You are in: eMedicine Specialties > Transplantation > Surgery Lung TransplantationArticle Last Updated: Jun 24, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St. Boniface General Hospital Sat Sharma is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association Coauthor(s): Helmut Unruh, MD, Director, Manitoba Lung Transplant Program; Head, Section of Thoracic Surgery, Director of Research, Department of Surgery, University of Manitoba, Winnipeg, Canada Editors: Jeffrey C Milliken, MD, Chief, Division of Cardiothoracic Surgery, University of California at Irvine Medical Center; Clinical Professor, Department of Surgery, University of California at Irvine School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Shreekanth V Karwande, MBBS, Chair, Professor, Department of Surgery, Division of Cardiothoracic Surgery, University of Utah School of Medicine and Medical Center; Michael E Zevitz, MD, Assistant Professor of Medicine, Finch University of the Health Sciences, The Chicago Medical School; Consulting Staff, Private Practice; Mary C Mancini, MD, PhD, Director of Cardiothoracic Transplantation, Professor, Department of Surgery, Louisiana State University Health Sciences Center Author and Editor Disclosure Synonyms and related keywords: lung transplants, end-stage pulmonary disease, chronic obstructive pulmonary disease, COPD, cystic fibrosis, CF INTRODUCTIONSection 2 of 11
  Lung transplantation is a life-preserving therapeutic intervention for a variety of end-stage pulmonary diseases that has been used successfully for the past 20 years. Since the early 1990s, more than 6400 lung transplants have been performed, and lung transplant programs exist in many countries. The agency for health care policy and research in the United States has concluded that "lung transplantation has evolved as a clinical procedure achieving a favorable risk-benefit ratio and acceptable 1- and 2-year survival rates." For excellent patient education resources, visit eMedicine's Lung and Airway Center and Procedures Center. Also, see eMedicine's patient education articles Heart and Lung Transplant and Bronchoscopy. History of the ProcedureAnimal experimentation by various pioneers, including Demikhov and Metras, in 1940s and 1950s demonstrated that the procedure is feasible technically. Hardy performed the first human lung transplantation in 1963. Following a left lung transplantation, the patient survived for 18 days. From 1963-1978, multiple attempts at lung transplantation failed because of rejection and problems with anastomotic bronchial healing. In the 1980s, the introduction of cyclosporin A, a powerful immunosuppressant, generated renewed interest in the area of organ transplantation, including lung transplantation. Alternative techniques for improving bronchial healing were devised. These techniques included refining the bronchial–pulmonary collateral circulation by limiting the length of the donor bronchus and revascularizing the bronchial circulation extrinsically by wrapping the anastomosis with omentum or a pericardial patch in early years. This step now largely has been discontinued as recognition of the importance of rejection in bronchial healing has been established. Combined heart–lung transplantation was performed at Stanford University in 1981 on a patient with primary pulmonary hypertension. The Toronto transplant group reported successful single-lung transplantation (SLT) in 1986 on 2 patients with pulmonary fibrosis. INDICATIONSSection 3 of 11
Patients with end-stage pulmonary disease should be considered for potential lung transplantation if they meet the following criteria:
Preoperative Evaluation of Specific DiseasesThe appropriate timing for referral to a transplant program is based on the patient's functional status and life expectancy. A symptomatic patient who is New York Heart Association (NYHA) class III or has a life expectancy of 1-2 years should be referred for a transplant assessment. The natural history of the specific pulmonary diseases and the knowledge of survival outcome following transplant surgery help the transplant team determine the appropriate timing for placing a patient on a waiting list. Obstructive airway diseases In patients with emphysema, survival has improved significantly with long-term oxygen therapy. Forced expiratory volume in 1 second (FEV1) of less than 30% predicted is associated with a 60-80% 2-year survival rate; therefore, lung transplantation should be offered to patients with emphysema who have an FEV1 substantially less than 30% predicted (ie, 20% of predicted). Associated factors considered are hypoxemia and hypercapnia, weight loss, frequent hospitalizations, and repeated exacerbations. Restrictive lung diseases The natural history of various interstitial diseases is quite variable. Idiopathic pulmonary fibrosis is associated with a median survival of approximately 5 years from the time of diagnosis. Lack of response to steroid therapy and a forced vital capacity (FVC) of less than 67% predicted are associated with a 50% survival rate at 2 years. Total lung capacity (TLC) of less than 60% predicted is another indicator of poor survival; 60% of these patients die within 2 years. Therefore, severe restrictive disease, hypoxemia, and poor performance status are the criteria used for transplant considerations. Pulmonary vascular diseases The median survival for patients with primary pulmonary hypertension is 2.8 years. The indicators of poor survival are NYHA functional class III or IV, elevated mean right atrial pressure, elevated mean pulmonary arterial pressure and decreased cardiac index, and reduced diffusion. Mean pulmonary arterial pressure of greater than 85 mm Hg is associated with a median survival of less than 12 months. A response to vasodilator therapy is associated with improved survival. Present treatment of choice for NYHA class III and IV patients with pulmonary hypertension is long-term prostacyclin therapy, especially if they fail to demonstrate vasoreactivity during formal vasodilator trial. Prostacyclin has demonstrated improved survival, improved exercise capacity, and better quality of life. Transplant is indicated only if the patients cannot tolerate or fail prostacyclin therapy. In patients who have developed severe right heart failure, the right heart pressures and functions return to near normal values following lung transplantation alone. Cystic fibrosis and bronchiectasis These patients develop a high risk of mortality when their FEV1 decreases to 30% or less. At this level of FEV, the mortality rate increases to 45% at 2 years. Other indicators of poor prognosis are weight loss, pneumothoraces, frequent hospitalization, and hemoptysis. These patients require bilateral lung transplantation, which may require a longer wait than SLT. Recently, Theodore Liou and colleagues have validated a 5-year survivorship model for cystic fibrosis. This model identified 8 characteristics in addition to FEV1 as a percentage of predicted normal values to accurately predict survival in patients with cystic fibrosis. The other variables included age, gender, weight-for-age z-score, pancreatic insufficiency, diabetes mellitus, infection with Staphylococcus aureus, infection with Burkholderia cepacia, and annual number of acute pulmonary exacerbations.1 The authors also have developed 2 worksheets, which help calculate weight-for-age z-score and 5-year predicted survival. This survivorship model has potential for use in investigating the effect of novel therapies and assignment of patients on lung transplantation waiting list. Guidelines for Timing ReferralsPatients should be referred for transplantation at a point in the course of their disease at which death is considered likely within several years, such that transplantation is expected to confer a survival advantage. Poor quality of life is an additional consideration. The following guidelines are adapted from Trulock.2
CONTRAINDICATIONSSection 4 of 11
The absolute contraindications are as follows:
