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)

P_aCO₂ >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

P_aCO₂ >6.7 kPa (50 mmHg) and P_aO₂ <7.3 kPa (55 mmHg)

Idiopathic Pulmonary Fibrosis

Symptomatic desaturation with rest or exercise

Progressive disease

Abnormal pulmonary function tests, particularly FVC <70% and DL_co <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; P_aCO₂, arterial partial pressure of carbon dioxide; P_aO₂, arterial partial pressure of oxygen; FVC, forced vital capacity; DL_CO, 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

Absolute

Other organ dysfunction, particularly:

Severe left ventricular dysfunction

Severe untreated coronary artery disease

Renal dysfunction (creatinine clearance < 50 ml/min)

Infection, particularly:

Hepatitis C with biopsy-proven liver disease

Hepatitis B antigen-positive

HIV/AIDS

Abnormal body mass index (<70% of ideal or >130% of ideal)

Not free from any substance addiction >6 months

Psychosocial problems that are likely to impact negatively on outcome

Relative

Invasive ventilation

Colonization by certain Burkholderia species, atypical

mycobacterium, or fungi

Symptomatic osteoporosis

Severe musculoskeletal disease affecting the thorax

High-dose systemic corticosteroids

Malignancy

>2 years ago after cure, or

>5 years for extracapsular renal cell cancer, breast cancer

≥ stage 2, Dukes B or C colon cancer, melanoma ≥level III

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 criteria ¹¹^–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; P_aO₂, 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

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 immunosuppression ¹⁸ 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.

Routine Postoperative Care

After lung transplantation, up to 90% of patients have some degree of reperfusion injury, which manifests as an increased alveolar-arterial oxygen gradient and perihilar edema on the chest radiograph.²⁵ In most patients this reperfusion injury is mild and does not delay progress. However, to avoid exacerbating reperfusion injury, all patients should be ventilated with a lung-protective strategy (see Chapter 29). Many patients with chronic lung disease have compensated respiratory acidosis, and attempts to ventilate to a normal carbon dioxide tension will result in marked alkalosis (and possibly high airway pressures).

Some have recommended the routine use of nitric oxide to prevent reperfusion injury, but in a randomized trial, inhaled nitric oxide at a dose of 20 parts per million was not associated with a reduction in reperfusion injury when compared to controls.²⁶ (Nitric oxide may have a role in the treatment of reperfusion injury; see later discussion). In patients who have undergone singlelung transplantation for emphysematous disease, low ventilation rates should be used to avoid dynamic hyperinflation in the native lung (see later discussion). Bronchospasm can occur both in the graft and in the remaining native lung and can be treated by inhaled bronchodilators.

Patients should be weaned from mechanical ventilation and extubated as soon as is practical so as to reduce the stress on bronchial anastomoses and decrease the incidence of pulmonary infection. Spontaneous breathing also reduces the likelihood of dynamic hyperinflation following single-lung transplantation. Thus, once patients are normothermic, are not bleeding excessively, and have stable gas exchange, they can be awakened, often within 6 to 12 hours of surgery. Apical chest drains are removed when there is no air leak, usually within 48 hours. Basal drains remain longer because pleural effusions commonly develop over the first week.

A conservative approach to fluid management is appropriate so as to avoid exacerbating any reperfusion injury. Low-dose norepinephrine may be used in preference to aggressive fluid therapy to support blood pressure. Modest oliguria and azotemia are acceptable.

Routine measures to prevent nosocomial infection are extremely important; these are described in Chapter 14. Institution of enteral nutrition within 2 to 3 days of surgery is important, because patients are commonly malnourished and catabolic. Graduated compression stockings to help prevent deep venous thrombosis should be used in all patients, but routine use of anticoagulants is probably not justified except when there is prolonged immobility. Bronchoscopy is usually performed within the first 2 to 4 weeks following surgery. At this time the bronchial anastomoses are inspected, washings are obtained for microbiologic analysis, and transbronchial biopsies are taken to look for acute rejection.

