing these criteria, although the oxygenation criterion (P/F ratio > 300 mm) has rarely been violated. Use of these "extended criteria" donors has been associated with outcomes similar to those achieved with standard criteria donors.

Implementation of special donor-management protocols that include judicious fluid management, therapeutic bronchoscopy, and lung recruitment maneuvers via the ventilator have led to increased harvest rates. In addition, lung harvest rates can be enhanced by employing a lung-protective ventilatory strategy (tidal volume 6-6 ml/kg, 8-10 cm PEEP), rather than more conventional ventilator settings (tidal volume 10-12 ml/kg, 3-5 cm PEEP).

An evolving technology that will likely become increasingly available in the next several years is ex vivo lung perfusion, which involves harvesting suboptimal lungs and placing them in a circuit that permits their continuous perfusion and ventilation. A hyperosmolar perfusate draws fluid out of the extravascular space, decreasing the amount of pulmonary edema and improving oxygenation. In this way, lungs that are unacceptable at the time of harvest because of poor oxygenation can be "reconditioned" and subsequently transplanted successfully.

Another emerging donor strategy is the use of "donation after cardiac death" (DCD) donors. n such cases, family members request withdrawal of care from a patient with devastating neurological injury (but not brain death) or other unrecoverable condition. With the family having independently consented to organ donation, life support is withdrawn in a controlled fashion, typically in an operating room, and organs are harvested after circulatory arrest ensues and death is pronounced. Preliminary experience has demonstrated that recipients of DCD lungs achieve short-term outcomes similar to those who receive organs from brain-dead donors.

Organ allocation

Rules governing organ allocation vary from country to country, but they typically employ a time-based or need-based ranking of candidates. A system based on both need (i.e., risk of death without transplantation) and "net transplant benefit" (i.e., the extent to which transplant will extend survival compared to the natural history of the underlying lung disease) was put in place in the U.S. in 2005. By including the "net transplant benefit," the system attempts to prevent allocation of organs to desperately ill patients with a high risk of death post-transplantation.

The U.S. allocation system uses statistical models to predict one-year survival with and without transplantation for each patient. These models use approximately a dozen objective parameters, the most influential of which are underlying diagnosis, oxygen requirements at rest, and need for mechanical ventilation. These survival projections are used to calculate a candidate's lung allocation score (LAS) using the equation "raw" LAS = [net transplant benefit (one-year survival with transplantation minus one-year survival without transplantation)] minus [medical urgency (1-year survival without transplantation)].

The score is then normalized to a 0-100 scale for ease of use. Because one-year survival without transplant is factored into both the net transplant benefit and the medical urgency measures, it has more impact on the LAS than post-transplant survival does.

By prioritizing patients with more advanced and imminently life-threatening disease, the LAS system has decreased the death rate of patients on the waiting list. It has facilitated transplantation of patients with IPF, previously the group at greatest risk for dying while awaiting transplantation, while assigning lower priority to patients with COPD. The system also has also made it feasible to transplant candidates expeditiously who develop respiratory failure requiring mechanical ventilation, although it remains to be determined whether outcomes in this high-risk population are sufficient to justify this practice.

In addition to the LAS score, lungs are allocated on the basis of blood group and size compatibility. Prospective HLA matching is not performed, but candidates identified to have anti-HLA antibodies at the time of listing must avoid donors with incompatible antigens.

Details of how the procedure is performed

Four surgical techniques are used to varying degrees: heart-lung, single-lung, bilateral-lung, and living-donor bi-lobar transplantation. The choice of procedure is dictated by such factors as underlying disease, age of the patient, survival and functional advantages of the procedure, and center-specific preferences.

Heart-Lung Transplantation (HLT)

While HLT was the first procedure to be performed successfully, it now accounts for less than 3 percent of all procedures. The main indication is Eisenmenger's syndrome with associated surgically uncorrectable cardiac defects. HLT is still occasionally performed in patients with IPAH, but it has become clear that the right ventricle has a remarkable capacity to recover once pulmonary artery pressures have normalized. As a result, bilateral lung transplantation (BLT) has supplanted HLT for the vast majority of IPAH patients, except those with severely decompensated right ventricular failure. HLT is also occasionally used for patients with advanced lung disease and concurrent severe left ventricular dysfunction or extensive coronary artery disease.