The lung transplant team evaluates each referral in view of potential risks and benefits to the patient and the ability and experience of the individuals at the transplant center. Some of the issues related to contraindications are discussed as follows:
WORKUPSection 5 of 11
Imaging Studies
TREATMENTSection 6 of 11
Medical TherapyInducing a state of immune suppression is the key to successful clinical lung transplantation. The immunosuppressive regimens used for lung transplantation are based on the successful protocols that have evolved for renal and heart transplantation. Most centers use a combination of cyclosporin A, azathioprine, and glucocorticoids as the 3-drug regimen for immunosuppression. Cyclosporin A Cyclosporin A is the most important immunosuppressive agent for lung transplantation. Intravenous administration usually is begun before the graft is implanted and then is continued postoperatively. Subsequent conversion to oral dosing is completed when gastrointestinal function is normal. Serum levels of 300-400 mg/mL usually are maintained for the first month, and, thereafter, levels of 150-200 mg/mL are considered therapeutic. Nephrotoxicity, the major adverse effect of cyclosporin, results from vasoconstriction of the afferent glomerular arterioles. Azathioprine Azathioprine is a purine analog that is converted to several active metabolites, including 6-mercaptopurine. These metabolites have inhibitory effects on the hematologic proliferation of T cells and B cells. Azathioprine is begun at a dosage of 2-2.5 mg/kg/d, and the dose is adjusted to maintain a WBC count of no less than 4000 cells/mm3. Corticosteroids Corticosteroids have a variety of effects on the immune system, primarily mediated by their interaction with a high-affinity cytoplasmic steroid receptor. Prednisone, prednisolone, and methylprednisolone all are used for transplant patients. Intraoperatively, methylprednisolone is administered prior to the reperfusion of the grafted lung. Postoperatively, moderate doses of corticosteroids in combination with cyclosporin A and azathioprine are used for the induction of immunosuppression. An oral dose of prednisone at 0.5 mg/kg/d usually is begun 5-7 days postoperatively. Antilymphocyte antibody preparations Antilymphocyte antibody preparations, the so-called cytolytic therapies, have been used in patients undergoing clinical lung transplantation. These preparations include antilymphocyte globulin, antithymocyte globulin, and a murine monoclonal antibody to the cluster of differentiation (CD) 3 complex of human lymphocyte (OKT3). The use of these agents generally is reserved for the treatment of refractory acute rejection, although their early use as induction agent is under investigation. Tacrolimus Tacrolimus (FK-506) is a macrolide compound with a mechanism of action similar to that of cyclosporin A through an immunophilin protein called the FK-binding protein. Tacrolimus has been used for induction immunosuppression as part of a 3-drug regimen with azathioprine and steroids and as a rescue therapy for patients with acute rejection that is unresponsive to the standard the 3-drug regimen. Toxicity is similar to that of cyclosporin and includes reversible renal dysfunction, hypertension, and neurotoxicity. Mycophenolate mofetil Mycophenolate mofetil (MMF) is a second-line immunosuppressive agent that may be used as an alternative to azathioprine in solid organ transplantation. The mechanism of action of MMF is via selective inhibition of T and B cell proliferation. MMF blocks de novo purine biosynthesis, a step that is required for the lymphocyte cell division. Increased selectivity and decreased toxicity of MMF is because T and B lymphocytes use only de novo pathway in purine biosynthesis, whereas, other cell lines that use both de novo and salvage pathways are not inhibited. Several prospective randomized trials have demonstrated a significant reduction in episodes of acute rejection with MMF compared with azathioprine in renal transplant recipients. Use of MMF also has shown comparable efficacy to azathioprine in reducing acute rejection in heart transplant patients.3 A few cohort studies have reported that patients treated with MMF experienced fewer acute rejection episodes in lung transplant recipients over a 12-month period.4 A recent multicenter, prospective, randomized trial of MMF versus azathioprine, demonstrated a comparable efficacy of these 2 agents in reducing episodes of acute rejection at 6 months of follow-up. Patients treated with MMF developed less frequent cytomegalovirus (CMV) infections, although other adverse events leading to discontinuation of medication were more frequent. Additional clinical trials are required to evaluate efficacy of MMF in reducing obliterative bronchiolitis and improvement in long-term survival. The usual dosing schedule is 1 g PO bid; the dose is titrated to maintain the white blood cell count more than 4000 cells/mm3. Nitric oxide Inhaled nitric oxide modulates pulmonary vascular tone via smooth muscle relaxation and can improve ventilation/perfusion matching and oxygenation in diseased lungs. The perioperative administration of inhaled nitric oxide may be beneficial in patients undergoing SLT and for patients who have severe pulmonary arterial hypertension. Administration of nitric oxide in the postoperative period for severe allograft dysfunction resulted in improved pulmonary hemodynamics.5 Nitric oxide has been demonstrated to produce reduced pulmonary vascular resistance, reduced mean pulmonary artery pressure, and significantly improved the PaO2/FiO2 ratio in severe postoperative allograft dysfunction. Early graft failure following lung transplantation has been described by various investigators as reimplantation edema, reperfusion edema, primary graft failure, or allograft dysfunction. Pathologically, this entity is diffuse alveolar damage. The clinical manifestations are those of noncardiogenic edema and include abnormal gas exchange, as well as hemodynamic alterations. This serious complication likely is caused by ischemia/reperfusion injury to the graft. The ischemia/reperfusion injury recruits polymorphonuclear neutrophils in the lung; their activation releases cytotoxic mediators and free oxygen molecules. Nitric oxide modulates ischemia/reperfusion injury by limiting the generation of superoxide anions and interfering with the neutrophil function and protecting against reactive oxygen species. Therefore, nitric oxide or a combination of nitric oxide and pentoxifylline administered before and throughout reperfusion are protective against ischemia/reperfusion injury. A recent retrospective publication demonstrated marked reduction in the mortality rate in the nitric oxide-pentoxifylline group versus the controlled group (4.3% versus 26%).6 Current approach to immunosuppressive therapy The induction therapy after lung transplantation may reduce and delay acute rejection episodes and may also reduce the incidence of chronic rejection. Unfortunately, no large, prospective, randomized, placebo-controlled trials exist to confirm the benefits of induction therapy compared with conventional immunosuppression and to compare different agents. Current evidence suggests that the induction with antithymocyte globulin seems to be the optimal choice, induction with OKT3 is likely less safe, and more data on induction with anti-interleukin-2 receptor monoclonal antibodies should be obtained. Maintenance therapy with triple-drug therapy is still the conventional practice lung transplantation. Careful therapeutic drug-monitoring strategies for cyclosporine A will hopefully result in less toxicity and better immunosuppression. Whether primary tacrolimus maintenance therapy may result in better prevention of acute and chronic rejection than cyclosporine A and whether tacrolimus is comparable to azathioprine or to mycophenolate are still unknown. This drug does not have definite benefits over azathioprine. Weaning of steroids is generally practiced but cannot be advocated for every lung transplant recipient. The first-line treatment of an episode of acute rejection is high-dose intravenous steroid