Analgesia

Effective analgesia is absolutely essential to facilitate early extubation, coughing and deep breathing, and compliance with physiotherapy. This goal is best achieved by a thoracic epidural blockade. It is a common practice to insert an epidural catheter when the patient is in the operating room prior to surgery. However, if this has not been done—for instance, because of an anticipated need for CPB with full anticoagulation—it is usually appropriate to insert the catheter when the patient is in the ICU, prior to waking the patient. The presence of normal blood clotting should be established prior to the procedure. Epidural dosing regimes are shown in Table 12-5. To minimize epidural-induced hypotension in patients who are being kept “dry,” epidural infusions containing high concentrations of local anesthetic solutions should be avoided. The epidural is usually discontinued once the chest drains have been removed, but it should not remain in place longer than 5 to 7 days because of the risk of infection.

Additional analgesia may be provided with acetaminophen, tramadol, and the judicious use of a strong opioid such as morphine. Nonsteroidal antiinflammatory drugs compound the nephrotoxic effects of calcineurine inhibitors and are best avoided.

Antimicrobials

Antibiotic prophylaxis following lung transplant surgery is similar to that required following any cardiothoracic procedure (see Chapter 35). There are two situations in which additional antibiotic coverage is required. First, when infection is identified in the donor lung, and second, in a recipient with suppurative lung disease. Results of sputum samples obtained preoperatively are used to guide antibiotic therapy.

The lungs of patients with cystic fibrosis and bronchiectasis are typically colonized with multiresistant organisms, particularly Pseudomonas aeruginosa and Burkholderia species. Although colonization by panresistant P. aeruginosa does not appear to increase the risk for mortality in lung transplant recipients,²⁷ colonization by certain Burkholderia species, particularly B. cenocepacia (formerly genomovar III), is associated with increased mortality rates,²⁸ and in some centers it constitutes a contraindication to lung transplantation.

Lifetime prophylaxis against Pneumocystis jirovecii (formerly carinii) by the use of co-trimoxazole is recommended for all lung transplant recipients. Prophylaxis against cytomegalovirus (CMV) by administering ganciclovir for 3 to 6 months is routine. Many centers also provide prophylaxis against Aspergillus species by administering itraconazole.

Early Complications

The most common causes of death in lung transplant recipients in the first 30 days are graft failure and infection. Complications that occur in the first 5 days are considered early complications.

Reperfusion Injury

Severe reperfusion injury (primary graft failure, ischemia-reperfusion injury) is the most common cause of early death following lung transplantation.^24,²⁹ The condition occurs in about 15% of all lung transplant recipients and has a mortality rate in excess of 40%.^23,²⁹ The cause of reperfusion injury is poorly understood and in many circumstances appears to be idiosyncratic. In one study, length of ischemic time, recipient age, underlying pulmonary disease, and the use of CPB were not identified as risk factors.²⁹ Reperfusion injury is not a process mediated by the immune system, but it is associated with an increased risk for developing early acute rejection.³⁰

Reperfusion injury presents as severe noncardiogenic pulmonary edema with widespread alveolar shadowing on the chest radiograph (Fig. 13-1), reduced lung compliance, impaired gas exchange, and frothy edema fluid in the endotracheal tube. There may be copious serous drainage from the chest tubes. The condition may be apparent immediately after graft reperfusion or, more commonly, it may develop slowly during the first few hours in the ICU.

Figure 13.1 Reperfusion injury. A, Intense reperfusion injury following single-lung transplantation. The entire left lung (graft) is densely consolidated. Two chest drains, a TEE probe, a central line, and a PAC can be seen. B, The same patient 7 days later. There is almost complete resolution of the reperfusion injury. Note that the native (emphysematous) right lung remains hyperexpanded.

Other causes of pulmonary edema must also be considered (Table 13-4). In particular, pulmonary vein obstruction due to an anastomotic problem or thrombus formation can also cause gross pulmonary edema. If pulmonary venous obstruction is suspected, TEE examination with careful inspection of the pulmonary veins should be performed. The finding of increased velocity within one or more pulmonary veins and loss of the usual phasic flow pattern on Doppler flow mapping are suggestive of the diagnosis.

