Chapter 13 Lung Transplantation
The first human lung transplant was performed in 1963 by Dr. James Hardy at the University of Mississippi.1 The recipient was a prisoner with lung cancer who survived for 18 days before succumbing to renal failure. Between 1963 and 1974, 36 patients underwent lung transplantation but only two recipients lived longer than a month. It was not until the introduction of cyclosporine in the early 1980s that lung transplantation became a realistic treatment option. In recent years the outcome following lung transplantation has remained relatively stable, with survival rates at 3 months of 90%, at 1 year of 80%, at 3 years of 60%, and at 5 years of 45%.2
The number of patients on the waiting list for lung transplantation in the United States is about 3500,3 but only about 1000 patients undergo the procedure each year, resulting in a median waiting time of just over 3 years.2 Furthermore, because of the limited number of transplants performed, only a small proportion of patients who could benefit from lung transplantation are actually listed for surgery. Although donor shortage is a problem for all solid-organ transplant programs, it is a particular problem for lung transplantation, because only 10% to 15% of multiple organ donors have lungs that are suitable for transplantation. In the United States, approximately 15% of patients die each year while awaiting lung transplantation.2
SINGLE, DOUBLE, OR HEART-LUNG TRANSPLANT
For most conditions in which lung transplantation is indicated, either a single or a bilateral sequential lung transplant may be performed. Outcomes of bilateral sequential lung transplantation are slightly better, but single-lung transplantation represents the most economic use of available organs. For conditions associated with pulmonary sepsis (cystic fibrosis, bronchiectasis), bilateral sequential lung transplant is required. For pulmonary hypertension, either single or bilateral sequential lung transplant may be performed, although bilateral sequential lung transplant is the preferred option worldwide.4,5 Even in the presence of significant right ventricular dysfunction, patients with pulmonary hypertension do not usually require heart-lung transplantation.6 The number of patients with primary pulmonary hypertension who undergo lung transplantation is becoming smaller with the development of more effective medical therapy.
Selection Criteria and Preoperative Management
Recipient Criteria
Candidates for lung transplantation must have end-stage pulmonary disease and limited life expectancy for which there is no other suitable treatment.7 Recommended age limits are 55 years for heart-lung transplantation, 60 years for bilateral lung transplantation, and 65 years for single lung transplantation. Disease-specific criteria for lung transplantation are summarized in Table 13-1. Contraindications to lung transplantation (Table 13-2) are related primarily to the presence of other end-organ disease.
Table 13-1 Disease-Specific Criteria for Lung Transplantation
| COPD |
| FEV1 <25% predicted (without reversibility) |
| PaCO2 >7.3 kPa (55 mmHg) |
| Elevated pulmonary artery pressures ± cor pulmonale |
| Cystic Fibrosis and Bronchiectasis |
| FEV1 <30% predicted |
| Rapidly progressive deterioration in respiratory status (even if FEV1 >30%), including recurrent admissions, massive hemoptysis, and increasing cachexia |
| PaCO2 >6.7 kPa (50 mmHg) and PaO2 <7.3 kPa (55 mmHg) |
| Idiopathic Pulmonary Fibrosis |
| Symptomatic desaturation with rest or exercise |
| Progressive disease |
| Abnormal pulmonary function tests, particularly FVC <70% and DLco <50%-60% of predicted |
| Systemic Disease with Pulmonary Fibrosis |
| As for idiopathic pulmonary fibrosis, but with stable/quiescent systemic disease |
| Pulmonary Hypertension (without congenital heart disease) |
| Symptomatic or progressive disease despite optimal medical treatment and NYHA functional class III or IV |
| CI <2 l/min/m2, RAP>15 mmHg, mean PAP >55 mmHg |
| Eisenmenger Syndrome |
| Severe progressive symptoms and NYHA III or IV functional class despite optimal treatment |
FEV1, forced expiratory volume in one second; PaCO2, arterial partial pressure of carbon dioxide; PaO2, arterial partial pressure of oxygen; FVC, forced vital capacity; DLCO, diffusing capacity of carbon monoxide; CI, cardiac index; RAP, right atrial pressure; PAP, pulmonary artery pressure; NYHA, New York Heart Association.
Table 13-2 Contraindications to Lung Transplantation
Preoperative Recipient Optimization
Nutritional status has an important bearing on the outcomes of lung transplantation. Patients with pretransplant body mass indexes less than 17 kg/m2 or more than 25 kg/m2 are at increased risk for early postoperative death.8 Patients with low body mass indexes should receive nutritional supplements. Enteral feeding via a percutaneous gastrostomy tube is commonly used for patients with cystic fibrosis and should be continued during the postoperative period. Compliance with a pulmonary rehabilitation program is a prerequisite for lung transplantation in patients with chronic obstructive pulmonary disease (COPD) and has been shown to improve outcomes of surgery.9 Corticosteroids should be discontinued or weaned to doses less than 20 mg/day of prednisone at the time of listing for transplantation because of their adverse effects on bone and muscle mass and the increased risk for colonization or infection by an opportunistic organism.10 Lung transplant recipients with cystic fibrosis and bronchiectasis may require regular courses of intravenous antibiotics to control pulmonary infection.