pulses. For ongoing or recurrent acute rejection, the strategy is to switch from cyclosporine to tacrolimus. The second choice for refractory acute rejection is treatment with antithrombocyte globulin (ATG) or OKT3. In refractory cases, high-dose intravenous immune globulin could be worth a try. For treatment of chronic rejection, the most difficult issue following lung transplantation remains unsettled. Patients taking a cyclosporine A regimen who are diagnosed with branchio-otorenal (BOR) syndrome should be switched to tacrolimus from cyclosporine for at least 3–6 months. No evidence supports a switch from azathioprine to mycophenolate in chronic rejection. For patients unresponsive to the change to tacrolimus from cyclosporine A, high-dose steroid pulses and ATG are still frequently used. Other possible therapies are total lymphoid irradiation and photopheresis, which are really a last resort. Recent studies have shown that tacrolimus is an effective therapeutic alternative to cyclosporine for primary immunosuppression in heart or lung transplantation. The prophylaxis for acute rejection is equivalent and may have a beneficial result on chronic rejection. The enhanced immunosuppressive activity of tacrolimus is achieved without increased risk of infection or malignancy. Therefore, tacrolimus and cyclosporine may be used based on adverse effects and failure of effect in different patients, as clinically determined. Surgical TherapyCertain features of the transplant center are associated with enhanced success. Experience has shown that transplant success correlates with the number of procedures performed at the center. Features that generally are accepted as desirable of a good program include the following:
Donor-related issues The donor selection criteria may vary from center to center, and the general guidelines that are used are listed below. Most transplant centers will use lungs from a donor who is positive for CMV for transplant into a donor who is not positive for CMV, but postoperative CMV prophylaxis will be required if this happens. Other acceptable donor criteria are as follows:
Recipient-related issues The overall goal of recipient selection is to identify individuals whose pulmonary function and prognosis justify transplantation. Present general guidelines for the selection of potential recipients are as follows:
Waiting list for lung transplantation The United Network for Organ Sharing allows preference to the patients on the transplant list who have been waiting longer than others. On average, a recipient waits 1 year or longer. According to the US Department of Health and Human Services, the median wait in 1995 was 553 days. Patients waiting for a single lung for transplantation have the shortest waiting time when compared to bilateral sequential transplantation or heart-lung transplantation. Because of the rather poor prognosis in patients with idiopathic pulmonary fibrosis, these patients receive a credit of 90 days while waiting for the lung transplantation. In 1994, patients who were waiting on the United Network transplant list had a mortality rate of 14%, but this has been estimated to be as high as 30%. Preoperative DetailsLung transplantation is a rapidly evolving field; therefore, a dogmatic approach cannot be recommended. Various issues that must be considered when choosing the procedure include the shortage of organ donors, the etiology of the original disease, and the center's experience with graft and patient survival. General guidelines for the selection of the procedure are based on the nature of the original disease and have been adapted from Egan et al, as follows:
Other factors that must be taken into account on an individual basis are ventilator dependence, previous cardiovascular thoracic surgery, and preexisting medical conditions (eg, hypertension, diabetes mellitus, osteoporosis). The posttransplantation medical regimen can worsen these illnesses. A previous thoracic procedure alone rarely precludes lung transplantation; however, if cardiopulmonary bypass (CPB) is required for the transplant procedure, a potential for complications exists. With current surgical techniques, pretransplantation corticosteroid therapy has not been associated with airway complications, and a maintenance dose of prednisone (10-20 mg/d) is not a contraindication for transplantation. Despite the chronic infections that occur in patients with cystic fibrosis, the infectious complications after transplantation have been comparable between patients with cystic fibrosis and patients without cystic fibrosis. Posttransplant infection with B cepacia can be associated with high mortality rates; however, similar outcomes have been reported in recipients with or without infection with resistant Pseudomonas aeruginosa. In most cases of patients with a previous malignancy, a minimum wait of 5 years between treatment and transplantation is recommended. Many transplant candidates also have the risk factors for coronary artery disease; therefore, a cardiac workup (including coronary angiography) is performed commonly. Severe coronary artery disease is a contraindication to lung transplantation; however, coronary artery bypass grafting at the same time as lung transplantation has been performed with a reasonably good outcome in some centres. Less invasive preoperative interventions such as percutaneous transluminal coronary angioplasty and stenting is preferred. Donor selection and harvesting Criteria for lung donation identify donors with evidence of good gas exchange and an absence of infection of the airway or parenchyma. The donor lung should appear healthy on chest radiographs. Donor lungs should be within 25-30% of the predicted size of the recipient's lungs. Upon bronchoscopy, the finding of diffuse bronchial mucosal inflammation is a contraindication for harvesting. However, lungs with purulent secretions that cannot be cleared with bronchoscopy and without mucosal inflammation, in the presence of a clear chest radiograph and preserved gas exchange, are suitable for donation. Furthermore, intraoperative inspection of the pleural space and lung is performed to assess unsuspected trauma, bullous disease, or mass lesions. Criteria for brain death in a donor An irreversible cessation of all brain and brainstem function is defined as brain death in a potential donor. In 1981, the President's Commission formulated guidelines for determining death. Brain death is determined by clinical criteria when 2 separate examinations are performed 24 hours apart or by ancillary studies to assess brain activities. An absence of drugs, hypothermia, or metabolic derangements must be confirmed. Brain death criteria are as follows:
Lung preservation With the current techniques, satisfactory graft function can be obtained after an ischemic interval of as long as 6-8 hours. Ischemic injury to the pulmonary vascular endothelium increases permeability and results in pulmonary edema. Hypothermic flush perfusion is the method used most commonly for pulmonary preservation in clinical practice. After systemic heparinization of the donor, the pulmonary vasculature is flushed with a cold solution. Commonly used solutions are modified Euro-Collins solution, University of Wisconsin solution, and Perfadex. These are delivered via a large pulmonary artery cannula at a volume of 50-60 mL/kg over 4-5 minutes. Most flush solutions are administered at a temperature of 4°C, while topical cooling is carried out by filling the pleural cavity with iced crystalloid solution. The harvested lungs are immersed in crystalloid solution, packed in ice, and transported at a temperature of 1-4°C. The infusion and transport is performed during active ventilation and static inflation with O2 respectively. Allocation of organs In United States, the allocation of lungs is based principally on waiting time; severity of illness or medical urgency is not taken into account. The donors and recipients are matched on the basis of major blood groups, organ size, and CMV serologic status. Transplantation of lobes from living donors is a recently