Lung Transplantation

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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

In this chapter the preoperative assessment and perioperative management of patients undergoing lung transplantation are reviewed, with emphasis on the early postoperative period.

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.

Heart-lung transplantation is an uncommon operation that is performed in only a few centers. The procedure is reserved for patients with end-stage pulmonary and cardiac disease (e.g., Eisenmenger syndrome in association with an uncorrectable intracardiac defect or left ventricular dysfunction).

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 criteria1114 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

Intraoperative Management

Patient monitoring during lung transplantation includes an arterial line, central venous and pulmonary artery catheters, and a transesophageal echocardiogram (TEE). Strict attention to aseptic technique is essential for all invasive procedures. The patient should be kept as warm as possible: the room should be heated (>20°C), and a fluid warmer and forced-air warming blanket should be used.

For single-lung transplantation, surgical access is obtained by means of a lateral thoracotomy incision, with the patient placed in the lateral position. Because two patients may receive transplants from a single donor, the choice of operative side may be limited, but in general the recipient side with the worst lung function is preferred. Surgical technique varies, but typically a standard pneumonectomy is performed and the donor lung is implanted by performing the anastomoses in a posterior-to-anterior sequence: the bronchus first, the pulmonary artery second, and the pulmonary veins third.

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.

In patients with COPD or interstitial lung disease, lung transplantation (either single or bilateral-sequential) can usually be performed without the use of cardiopulmonary bypass (CPB) by using selective lung ventilation via a double-lumen endotracheal tube. However, in certain situations CPB is required. Patients with severe pulmonary hypertension typically do not tolerate the increase in pulmonary vascular resistance associated with the clamping of one pulmonary artery. Therefore, CPB is used electively in this patient group. CPB may also be required as an emergency intervention due to an acute deterioration in cardiac or respiratory function. Cardiac dysfunction may arise from incessant arrhythmias or acute right ventricular failure, both of which are provoked by acidosis, hypercarbia, hypoxemia, and surgical manipulations. The adverse hemodynamic effects of surgical manipulations are more pronounced in the presence of dense adhesions, such as those that occur in patients with cystic fibrosis or bronchiectasis. Also, patients with suppurative lung disease may not tolerate one-lung ventilation because of the recurrent plugging of the double-lumen tube by thick secretions. Emergency CPB also may be required during a bilateral sequential transplantation if a severe reperfusion injury develops in the first transplanted lung.

There are clear advantages in avoiding CPB, but they should not occur at the cost of prolonged periods of hypotension, hypoxemia, and acidosis. Ideally, CPB is used on an elective basis in appropriately selected patients rather than as a rescue maneuver in impending cardiac arrest.

Heart-lung transplantation is performed via a median sternotomy or clamshell incision with the use of CPB. During explantation of the native heart and lungs, it is essential to identify and preserve both phrenic nerves and to secure hemostasis of the bronchial vessels in the subcarinal space, because subsequent exposure of this region is extremely difficult. The donor heart-lung block is sutured in via tracheal, atrial, and aortic anastomoses. Prior to decannulation, the heart and pulmonary circulation must be fully de-aired.

For all transplant procedures, the times at which reperfusion occurs should be noted so the total ischemic time of the organs can be calculated. Methylprednisolone is typically administered at the time of reperfusion.

At the completion of surgery, the bronchial anastomoses are inspected bronchoscopically. Unless independent lung ventilation is being considered, the double-lumen tube is exchanged for a single-lumen tube prior to the patient’s transfer to the cardiothoracic intensive care unit (ICU).

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

The calcineurine inhibitors, cyclosporine and tacrolimus, form the mainstay of immunosuppression for solidorgan transplantation. These agents inhibit the release of interleukin-2 from T helper cells in response to an antigenic signal, thereby reducing activation of T lymphocytes.

Both cyclosporine and tacrolimus can be given intravenously, with conversion to oral dosing as soon as practical. Daily drug levels should be obtained in the early postoperative period to ensure adequate immunosuppression and to minimize the risk for nephrotoxicity.

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.

Antiproliferative Agents

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