Donor Criteria
The optimal donor criteria11–14 for lung transplantation are summarized in Table 13-3. However, because of the limited number of suitable organs, there is substantial pressure to use marginal donors. Although good outcomes have been obtained with graft ischemic times longer than 6 hours, data indicate a reduction in survival rates when the ischemic time exceeds 5.5 hours.15 Donor lungs with a positive gram stain on tracheal aspirate or bronchial washings may be considered for transplantation depending on other factors, such as the chest radiograph appearances and the gas exchange. Marginal oxygenation in the donor can be managed with various ventilatory strategies to improve gas exchange (see Chapter 29). If there is evidence of unilateral chest sepsis in a potential donor, a single-lung transplant using the noninfected donor lung may be considered. The decision to use a marginal organ is difficult and depends not only on donor factors but also on the sickness of the potential recipient and the likelihood of another organ becoming available.
Table 13-3 Ideal Donor Criteria for Lung Transplantation
| Ischemic time < 6 hours |
| Age < 55 years |
| ABO blood group compatible |
| Clear chest radiograph |
| PaO2 > 40 kPa (300 mmHg) with 100% oxygen and 5 cm |
| H2O PEEP |
| Smoking history <20 pack years |
| Absence of chest trauma |
| Absence of purulent secretions at bronchoscopy |
| Absence of organisms on sputum gram stain |
| No prior cardiopulmonary surgery |
PEEP, positive end expiratory pressure; PaO2, arterial partial pressure of oxygen.
From Orens JB, Boehler A, de Perrot M, et al: A review of lung transplant donor acceptability criteria. J Heart Lung Transplant 22:1183-1200, 2003.
Recipient-Donor Matching
The matching of donors and recipients of thoracic organs (heart and lungs) is based on compatibility, geographic location, and medical urgency, as outlined in Chapter 14. For lung transplantation, a number of criteria are used to ensure size matching, including height, thoracic circumference, and chest radiograph dimensions. A recent study has shown that predicted total lung capacity based on height and gender provides more accurate size matching than height alone.16
Living Lobar Lung Donors
Living lobar lung transplantation was introduced in 1993 for individuals too unwell to await cadaveric organs. In this procedure, right and left lower lobes from two healthy donors are implanted in the recipient in the place of the whole right and left lungs. A recent review of the outcomes of this technique in a single center showed survival rates at 1 year of 70%, at 3 years of 54%, and at 5 years of 45%.17 These rates are comparable to those obtained in conventional lung transplantation.
Intraoperative Management
Surgical access for bilateral sequential lung transplant is usually made by performing a transsternal bilateral thoracotomy (a “clamshell” incision) with the patient in a supine position. The procedure involves performing two single-lung transplants, one after the other. The side with the worse lung function is typically resected first.
Immunosuppression
Standard immunosuppression18 in lung transplantation consists of triple therapy, including a calcineurine inhibitor (cyclosporine, tacrolimus), an antiproliferative agent (azathioprine, mycophenolate mofetil), and a corticosteroid (methylprednisolone, prednisone). In a recent survey of North American practice, the most commonly used regimen consisted of tacrolimus, mycophenolate mofetil, and prednisone.5 The first doses of immunosuppression are given prior to surgery and continued postoperatively. If there is evidence of postoperative acute renal dysfunction, the calcineurine inhibitor may be withheld for a few days or another class of drug may be substituted. In some centers, induction therapy that is commonly either an anti-lymphocyte antibody or interleukin 2 (IL-2) blocker is administered during the early postoperative period.
Calcineurine Inhibitors
Cyclosporine can be given as a continuous infusion or in divided doses (1 to 3 mg/kg/day). The oral dose is calculated at 3 to 9 mg/kg/day in two divided doses or converted from the intravenous dose based on a bioavailability of about 30%. Patients with cystic fibrosis have poor absorption of cyclosporine (bioavailability may be as low as 20%) and should take the drug with pancreatic enzyme supplementation. Cyclosporin may be given three (rather than two) times a day in this group to combat reduced absorption. Traditionally, trough cyclosporine serum levels are obtained immediately prior to the next dose (C0 levels). Recently, dose optimization based on serum levels obtained 2 hours postdose (C2) has been shown to reduce the incidence of nephrotoxicity without increasing the incidence of acute rejection.19,20 The target serum level varies according to the assay used and whether C0 or C2 levels are obtained. Tacrolimus can be given intravenously (0.01 to 0.05 mg/kg/day) or orally 0.1 to 0.3 mg/kg/day in two divided doses.21 Trough levels obtained immediately prior to the next dose are used to attain dose optimization.
The main side effect of the calcineurine inhibitors is renal dysfunction.22,23 Renal impairment is dose related and is reversible on drug withdrawal. If renal impairment develops, it may be appropriate to withhold the drug temporarily, reduce the dose, or use an alternative such as a target-of-rapamycin (TOR) inhibitor (see later material). Other side effects include acute delirium, hypertension, dyslipidemia, impaired glucose tolerance, gout, gingival hypertrophy, and hirsutism. Tacrolimus commonly causes a fine tremor but results in less hirsutism and gingival hypertrophy than does cyclosporine.
Calcineurine inhibitors (and sirolimus) are metabolized by the cytochrome P450 (CYP) 3A enzyme system, which is subject to inhibition (decreased metabolism) and induction (increased metabolism) by certain drugs (see Table 4-3). CYP3A inhibition is exploited therapeutically by using diltiazem (an inhibitor of CYP3A) as an antihypertensive agent, thereby reducing the required dose of the calcineurine inhibitor.