developed technique involving bilateral implantation of the lower lobes from 2 blood group–compatible living donors. The procedure has been performed in patients with cystic fibrosis, although the indications recently have been broadened. The functional and survival outcomes are similar to those achieved with conventional transplantation of cadaveric lungs. Donation of a lobe decreases the donor's lung volume by an average of approximately 15% and, consequently, is not associated with long-term functional limitation. Intraoperative DetailsAnesthetic management An understanding of the physiology of the various lung transplant recipients with different disease states leads to greater insight into perioperative ventilator management. All lung transplantation procedures should be performed with CPB available on standby. If CPB is required, the routine use of aprotinin infusion has resulted in reduced postoperative hemorrhage. Aprotinin, an antifibrinolytic agent used to reduce operative blood loss in patients undergoing open heart surgery, is now only available via a limited-access protocol. Fergusson et al reported an increased risk for death compared with tranexamic acid or aminocaproic acid in high-risk cardiac surgery.7 Click here for more information and to complete a Medscape CME activity on this subject. Single-lung transplantation For SLT, the native lung with the poorest pulmonary function according to the preoperative quantitative perfusion scan is excised. If both the lungs have similar function, the right side is preferred because surgical exposure and instituting CPB (if required) is easier. The lung is exposed via a generous posterolateral thoracotomy through the fifth intercostal space. The ipsilateral groin is included in the surgical field in the event that cannulation of the heart via the chest is not possible and femoral vessels are required for partial CPB. Following excision of the native lung, the donor lung is wrapped in sponges soaked with cold crystalloid solution and placed into the hemithorax. The bronchial anastomosis is performed first. Although several techniques have been described, the length of both the donor and recipient bronchi is minimized in order to preserve collateral blood supply and to achieve some degree of anastomotic overlap. The smaller bronchus is telescoped into the larger bronchus with either a technique of interrupted sutures or a combination of running sutures on the membranous layer and interrupted sutures externally. The anastomosis is covered by local peribronchial tissue, pedicle flaps of thymic tissue, or pericardial fat. The pulmonary artery anastomosis of the donor and recipient vessels requires careful approximation to avoid kinking. For the left atrial anastomosis, the confluence of the recipient pulmonary veins is incised to create a left atrial cuff. After completion of these anastomoses, the lung is reinflated gently; the perfusion is reestablished after evacuating air via the left atrial suture line. Following resumption of ventilation to the donor lung, the suture lines are secured. Hemostasis is obtained, 2 chest tubes are placed, and the chest is closed in a standard fashion. Following reintubation with a single lumen tube, flexible bronchoscopy is performed to inspect the bronchial anastomosis and clear the airway of blood or residual secretions. Pulmonary vein augmentation for single-lung transplantation Donor harvesting procedure requires careful surgical technique to preserve an adequate donor left atrial cuff around the confluence of the superior and inferior pulmonary veins. The surgeon divides the donor left atrium halfway between the left venous confluence and the coronary sinus. In some situations, especially when the heart and lungs are harvested separately, the donor lungs are left with little or no atrial tissue around the venous confluence. Construction of a neoatrial cuff from the divided edges of each of the 2 pulmonary veins ensures utilization of graft for transplantation. The newly formed cuff then is used for atrial anastomosis. This technique can be applied to the left or right lung and also can be applied to create an additional length of pulmonary artery. These simple but effective surgical techniques expand the donor availability for lung transplantation. Double-lung transplantation The most frequently performed double-lung transplantation (DLT) procedure actually is bilateral sequential SLT. This procedure is associated with a significantly lower incidence of bronchial complications than the en-bloc DLT procedure and is technically less difficult to perform than en-bloc DLT. The exposure for bilateral sequential lung transplantation is via bilateral anterolateral thoracotomies through the fourth or fifth intercostal space, connected by a transverse sternotomy, ie, the "clam-shell" incision. Generally, the entire incision is made at the beginning of the procedure, and both lungs are mobilized completely. For patients with emphysema who undergo DLT, the contralateral hemithorax may be left closed until after the first lung graft is completed. Mobilization and pneumonectomy of the native lung and the implantation of the lung graft are conducted in the same manner as described for SLT. Thymic and anterior mediastinal tissue may be mobilized to cover the bronchial anastomosis. Heart-lung transplantation Either a standard median sternotomy or a clam-shell incision may be used for heart-lung transplantation. Following the institution of CPB, the lungs are removed by an extrapericardial approach, ie, incising and stapling of the bronchovascular structures at the pulmonary hila. The donor right atrium is incised from the inferior vena cava to the right atrial appendage. The right atrium is examined to exclude an atrial septal defect and for adequate closure of the superior vena cava. If a tracheal anastomosis is used, the posterior pericardium is incised between the ascending aorta and the superior vena cava to expose the distal trachea. Some centers prefer bilateral bronchial anastomosis using a telescoping technique as described for SLT. This approach avoids dissection in the posterior mediastinum and may be associated with fewer anastomotic complications. After the right atrial anastomosis is completed, the aortic anastomosis is performed. The aortic cross clamp is removed, and, after reinflation of the lungs, the heart is de-aired via the pulmonary artery and the left ventricle. The heart is defibrillated to begin circulation, and the patient is weaned from CPB. Postoperative DetailsThe postoperative period is the crucial time when unexpected complications may develop. Most centers follow the standard treatment protocols and monitor patients who have undergone transplantation at regular multidisciplinary rounds. Respiratory management Patients should be maintained on a nontoxic fraction of inspired oxygen, and barotrauma should be minimized. Volume control ventilation with a tidal volume of 8-10 mL/kg and a peak end-expiratory pressure (PEEP) of 5 cm H2O generally is instituted. The transplanted lung is susceptible to capillary leak in the postoperative period. Therefore, the pulmonary capillary wedge pressure should be kept lower to minimize the formation of low-pressure pulmonary edema. Aggressive diuresis while maintaining adequate cardiac output and tissue perfusion is recommended. Attention to bronchial hygiene is important. Frequent suctioning and bronchoscopy may be necessary for postoperative atelectasis in patients who have undergone lung transplant. Hyperinflation of the native lung may occur in patients with emphysema. This may lead to barotrauma and the development of air leaks that require chest tube placement. Phrenic nerve injury is known to occur in a significant number of patients. Unilateral phrenic nerve paralysis may compromise respiratory status to some extent, and bilateral phrenic nerve injury certainly would result in prolonged mechanical ventilation. In most patients, phrenic nerve palsy is transient and generally improves over the following weeks to months. Adequate postoperative analgesia