Single-Lung Transplantation (SLT)

Until relatively recently, SLT was the most commonly performed procedure. It is usually performed via a standard posterolateral thoracotomy incision, but some surgeons now prefer a less invasive axillary muscle-sparing thoracotomy incision. Technically the most straightforward procedure, SLT is well-suited for frail patients who would have difficulty enduring the rigors of BLT. It also provides the most efficient use of the limited donor pool, permitting two recipients to benefit from a single donor.

SLT is an acceptable procedure for patients with IPF and COPD, although native lung hyperinflation in COPD can (rarely) compromise the function of the allograft. SLT is contraindicated for patients with CF and other suppurative lung diseases because of concerns that a native lung left in place could infect the allograft. SLT is also avoided in patients with severe idiopathic or secondary forms of pulmonary hypertension; the allograft would have to accommodate the entire cardiac output because of the high vascular resistance in the native lung, which can lead to exaggerated reperfusion pulmonary edema.

Bilateral Lung Transplantation (BLT)

BLT has recently emerged as the most commonly performed of the available procedures. Rather than en bloc transplantation of both lungs, it involves performance of two single-lung procedures during a single operative session. In the absence of significant pulmonary hypertension, cardiopulmonary bypass (and the attendant bleeding complications) can often be avoided by sustaining the patient on the contralateral lung during implantation of each allograft.

Surgical approaches include a transverse thoracosternotomy (clamshell) incision, bilateral anterior thoracotomies (sparing the sternum), and median sternotomy. BLT is the exclusive procedure for CF and non-CF bronchiectasis and for severe idiopathic and secondary forms of pulmonary hypertension. It is associated with superior survival compared to SLT in COPD patients under age sixty, and it now accounts for approximately two-thirds of procedures performed in that population. It also is employed in over half of all transplants in patients with IPF, although, unlike the case with COPD, no survival benefit over SLT has been demonstrated in this patient population.

Living-donor Bi-lobar Transplantation (LDT)

TLDT was developed under the prior time-based allocation system in the U.S., largely to serve the needs of candidates whose rapidly deteriorating status made it unlikely that they would survive to receive organs from a cadaveric donor. The procedure involves donation of a lower lobe from each of two living, blood-group-compatible donors, and in order to ensure that the lobes are sufficient to fill the hemithoraces, the donors are ideally taller than the recipient. Therefore, patients with CF are well-suited to this procedure because of their small stature even as adults.

Outcomes following living-donor transplantation approximate those achieved with cadaver organs. The procedure is now performed rarely since it offers no survival advantage to recipients, it poses risk to two otherwise healthy donors, and its chief purpose of expediting transplantation has been addressed by the new allocation system.

Post-transplant Management: Immunosuppression

Individuals involved in the care of lung transplant recipients must be familiar with the administration, side effects, and drug interactions of the immunosuppressive agents employed to prevent rejection (Table 3) (Figure 3). The calcineurin inhibitors tacrolimus and cyclosporine form the cornerstone of therapy, but they also pose the greatest challenges with respect to safe and tolerable administration.

Table 3

The bioavailability of these agents is poor and unpredictable, requiring frequent monitoring of trough blood levels to ensure appropriate dosing. These agents are metabolized via the hepatic cytochrome P450 enzyme system, and blood levels are affected by concurrent administration of other drugs that up- or down-regulate this pathway. Nephrotoxicity that is due to calcineurin inhibitors is nearly universal.

Post-transplant Management: Medical Comorbidities

In addition to specific issues related to maintenance and monitoring of lung allograft health, management of medical comorbidities is an essential component in the care of lung transplant recipients. In particular, the immunosuppressive agents administered post-transplantation often exacerbate pre-existing medical conditions or lead to their de novo development. Common medical issues encountered include osteoporosis, hypertension, chronic kidney disease, coronary artery disease, diabetes mellitus, gastroparesis, gastroesophageal reflux disease, and hyperlipidemia.

Interpretation of Results

Not applicable

Performance characteristics of the procedure (applies only to diagnostic procedures)

Not applicable

Outcomes

Survival

Current survival rates following lung transplantation are 79 percent at one year, 63 percent at three years, 52 percent at five years, and 29 percent at ten years, with a median survival of 5.7 years. Although one-year survival approximates that of heart and liver transplant recipients, five-year survival remains considerably below the 75 percent rate associated with these other procedures. Mortality is highest in the first post-transplant year, with primary graft dysfunction and infection the leading causes of early deaths. Beyond the first year, bronchiolits obliterans syndrome and infection account for the majority of deaths.