Table 13-4 Differential Diagnosis of Pulmonary Edema in the First 48 Hours Following Lung Transplantation

Reperfusion injury

Pulmonary vein obstruction

Excess fluid administration

Cardiogenic pulmonary edema (e.g., due to myocardial ischemia)

Aspiration (rare)

Hyperacute rejection

In contrast to other solid-organ transplantation, hyperacute rejection is not well described following lung transplantation. However, it is likely that some cases of overwhelming pulmonary edema that occur very soon after surgery are due to hyperacute rejection and not to reperfusion injury.³¹ There is no specific treatment for hyperacute rejection other than retransplantation, and death is likely.

The treatment of reperfusion injury is supportive. A lung-protective ventilatory strategy should be employed, with high levels of positive end-expiratory pressure (PEEP). Inhaled nitric oxide is beneficial, at least during the acute period.³⁰ Other pulmonary vasodilators such as nitroglycerin may reduce pulmonary vascular resistance (and improve right ventricular function) but at the cost of inhibiting hypoxic pulmonary vasoconstriction and exacerbating hypoxemia.

Diuretics and fluid restriction should be employed to achieve the lowest pulmonary artery wedge pressure that is consistent with acceptable hemodynamics. Vasopressors may be required to support the blood pressure. Hemoglobin should be maintained above 90 g/l. Renal dysfunction secondary to modest hypovolemia may be preferable to exacerbating the reperfusion injury by means of fluid resuscitation.

Unfortunately, modest hypovolemia in conjunction with right ventricular dysfunction and the need for high levels of PEEP can result in severe hypotension. Hypovolemia can also worsen hypoxemia. Thus it is possible to enter a vicious circle of progressive cardiac and respiratory decline.

For patients with life-threatening reperfusion injury, extracorporeal membrane oxygenation (ECMO) should be considered (see Chapter 22). A number of centers have reported good outcomes by using this technique.³²^–³⁴ Ideally, ECMO should be initiated early, before cardiovascular collapse occurs. This has the advantage of allowing ECMO to be commenced in a controlled fashion, and it may also permit the use of venovenous ECMO, which is associated with a lower incidence of complications than is found with arteriovenous ECMO.

Dynamic Hyperinflation of the Native Lung

Dynamic hyperinflation of the native lung is a problem that occurs in patients with emphysematous disease undergoing single-lung transplantation, particularly when there is significant reperfusion injury in the graft. The problem arises because of differences in the compliance between the native lung (high compliance) and the transplanted lung (low compliance). With positive pressure ventilation through a single-lumen endotracheal tube, there is preferential ventilation of the native emphysematous lung. This can result in gross overdistension of the native lung, underventilation of the graft, and mediastinal shift (Fig. 13-2A). Moderate degrees of dynamic hyperinflation are surprisingly well tolerated. However, severe dynamic hyperinflation is associated with hypoxemia, hypercarbia, and hemodynamic collapse. The differential diagnosis includes tension pneumothorax in the native lung and mucus plugging in the graft (Table 13-5). Inappropriate insertion of a chest drain in this situation can cause a major air leak, potentially compounding the ventilatory problems.

Figure 13.2 Dynamic hyperinflation following single-lung transplantation. A, gross overdistension of the native (left) lung, with rightward displacement of the mediastinum. The transplanted (right) lung is underexpanded. B, the same patient within a few hours of commencing independent lung ventilation; complete resolution of the left-sided hyperinflation has occurred. The reperfusion injury in the right lung appears less serious now that the lung is fully expanded. A left-sided double-lumen endotracheal tube can be seen.

Table 13-5 Differential Diagnosis of Hyperexpansion of the Native Lung Following Single-Lung Transplant

Air trapping within the native lung

Tension pneumothorax on the side of the native lung

Mucus plugging within the transplanted lung

Phrenic nerve injury on the operative side

If dynamic hyperinflation is apparent on the chest radiograph but the patient is stable, simple interventions (e.g., β agonists) are usually sufficient. These include avoiding ventilatory strategies that promote air trapping within the native lung (such as rapid rates, high PEEP, and short expiratory times; see Chapter 29) and converting the patient to a spontaneous breathing mode. However, severe dynamic hyperinflation that is associated with impaired gas exchange and hypotension requires urgent institution of independent lung ventilation (see Fig. 13-2B).