is helpful in weaning these patients from the ventilator. Extubation is performed when the patient's mental status is normal and when the patient has achieved reasonable spontaneous ventilation and gas exchange, generally 48-72 hours following the procedure. In patients with significant pulmonary hypertension who undergo transplantation, a risk exists for the development of pulmonary edema in the donor lung. Hemodynamics Postoperative hypotension may be related to hypovolemia, sepsis, or vascular anastomotic complications. Left or right ventricular failure secondary to myocardial ischemia or infarction should be considered in the differential. Postoperative supraventricular dysrhythmias are common in the initial few weeks. The dysrhythmias may occur because of electrolyte abnormalities, hypervolemia, inotropic drugs, and secondary to intraoperative manipulation of the heart. The arrhythmias respond to routine management with digoxin and calcium channel blockers, and, sometimes, electrical cardioversion is performed if hemodynamic collapse is present. Postoperative gastrointestinal complications A paralytic ileus or gastroparesis may develop postoperatively. These may be related to electrolyte abnormalities, narcotics, or the effect of drugs. They improve following routine management. Postoperative renal complications Immunosuppressive agents, such as cyclosporin A and tacrolimus, are nephrotoxic. Their blood levels should be monitored in the postoperative phase. Fluid management The goal of fluid management after lung transplantation is to minimize edema formation in the transplanted lung while maintaining adequate cardiac function. The effects of ischemia and reperfusion injury and the absence of lymphatics all may contribute to the development of pulmonary edema. Pulmonary capillary wedge pressure should be kept as low as possible after surgery, without compromising ventricular preload and cardiac output. Antimicrobial therapy Bacterial prophylaxis against gram-positive organisms and a broad-spectrum antibiotics for the organisms identified preoperatively should be administered. Patients with cystic fibrosis require coverage for pseudomonal species, usually with antipseudomonal cephalosporin. Routine prophylaxis for fungal organisms is useful when the recipient's sputum cultures show the presence of Aspergillus. Herpes simplex infections have been eliminated by routine acyclovir prophylaxis after lung transplantation. CMV infection remains a significant problem following lung transplantation. The incidence of CMV infection after lung transplantation is related to the preoperative CMV status of both the donor and the recipient. The use of ganciclovir prophylaxis has reduced the incidence of primary disease significantly and has improved outcome. Pneumocystis carinii infection has been eliminated by the routine use of trimethoprim-sulfamethoxazole, which is administered 3 times per week following surgery. Nutrition Maintaining optimal nutrition in the postoperative period is beneficial for improving surgical outcome. When prolonged ventilatory support is required, the use of intravenous nutrition or enteral alimentation is mandatory. Surgical complications Major technical complications following lung transplantation are rare. Postoperative hemorrhage requiring exploration is uncommon, particularly with the routine use of aprotinin during CPB. Pulmonary artery obstruction can occur as a result of anastomotic stenosis, kinking, or extrinsic compression. Left atrial anastomotic obstruction also can occur because of faulty anastomotic technique or extrinsic compression by a clot, pericardium, or an omental flap. Acute graft dysfunction without evidence of vascular anastomotic complications has been described. The cause is not known, but unsuspected contusion or aspiration could be possible causes. Management includes evaluation of the vascular anastomosis and maintenance of oxygenation. Pleural space complications are not uncommon, but their occurrence is considered rare. Pneumothorax may occur on either side of the lung graft or on the side of the native lung. Pleural effusions are common after lung transplantation, particularly when a significant size disparity exists. Management of these effusions usually is conservative in nature, using diuretic therapy. Thoracentesis and tube drainage are indicated only if an effusion is complicated by pneumothorax or respiratory compromise. Airway complications have been significantly less common in the recent reports of lung transplantation. Because revascularization of the bronchial arterial circulation is not present, the donor bronchus must rely on collateral perfusion from the pulmonary circulation in the initial postimplementation period. Airway ischemia manifests as mucosal ulcerations followed by abnormalities that can range from anastomotic dehiscence to an anastomotic stenosis. However, present surgical techniques have limited the scope of these complications. Follow-upMonitoring and surveillance of the patient after the lung transplant procedure is divided into immediate, early, and late periods. Immediate postoperative period In the immediate postoperative period, the patient is monitored invasively with arterial, central venous, and Swan Ganz catheters. Chest radiographs are performed on a daily basis. Reperfusion injury is suggested by hypoxemia and diffuse infiltrates. A perfusion scan within the first week may provide additional assessment of the function of a single-lung graft. Routine immediate prophylaxis with antibiotics is performed. Patients with bronchiectasis or cystic fibrosis require antipseudomonal prophylaxis. Adequate pain control is important for aggressive chest physiotherapy and early rehabilitation of these individuals. Early postoperative period The first 3 months following transplantation is the early postoperative period. Daily chest radiographs are required in the first postoperative week. These are reduced in frequency according to the patient's clinical status. Spirometry is performed as soon as is practical after surgery, at predischarge, and periodically thereafter. Some centers have the patients perform daily home spirometry and report any drop in FEV1 of 5-10%. The FEV1, FVC, and diffusing capacity steadily rise in the lung transplant recipient during the first 3 months. Fiberoptic bronchoscopy and bronchoalveolar lavage are performed if the patient demonstrates new infiltrates on chest radiographs, a decrease in lung function on spirometry, or the presence of symptoms. At least 6 biopsies are obtained for adequate diagnosis of acute lung rejection. The role of routine transbronchial lung biopsy in an asymptomatic patient with stable lung function has not been defined adequately. However, most centers perform surveillance bronchoscopies and transbronchial biopsies in order to detect asymptomatic acute rejection. Acute rejections that are greater than A2 category are treated with enhanced immunosuppression. The overall utility of this practice has not been established in clinical trials. Late postoperative period Late monitoring is beyond 3 months following transplantation. Chronic rejection characterized by obliterative bronchiolitis commonly presents 6-18 months after transplantation. The diagnosis of obliterative bronchiolitis is based on physiologic and pathologic criteria. A sustained decrease in FEV1 generally is followed by fiberoptic bronchoscopy and transbronchial biopsy to exclude rejection. COMPLICATIONSSection 7 of 11