The limitations on long-term survival following lung transplantation have raised the important question of whether and for whom transplant actually confers a survival advantage over the natural history of the underlying lung disease. In the absence of randomized trials, this question has been addressed by using statistical modeling to compare observed post-transplant survival to survival of wait-listed patients or by simulating survival with and without transplantation using predictive equations.

In the case of IPF, a disease associated with a median survival of only four or five years, studies have consistently suggested that lung transplantation confers a survival advantage.

For the CF population, studies have suggested that only adults who have a predicted five-year natural history survival of less than 50 percent and who do not have Burkholderia cepaciaor CF-associated arthropathy are likely to derive a survival advantage from transplantation. While controversial, some studies have suggested that lung transplantation rarely confers a survival advantage for CF patients under age eighteen.

Since long-term survival is possible even in the advanced stages of COPD, it is not surprising that studies have yielded conflicting results on whether lung transplantation confers a survival advantage in this population.

Pulmonary Function

Pulmonary function tends to peak 3-6 months following transplantation, as the adverse effects of post-operative pain, weakness, and initial graft injury subside. Recipients of BLT tend to achieve normal spirometric parameters, while SLT recipients experience marked but incomplete improvement, with FEV1 typically reaching 50-60 percent predicted. Oxygenation improves rapidly, permitting the majority of patients to be weaned off of supplemental oxygen during the first post-transplant week. Hypercapnia can take longer to resolve because of residual impairment of central respiratory drive.

Exercise Capacity

The majority of lung transplant recipients achieve functional independence and can resume an active lifestyle. On average, BLT recipients demonstrate greater improvement in six-minute walk test distance than SLT recipients do, but this may reflect, at least in part, the generally younger age of BLT recipients. Differences in peak exercise performance assessed by cardiopulmonary exercise testing are less apparent. Specifically, both SLT and BLT recipients typically achieve a maximum oxygen consumption of 40-60 percent predicted.

Suboptimal peak exercise performance persists in recipients tested as late as two years following transplantation, suggesting that deconditioning is not likely playing a major role. Characteristically, breathing reserve, oxygen saturation, and heart rate reserve remain normal at the time that exercise is terminated, while anaerobic threshold is reduced, a pattern suggestive of skeletal muscle dysfunction. Several studies have suggested that calcineurin inhibitors impair muscle mitochondrial respiration and account for the limitation in peak exercise performance.

Hemodynamics

Elevated pulmonary artery pressures normalize almost immediately following transplantation; their failure to do so suggests the presence of significant acute lung injury or pulmonary arterial or venous anastomotic narrowing. With normalization of pulmonary pressures, right ventricular geometry and performance normalize more gradually. A threshold of pre-transplant right ventricular dysfunction, below which recovery is unlikely, has yet to be defined.

Alternative and/or additional procedures to consider

Not applicable

Complications and their management

This section highlights the most common complications following lung transplantation. More detailed discussions of infectious and noninfectious complications are discussed in chapters 4398 and 4372, respectively.

Infectious Complications

Bacterial pneumonia is a common complication encountered in the early post-transplant period. Pseudomonas aeruginosa and Staphylococcus aureus are responsible for the majority of these infections. Bacterial infections in the lower respiratory tract in the form of purulent bronchitis, bronchiectasis, and pneumonia re-emerge as a late complication in patients who develop bronchiolitis obliterans syndrome (BOS).

Cytomegalovirus (CMV) predominates as the most common viral pathogen. Infection can result from acquisition of virus from the donor or from reactivation of latent infection remotely acquired by the recipient. Seronegative recipients who receive lungs from seropositive donors are at greatest risk for CMV infection, and it is these primary infections that tend to be the most severe. Administration of valganciclovir for the initial 6-12 months following transplantation has been shown to be an effective prophylactic strategy for these recipients, as well as for seropositive recipients.

CMV infections can be asymptomatic; when clinically apparent, they can present with generalized symptoms of fever and malaise, or with organ-specific symptoms reflecting involvement of the lungs, gastrointestinal tract, or central nervous system. Treatment consists of a several week course of Intravenous ganciclovir or, in milder cases, valganciclovir.

Lung transplant recipients are uniquely predisposed to aspergillus infection of the bronchial anastomosis and the bronchial mucusa. These airway infections usually respond to treatment with voriconazole or a related azole, but they can occasionally lead to anastomotic strictures or, rarely, to formation of a bronchial-to-pulmonary-artery fistula with massive hemoptysis.