Independent Lung Ventilation.

Independent lung ventilation is required in up to 10% of single-lung transplant recipients.³⁵ The technique is performed via a double-lumen endotracheal tube placement and is described in Chapter 40. Accurate and timely placement of double-lumen endotracheal tubes can be difficult and should be undertaken by someone experienced in their use. The appropriate ventilatory strategies for the two lungs are quite different because the transplanted lung typically has restrictive physiology, whereas the native lung has obstructive physiology. The implications of this are explained in Chapter 29. Suggested initial ventilator settings are outlined in Table 13-6.

Table 13-6 Initial Ventilator Settings at the Start of Independent Lung Ventilation for Dynamic Hyperinflation in Single-Lung Transplant Recipients

Native (emphysematous) Lung

Ventilatory rate of 4-8 breaths/min

Inspiratory time of 1.5 sec

Expiratory time of 6-13.5 sec

PEEP ≤ 5 cm H₂O

Tidal volume of 4-8 ml/kg (depending on plateau pressure)

Graft

Ventilatory rate of 14-18 breaths/min

Inspiratory time of 1.2 sec

Expiratory time of 2-3 sec

PEEP 10-15 cm H₂O

Tidal volume of 3-5 ml/kg (depending on plateau pressure)

PEEP, positive end expiratory pressure.

Correct positioning of the double-lumen tube is critical to the success of independent lung ventilation, and the tube can be easily dislodged by patient movement. In addition, this mode of ventilation is very uncomfortable for a patient who is awake. For these reasons, patients should initially be sedated and paralyzed. Subsequently, it may be possible to use sedation only, or even allow the patient to waken and spontaneously breathe with the native lung while the graft is mechanically ventilated. As the compliance of the graft gradually improves, usually over 24 to 72 hours, normal ventilation can be resumed. Initially this is done with the double-lumen tube in place, so independent lung ventilation can be rapidly reinstituted if hyperinflation recurs.

Occasionally, prolonged independent lung ventilation is required. In one report, good outcomes were reported in two patients after 25 and 35 days of independent lung ventilation.³⁶ One treatment option for intractable native lung hyperinflation is lung volume reduction surgery in the native lung. Concomitant single-lung transplantation and lung volume reduction surgery has been suggested as a way of avoiding postoperative dynamic hyperinflation.³⁵

Hemodynamic Instability

There are numerous potential causes of hemodynamic instability, but the following should always be considered specifically after lung transplantation: (1) hypovolemia; (2) right ventricular dysfunction; (3) raised intrathoracic pressure. All patients with unexplained hypotension should undergo urgent chest radiographs, and if they do not reveal the cause, TEE examination.

Hypovolemia.

Hypovolemia is common following lung transplantation due to relative fluid restriction, blood loss, interstitial (third-space) losses, and the effects of epidural analgesia. Occasionally, large fluid losses can occur into the pleural spaces and not be revealed in the chest drains or on the chest radiograph. TEE examination or chest ultrasound should be performed if intrathoracic fluid accumulation is suspected. Patients who are critically unwell with severe reperfusion injury can develop marked third-space losses and whole-body edema. Hypovolemia dramatically exacerbates hypotension caused by other conditions (e.g., raised intrathoracic pressure).

Right Ventricular Dysfunction.

Patients undergoing lung transplantation almost always have impaired right ventricular function due to the effects of chronic and acute pulmonary hypertension. Acute increases in pulmonary vascular resistance associated with ventilator dysynchrony, hypoxemia, hypercarbia, and acidosis can precipitate acute right ventricular failure. In the presence of a patent foramen ovale, right ventricular dysfunction can cause acute worsening of hypoxemia (caused by right-to-left intraatrial shunting), further increasing pulmonary vascular resistance.

Raised Intrathoracic Pressure.