Reimplantation ResponseThe reimplantation response, ie, reperfusion edema, is felt to be a form of noncardiogenic pulmonary edema related to surgical trauma, organ ischemia, denervation, and lymphatic interruption. The condition occurs in more than 97% of transplanted lungs. Reimplantation response is a diagnosis of exclusion, ie, left ventricular failure, transplant rejection, fluid overload, and infection all must be excluded. The response almost always begins by the first day after the transplant and always is present by day 3. It frequently progresses over the first few days but peaks by day 4 or 5. Another etiology, such as infection or rejection, should be considered for any new process beginning after this time. Most patients have normal findings or only minimal residual abnormality by 10 days after the transplant. Graft DysfunctionEarly graft dysfunction occurs within the first 24 hours after the transplant. It occurs in fewer than 10% of cases and is characterized histologically by diffuse alveolar damage. The dysfunction usually is the result of severe donor lung ischemia, donor lung injury, or vascular anastomotic stenosis. Hyperacute rejection Hyperacute rejection occurs in cases of an immunoglobulin G donor-specific human leukocyte antigen (HLA) antibody-positive crossmatch and results in acute diffuse alveolar damage. Acute rejection Most patients develop at least one episode of rejection within the first 3 weeks following transplantation, typically in the first 5-10 days. Patients with rejection can develop dyspnea, fever, leukocytosis, and a widened alveolar-arterial oxygen gradient; however, patients with mild rejection can be asymptomatic. Pulmonary function testing may show a decrease in FEV1 and VC. Transbronchial biopsy usually is performed to establish the diagnosis and exclude infection (sensitivity 72-94%). Often, a dramatic response to treatment with corticosteroids and increased immunosuppression is observed within 24 hours. Pathologically, acute rejection initially manifests as a perivascular lymphocytic infiltrate. With progression, this infiltrate becomes more widespread and extends into the alveolar septa and, subsequently, into the alveoli. In approximately half the cases of rejection, the findings on chest radiograph are normal. If observed, the findings often are nonspecific, such as new, worsening, or persistent perihilar and basal reticular interstitial disease (ie, septal lines) and/or consolidations 5-10 days after the transplant. Findings observed on CT scans include ground-glass opacities, septal thickening, nodules, and consolidations. If findings are present, rejection can be confirmed by their rapid clearing, typically within 48 hours of steroid therapy. The infiltrates observed during the first week after the lung transplantation usually are caused by the reimplantation response (ie, reperfusion edema). Persistent infiltrates beyond the first week suggest infection or acute rejection. Infection during the first month after the transplant usually is bacterial in nature, and opportunistic infections become more common after that time. The presence of nodules on the chest radiograph results from infection, a PTLD, or a recent transbronchial biopsy. Pulmonary RejectionSolid organ rejection has been classified into 3 categories based on well-defined clinical and histologic features—hyperacute rejection, acute rejection, and chronic rejection. Hyperactive rejection Hyperacute rejection arises within minutes after the newly transplanted organ begins to be perfused. Hyperacute rejection is mediated through preexisting antibodies against ABO blood groups, HLAs, or other antigens that interact with vascular endothelium. These cause activation of complement and the other cytokines and also lead to cell-mediated injury. The grafted organ demonstrates intravascular thrombosis, necrosis of vessel walls, and preoperative infiltration with mononuclear and polymorphonuclear cells. ABO blood group matching and preoperative screening for antibodies against common antigens largely has eliminated this problem. Acute rejection Acute rejection is the host's response the host recognizes the graft as foreign. The elements of the major histocompatability complex (MHC) are the factors responsible for recognizing the grafted organ and initiating cell-mediated inflammation. Two major classes of HLA antigens exist, and these are divided into class I and class II. Class I are HLA-A, HLA-B, and HLA-C; these are expressed on nearly all cells. They interact with CD8+ and T cells. Class II antigens (HLA-DP, HLA-DQ, HLA-DR) are expressed on specific cells, such as B lymphocytes, mononuclear phagocytes, and dendritic cells. Acute rejection is diagnosed by clinical and histological criteria. The clinical criteria commonly are adopted for diagnosis in the early postoperative period. The features of acute rejection are dyspnea, fatigue, dry cough, low-grade fever, a decrease in oxygenation of greater than 10 mm Hg, the development of new or changing radiographic opacities, and a decrease in FEV1 of more than 10% below baseline value. Infections are the other most common differential diagnoses and cause significant morbidity in the early postoperative period; therefore, they must be excluded. Because the clinical criteria present later, when the acute rejection is more severe, they may be nonspecific in the early stages and many centers confirm the presence of rejection histologically. Acute rejection is classified into 5 grades based on the severity and extent of the perivascular lymphocytic infiltration. The range is from no significant abnormality (grade A0) to severe abnormality (grade A4), in which extensive involvement of the interstitium and air space is present over and above, pneumocyte damage is present, and vasculitis (and even parenchymal infarction) are present. The clinical course of acute rejection can be variable. Most individuals develop at least 1 episode of acute rejection within the first 3 months. A significant number of patients are asymptomatic and are diagnosed by surveillance transbronchial biopsy. Chest radiographs may be helpful because ill-defined perihilar and lower lobe opacities, along with septal lines and pleural effusions, may suggest acute rejection. Episodes of acute rejection are prevented by induction and maintenance of satisfactory immunosuppression. Most centers routinely use a triple immunosuppressive regimen, consisting of corticosteroids, azathioprine, and either cyclosporin A or tacrolimus. The mainstay of therapy for acute rejection is pulse intravenous methylprednisolone, followed by higher oral prednisone doses. Cyclosporin A and azathioprine are maximized. Methylprednisolone is used in a dose of 500-1000 mg/d intravenously, and oral prednisone is increased to 0.5-1 mg/kg/d with subsequent tapering. Steroid-resistant acute rejections may be treated with OKT3 therapy, which usually results in successful resolution of most cases of acute rejection. Obliterative bronchiolitis (chronic rejection) The incidence of obliterative bronchiolitis is highest during the first 2 years following lung transplantation. However, the risk of obliterative bronchiolitis may increase to 60-80% 5-10 years after the lung transplantation procedure. It is the most important complication that adversely affects the long-term survival of graft recipients. Symptoms occur secondary to the airflow obstruction that progresses over time. These patients develop exertional dyspnea, a nonproductive cough, wheezing, and/or low-grade fever. Although the symptoms resemble bronchial asthma, the limited response to bronchodilator and corticosteroid therapy makes these ineffective. Obliterative bronchiolitis has a variable course. The disease may be progressive, it may plateau, or it may progress gradually in a stepwise fashion. Therefore, early detection of this complication is paramount. Obliterative bronchiolitis is staged according to the level of airflow obstruction as measured by FEV1. Four stages are described, based on severity, from grade 0 to grade III, as follows:
Pathologically, bronchiolar inflammation and narrowing of the lumen are present, and bronchiectasis is present in larger airways. The active lesions demonstrate lymphocytic inflammation and the formation of granulation tissue. Fibrotic tissue compromises the airway lumen in a constrictive fashion. In advanced stages, collagen is deposited and fibrosis of the bronchiolar wall can cause occlusion of the lumen. The pathogenesis of obliterative bronchiolitis may be initiated by alloimmune and infectious inflammation of bronchiolar structures, followed by a fibroproliferative response. Diagnosis is confirmed by high-resolution CT (HRCT) scans and a complete battery of pulmonary function tests. HRCT scans demonstrate bronchiectasis, thickening of septal lines, hyperlucency, peribronchial and perivascular infiltrates, and mosaic attenuation of lung parenchyma. Because of the air trapped in different regions of the lung, the mosaic pattern is most prominent during expiratory images. Pulmonary function tests reveal expiratory airflow obstruction. A decrement in the FEV1 and FEV1-to-FVC ratio occurs. The diffusing capacity of lung volumes generally is maintained or may decrease slightly. Bronchoscopy and lung biopsy Transbronchial biopsies have a low sensitivity, documented to be 15-60%. For definitive diagnosis, an open lung biopsy may be required, although the diagnosis often is made clinically. Some patients (as many as 10%) may develop bronchiolitis obliterans–organizing pneumonia (BOOP). These patients typically present with a more rapid onset of hypoxemia. Chest radiographs in these patients reveal areas of consolidation. Patients respond to high-dose corticosteroid administration, which clears the radiographic abnormalities. Prevention and treatment Acute rejection is a major risk factor for obliterative bronchiolitis. Therefore, prevention of acute rejection likely leads to a decreased incidence of obliterative bronchiolitis. Some centers perform surveillance transbronchial biopsies during the first 2 years following transplantation. When the biopsies demonstrate acute rejection of grade II or higher, patients are treated with intensified immunosuppression. CMV infection also may be a risk factor for the development of obliterative bronchiolitis. Therefore, preventing CMV infection by transfusing CMV-negative blood products and using prophylactic ganciclovir may reduce the incidence of this devastating disease. Early detection of obliterative bronchiolitis in a preclinical stage is ideal so that aggressive attempts can be made to prevent a fully developed syndrome. However, to date, no particular marker to indicate obliterative bronchiolitis, either from the peripheral blood or bronchoalveolar lavage fluid, has predicted a risk for this disease. The treatment for established obliterative bronchiolitis has not proven to be effective. Treatment consists of administering additional immunosuppressive agents. High-dose intravenous methylprednisolone and antilymphocyte antibody preparations, including all OKT3 and ATG may stabilize the declining function of the lung. The newer medications, such as tacrolimus or methotrexate, may be prescribed for individuals who do not respond to the other immunosuppressives. Other experimental therapies, such as using Rapamycin, are undergoing clinical trials presently. Airway ComplicationsA systemic arterial supply is not established at the time of lung transplantation surgery. Viability of the anastomosis depends on collateral flow from the pulmonary circulation. For end-to-end anastomoses, the use of an omental, pericardial, or intercostal muscle anastomotic wrap in the early postoperative period has reduced the incidence of ischemia-induced airway necrosis and dehiscence. More recently, many institutions have switched to a procedure that does not require a wrap procedure, one that uses a telescoping anastomosis. Nonetheless, procedures that employ wrapping with pericardium or some other tissue still are performed occasionally. In the telescoping anastomosis, the membranous (ie, outer) portion of the donor bronchus is sutured end-to-end to the recipient bronchus, but the cartilaginous inner portion is inserted into the recipient bronchus for 1 or 2 cartilaginous rings. The internal margin of the anastomosis is not sutured and may result in an endoluminal flap. Bronchial dehiscence Bronchial dehiscence is the most common anastomotic airway complication in the early postoperative period. It occurs in 2-3% of cases. Ischemia at the anastomotic site is the major factor in the development of this complication. Dehiscence probably is best assessed by bronchoscopy; however, CT scans typically demonstrate the presence of extraluminal gas, which is 100% sensitive and 72% specific for dehiscence. Patients with telescoping anastomoses also may develop small anastomotic diverticula, which appear as smooth rounded air collections at the inferior-medial aspect of the anastomosis. Stricture Anastomotic stricture occurs in approximately 10% of cases, and the risk for stenosis may be increased with a telescoping anastomosis. Stenoses often manifest with progressive airflow obstruction that can be difficult to differentiate from other causes, such as acute rejection or bronchiolitis obliterans syndrome. Stricture probably is best evaluated by bronchoscopy; however, CT scans often demonstrate the area of narrowing. Treatment is stenting, typically with an expandable metallic stent. More recently, balloon dilatation has obviated the need for stents in some centres. Vascular ComplicationsStenoses at vascular anastomoses are uncommon (fewer than 4% of cases) but are more common at the arterial anastomosis than at the venous anastomosis. The risk of pulmonary infarction is greatest in the immediate postoperative period because the newly transplanted lung does not have an alternate pathway for bronchial circulation. Miscellaneous ComplicationsDiaphragmatic dysfunction resulting from phrenic nerve paralysis is uncommon (fewer than 4% of cases). InfectionsInfection is the leading cause of death in lung transplant recipients. Factors that increase a patient's susceptibility to infection after transplant include immunosuppression, reduced mucociliary clearance, decreased cough reflex resulting from denervation, and interruption of lymphatic drainage. Bacterial/viral pneumonia Bacterial pneumonias are the most common infection following lung transplantation and occur in more than 35% of patients during the first year after the transplant (highest incidence is during the first month posttransplant). Bacterial pneumonias remain a major infectious complication throughout the patient's life. The donor lung is affected more commonly. Gram-negative organisms are most common, especially Enterobacter and Pseudomonas. Bronchitis secondary to Pseudomonas species or S aureus infection also is observed. Bacterial pneumonia typically manifests radiographically as a lobar or multilobar consolidation. Viral pneumonias develop in approximately 11% of patients who have undergone lung transplants, and they occur at any time following transplantation. Opportunistic infections Opportunistic infections also are common after lung transplant surgery (34-59% of patients), but the infections do not seem to affect overall patient mortality rates. Cytomegalovirus infection CMV is the second most common cause of pneumonia in patients who have received lung transplants, and it is the most common opportunistic infection (35-60% of opportunistic infections). CMV is the most significant viral infection, and it usually occurs 1-4 months after the transplant. Primary infection is the most serious and is observed in 50-100% of patients who are seronegative who receive grafts from a donor who is seropositive. In patients who are seropositive, secondary CMV infection develops from reactivation of latent disease following the institution of immunosuppressive therapy or from infection with a different strain of CMV. Infected patients may be asymptomatic or may develop a fulminant pneumonia, possibly with extrathoracic findings such as retinitis, hepatitis, and gastritis. Presenting symptoms include dyspnea, fever, and cough. The diagnosis of CMV pneumonia can be made by bronchoscopy with lavage and biopsy. Prophylactic therapy with acyclovir and immune globulin has not reduced the incidence of CMV infection in patients who have undergone transplant procedures. The most common finding on chest radiographs in patients with CMV infection is diffuse parenchymal haziness. CT scan findings in patients with CMV infection include areas of ground-glass attenuation; reticulation; multiple, small, ill-defined 1- to 3-mm