Invasive aspergillosis is a far more serious form of infection. Most cases involve the lung parenchyma, presenting as one or multiple nodular or cavitary opacities on chest x-ray and CT. Extrapulmonary and disseminated disease may accompany primary pulmonary infection or may occur independently. Voriconazole is the treatment of choice, while echinocandins and lipid formulations of amphotericin B are second-line agents. Despite the availability of these agents, invasive aspergillosis is associated with a 60 percent mortality rate in the lung transplant population.

Non-Infectious Complications

Primary graft dysfunction (PGD). PGD is a form of acute allograft injury characterized by the development of non-cardiogenic pulmonary edema within seventy-two hours of transplantation in the absence of identifiable secondary causes like volume overload, aspiration, pulmonary venous outflow obstruction, or hyperacute rejection. PGD is thought to be a consequence of ischemia-reperfusion injury, but inflammatory events associated with donor brain death, surgical trauma, and lymphatic disruption may be contributing factors. In most cases, the injury is mild and transient, but in approximately 10 percent of cases, hypoxemia is severe and the course is protracted. Mortality associated with severe PGD is in the range of 30-40 percent.

Airway Complications. Dehiscence of the bronchial anastomosis is an uncommon early complication. Mild forms are often asymptomatic and are noted only on surveillance bronchoscopy. More extensive dehiscence, heralded by spontaneous pneumothorax or pneumomediastinum, can be lethal if it is progressive. Treatment includes chest tube evacuation of pneumothoraces, prophylactic antibiotics to prevent mediastinitis, and reduction of corticosteroids to facilitate healing. In severe cases, bare metal bronchial stents can be inserted across the dehiscence in an attempt to induce formation of granulation tissue.

The most common airway complication is bronchial stenosis that is due to fibrous stricture, excessive granulation tissue, or bronchomalacia. Bronchial stenosis typically occurs at the site of the bronchial anastomosis, but fibrous strictures can also involve more distal airways. Most cases can be managed with balloon dilatation, laser debridement, and stent placement via fiberoptic or rigid bronchoscopy.

Acute rejection (AR). AR commonly occurs in the first post-transplant year, with the frequency declining markedly beyond this point. AR is clinically silent in up to 40 percent of cases, detected only on surveillance biopsies. When clinically overt, symptoms include low-grade fever, dyspnea, and cough. Accompanying features include a decline in oxygenation and spirometric parameters, and the presence of opacities on chest x-ray and chest CT.

Transbronchial lung biopsy, the gold standard for diagnosis, demonstrates perivascular lymphocytic infiltrates that, in severe cases, spill over into the adjacent interstitium and alveolar airspaces. Treatment consists of high-dose corticosteroids, typically administered as a three-day pulse of intravenous solumedrol. This treatment usually leads to rapid improvement in symptoms, pulmonary function, and radiographic abnormalities, although follow-up biopsies demonstrate persistent rejection in up to a quarter of patients.

Bronchiolitis obliterans syndrome (BOS). BOS is characterized by the development of progressive and largely irreversible airflow obstruction. Because the underlying fibroproliferative obliteration of the small airways is difficult to demonstrate by transbronchial lung biopsy, the diagnosis of BOS relies on an otherwise unexplained and sustained fall in FEV1 below post-transplant baseline. Recurrent or severe episodes of AR are the major risk factor for subsequent development of BOS, which has led to the notion that BOS is a form of chronic allograft rejection. However, a number of non-immunological insults, including aspiration, community-acquired respiratory infections, CMV pneumonitis, and PGD, have also been identified as risk factors.

BOS is uncommon in the first post-transplant year, but there is a steady rise in its prevalence beyond this point. Once BOS is present, its course is highly variable, with some patients experiencing rapid decline in lung function over weeks to months and others experiencing prolonged periods of stability. Treatment once involved augmentation of immunosuppression, but there is no convincing evidence that this treatment is effective. More recently, interest has focused on the use of macrolides, based on the ability of these agents to suppress airway inflammation. Several retrospective studies have documented short-term improvement in FEV1 in approximately 30-40 percent of BOS patients treated with azithromycin, although this benefit was often transient. BOS is the major cause of late allograft failure and recipient death, and it is the leading indication for retransplantation.

What’s the evidence?

Angel, LF, Levine, DJ, Restrepo, MI. "Impact of a lung transplantation donor-management protocol on lung donation and recipient outcomes.". Am J Respir Crit Care Med. vol. 174. 2006. pp. 710-716.

(A prospective study demonstrating the favorable impact of implementing a standardized lung donor management protocol on lung harvest rates.)