nodules; and, even less commonly, areas of dense consolidation. Herpes simplex virus infection A less common cause of viral infections includes the herpes simplex virus (HSV). Patients with HSV infection present with fever, cough, and dyspnea, but they demonstrate symptomatic improvement after therapy with intravenous acyclovir. Radiographic findings may be absent or may demonstrate diffuse ground-glass opacities. Fungal infections Opportunistic fungal infections are less common than viral infections, but they are associated with higher mortality. Fungal pneumonias usually occur 10-60 days following transplant and more commonly involve the transplanted lung. The most common findings of fungal infection on CT scans are a combination of nodules (multiple, variable sizes, irregular margins), consolidation, and ground-glass opacification. Pleural effusion also is common (63% of cases). Aspergillus infection Locally invasive or disseminated Aspergillus infection accounts for 2-33% of posttransplant infections and 4-7% of deaths in patients who undergo lung transplants. Aspergillus infection most commonly is characterized by local invasion of a necrotic bronchial anastomosis (ie, ulcerative tracheobronchitis), which typically occurs within 4 months of transplantation. Pneumocystis carinii pneumonia Patients who have undergone lung transplant procedures have an increased susceptibility to P carinii infection, but prophylaxis with trimethoprim-sulfamethoxazole is effective in preventing the infection (incidence is nearly 0%). Without prophylaxis, the incidence of P carinii infection approaches 90%. Posttransplantation Lymphoproliferative DisordersPatients who have undergone organ transplantation are at increased risk for developing PTLDs ranging from benign polyclonal hyperplasia to aggressive high-grade lymphoma (most are B-cell type). The disorders tend to occur within 1 year after transplantation (peak is 3-4 mo posttransplant). PTLDs develop in 4-10% of patients who have undergone lung transplants, as opposed to an approximate 2% incidence in other solid organ transplant recipients. Patients with PTLDs may be asymptomatic, or they may have nonspecific complaints such as fever, weight loss, dyspnea, and lethargy. Following lung transplant, PTLDs most commonly are isolated to the lung. Solitary or multiple pulmonary nodules ranging in size from 1-2 mm to 5 cm are the most common pulmonary manifestations in patients with PTLDs. Mediastinal and hilar adenopathy also can be observed in 22-50% of cases. Patients who present with a solitary pulmonary nodule have a better overall prognosis. T-cell PTLDs tend to occur later and tend not to be associated with Epstein-Barr virus (EBV) infection. T-cell PTLDs are associated with a worse prognosis. Differential considerations for multiple lung nodules include infection (ie, bacterial or fungal), especially with Aspergillus or Nocardia. These infections tend to cavitate and have an upper-lobe predominance. Furthermore, repeated transbronchial biopsies are known to produce parenchymal nodular densities of no special significance. Most PTLDs are associated with concomitant EBV infections, and this may be the etiologic agent. EBV stimulates B-lymphocyte proliferation, which is unopposed because of a cyclosporin-induced inhibition of T lymphocytes. Treatment consists of decreasing or ceasing immunosuppressive therapy (ie, cyclosporin) and administering antiviral agents (ie, acyclovir). After immunomodulation, regression occurs in 23-61% of patients. OUTCOME AND PROGNOSISSection 8 of 11
The International Society for Heart and Lung Transplantation and the St Louis International Lung Transplantation Registry report 1-year survival rates of 71% and 5-year survival rates of 45% following lung transplantation. Early mortality is caused by bacterial or CMV infections (35%), graft failure (13%), heart failure (9%), rejection (5%), bleeding (6%), anastomosis failure (5%), and other causes (27%). Late mortality is caused by infections (30%), obliterative bronchiolitis (29%), malignancy (6%), respiratory failure (5%), bleeding (4%), and other causes (26%). Infections and obliterative bronchiolitis remain the 2 most challenging issues in the long-term follow-up of patients who have undergone lung transplants. According to the registry of the International Society of Heart and Lung Transplantation, 1-year, 3-year, and 5-year actuarial survival rates after lung transplantation are 70.7%, 54.8%, and 42.6%, respectively. Median survival is 3.7 years. These rates lag behind those of heart and liver transplantation, for which 5-year actuarial survival is approximately 70%. Whether lung transplantation truly increases survival over the natural history of the underlying disease remains difficult to ascertain in the absence of randomized trials. A survival advantage has been reported for patients with cystic fibrosis and pulmonary fibrosis who have received transplants, but this advantage has not been demonstrated for patients with emphysema. Patients are referred for transplantation at a point in the course of their disease at which death is considered likely within several years. Therefore, transplantation would be expected to confer a survival advantage. Severe dyspnea and poor quality of life can be additional considerations for lung transplantation. The mortality rates are highest in the year following transplantation. The leading causes of early death are infections and graft failure. No significant difference in survival exists between recipients of SLTs versus recipients of sequential DLTs. FUTURE AND CONTROVERSIESSection 9 of 11
Cost of lung transplantation Highly sophisticated and extraordinary therapies, such as lung transplantation, are performed at a great cost to society. Presently, active research is being conducted on enhancing the patient's quality of life following lung transplantation. Several studies have reported a significant improvement in different quality-of-life domains, tested pretransplant and posttransplant. Other studies comparing candidates and lung transplant recipients have demonstrated significant improvements in energy levels, physical functioning, mobility, and symptoms such as dyspnea and anxiety. The recipients have expressed greater satisfaction with their lives and their health following lung transplantation. Attempts to compute the costs of lung transplantation to general society and to determine the cost effectiveness of this therapy have been made. Cost evaluations should take into account both the actual cost and the improved quality of life provided by this therapy compared to standard care. The cost is expressed in units of QUALY (quality-adjusted life-year), which reflects the real or anticipated survival time and health-related quality of life. The University of Washington Medical Center estimated that lung transplantation costs $176,817 per QUALY compared to traditional therapy. Canadian centers have reported a lower cost effectiveness of lung transplantation ($62,860 per life-year gained, Canadian dollars, 1993). Living donor tranplantation Living lobar lung transplantation was developed as a procedure for adult and pediatric patients considered too ill to await cadaveric transplantation. Despite fairly extensive experience, no donor mortality has been reported, and morbidity has been relatively low. Compared to bilateral cadaveric lung transplants, long-term studies have shown that the relatively smaller-sized lobes can provide similar pulmonary function and exercise capacity. Living lobar lung transplantation should be considered in a patient with a clinically deteriorating condition. Although no deaths have been reported in the donor cohort, a risk of death between 0.5% and 1% should be quoted, pending further data. A case series of 128 living lobar lung transplantations performed in 123 patients between 1993 and 2003 was published. The actuarial survival among the living lobar recipients was 70%, 54%, and 45%, at 1, 3, and 5 years, respectively. MULTIMEDIASection 10 of 11
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