Christie, JD, Edwards, LB, Kucheryavaya, AY. "The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult lung and heart-lung transplant report - 2010". J Heart Lung Transplant. vol. 29. 2010. pp. 1104-1118.

(An international registry that provides extensive statistics on more than 32,000 lung transplants and more than 3500 heart-lung transplants since 1985.)

Cypel, M, Yeung, JC, Liu, M. "Normothermic ex vivo lung perfusion in clinical lung transplantation". N Engl J Med. vol. 364. 2011. pp. 1431-1440.

(Documents experience at the University of Toronto with twenty transplants performed using lungs reconditioned via ex vivo perfusion prior to implantation.)

DeOliveira, NC, Osaki, S, Maloney, JD. "Lung transplantation with donation after cardiac death donors: long-term follow-up in a single center". J Thorac Cardiovasc Surg. vol. 139. 2010. pp. 1306-1315.

(Study of eighteen recipients of lungs from DCD donors.)

Kotloff, RM. "Does lung transplantation confer a survival benefit?". Current Opin Organ Transplant. vol. 14. 2009. pp. 499-503.

((Review of disease-specific studies that have compared natural history survival with post-transplant survival.)

Liou, TG, Adler, FR, Cox, DR, Cahill, BC. "Lung transplantation and survival in children with cystic fibrosis". N Engl J Med. vol. 357. 2007. pp. 2143-2152.

(This study, which employs proportional hazards survival modeling to examine the effect of transplant on survival in the pediatric CF population, concludes that pediatric CF recipients rarely derive a survival benefit.)

Liou, TG, Adler, FR, Huang, D. "Use of lung transplantation survival models to refine patient selection in cystic fibrosis". Am J Respir Crit Care Med. vol. 171. 2005. pp. 1053-1059.

(Uses survival models to define the characteristics of CF patients most likely to derive a survival benefit from lung transplantation.)

Mascia, L, Pasero, D, Slutsky, AS. "Effect of a lung protective strategy for organ donors on eligibility and availability of lungs for transplantation: a randomized controlled trial". JAMA. vol. 304. 2010. pp. 2620-2627.

(Demonstrates increased lung-harvest rates among donors ventilated with low tidal volume/high PEEP compared to donors ventilated with conventional settings.)

Mason, DP, Thuita, L, Nowicki, ER. "Should lung transplantation be performed for patients on mechanical respiratory support? The US experience". J Thorac Cardiovasc Surg. vol. 139. 2010. pp. 765-773.

(Documents the outcomes of lung transplant recipients who were on mechanical ventilation or extracorporeal membrane oxygenator support prior to transplantation.)

Orens, JB, Estenne, M, Arcasoy, S. "International guidelines for the selection of lung transplant candidates: 2006 update - a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation". J Heart Lung Transplant. vol. 25. 2006. pp. 745-755.

(Provides general and disease-specific selection criteria and guidelines for when patients should be referred and listed for lung transplantation.)

Russo, MJ, Iribarne, A, Hong, KN. "High lung allocation score is associated with increased morbidity and mortality following transplantation". Chest. vol. 37. 2010. pp. 651-657.

(This examination of the relationship between lung allocation scores and outcomes demonstrates significantly higher mortality and morbidity among patients with high lung allocation scores.)

Thabut, G, Ravaud, P, Christie, J. "Determinants of the survival benefit of lung transplantation in COPD patients". Am J Respir Crit Care Med. vol. 177. 2008. pp. 1156-1163.

(Defines the characteristics of COPD patients who are most likely to derive a survival benefit from lung transplantation.)

Thabut, G, Christie, JD, Ravaud, P. "Survival after bilateral versus single lung transplantation for idiopathic pulmonary fibrosis". Ann Intern Med. vol. 151. 2009. pp. 767-774.

((Demonstrates that overall survival following single and bilateral transplantation for IPF is similar.)

Van Raemdonck, D, Neyrinck, A, Verleden, GM. "Lung donor selection and management". Proc Am Thorac Soc. vol. 6. 2009. pp. 28-38.

(Summarizes the experience of using both standard criteria and extended criteria lung donors.)

Yusen, RD, Shearon, TH, Qian, Y. "Lung transplantation in the United States, 1999-2008". Am J Transplant. 2010. pp. 1047-1068.

(Provides extensive statistics on lung transplants performed in the US over a ten-year period and examines the impact of the new allocation system on composition of the waiting list, recipient characteristics, and outcomes.)
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