Obstructed venous return resulting from high ventilatory pressures and high PEEP, dynamic hyperinflation, or ventilator dysynchrony can precipitate hemodynamic collapse. The problem is exacerbated if the graft is relatively large for the recipient. The diagnosis of obstructed venous return may be suspected if there is high central venous pressure, marked pulsus paradoxus on the arterial waveform, and high airway pressures. If this condition is suspected, the patient should be briefly disconnected from the ventilator; if this does not resolve the problem, the patient should be paralyzed and a chest radiograph, and possibly a TEE examination, should be obtained.

Surgical Complications

Specific surgical complications include pulmonary vein obstruction (see earlier material), airway dehiscence or obstruction, and phrenic nerve injury. Together, surgical complications account for 10% of early deaths.²⁴

Dehiscence or narrowing of the bronchial anastomosis is usually caused by bronchial ischemia. Narrowing of the airway can result in retained secretions, lobar or even whole-lung collapse, and infection. Dehiscence of the bronchial anastomoses results in a persistent air leak or a bronchopleural fistula. If a bronchial anastomotic problem is suspected or there is persisting lobar collapse, bronchoscopy should be performed. Phrenic nerve injury following surgery is a cause of recurrent lower lobe infection and contributes to the need for prolonged mechanical ventilation.

Acute Renal Failure

Some degree of renal impairment is common following lung transplantation due to the combined effects of fluid restriction and calcineurine inhibitors. Hypotension, if it occurs, also contributes to renal dysfunction, as does the use of other nephrotoxic drugs, such as aminoglycosides and amphotericin. There should be a low threshold for initiating renal replacement therapy because of the adverse effects of fluid overload on graft function.

Hyperammonemia Syndrome

Hyperammonemia syndrome ³⁷ is a rare complication of transplantation; there is a reported incidence of its occurrence after lung transplantation of 4.1%.³⁸ The condition is characterized by an elevated serum ammonia level (4 to 150 times normal), relatively normal liver function tests, and encephalopathy. Patients initially develop confusion and agitation, which may progress to seizures, coma, cerebral edema, and death. The cause is unknown but the condition is more likely in patients who have had “catabolic” stressors, such as gastrointestinal bleeding, reperfusion injury, and sepsis. Renal failure and high protein intake (as enteral or parenteral nutrition) contribute to the syndrome.

The differential diagnosis includes other causes of delirium, such as the side effects of immunosuppressive drugs (corticosteroids and calcineurine inhibitors); impaired gas exchange (hypoxemia and hypercarbia); sepsis; electrolyte disorder; and withdrawal syndromes (see Chapter 37).

If the diagnosis of hyperammonemia is suspected, a serum ammonia level should be obtained. To help clarify the diagnosis it may be appropriate to temporarily withhold corticosteroids and calcineurine inhibitors and use alternative methods of immunosuppression.

Treatment of hyperammonemia involves reducing the production of, and increasing the removal of, nitrogenous wastes. Thus, protein intake should be greatly reduced (but caloric intake maintained); renal replacement therapy should be instituted; and enteral lactulose should be administered. If the patient is comatose, an intracranial pressure monitoring device should be inserted. The mortality rate among those in whom coma develops is very high.

Later Complications

Infection, chronic rejection (the bronchiolitis obliterans syndrome), and malignancy are the most common causes of late (>5 days) mortality following lung transplantation.

Acute Rejection

The incidence of acute rejection following lung transplantation is higher than that in other solid-organ transplants.^39,⁴⁰ The first episode typically occurs after the first week, the peak incidence occurs 2 to 4 weeks following surgery.

Acute rejection is often asymptomatic and is detected in transbronchial biopsies performed during routine surveillance bronchoscopy. Symptoms, if present, are usually nonspecific, such as deterioration in respiratory function, low-grade fever, and malaise. The main differential diagnosis is infection. If either diagnosis is suspected, bronchoscopy with transbronchial biopsy should be performed. Treatment of acute rejection is a short course of high-dose corticosteroids and, possibly, augmentation of baseline immunosuppression. The frequency and severity of episodes of acute rejection are risk factors for the development of chronic rejection.⁴⁰

Infection

The combination of poor nutritional status, major surgery, prolonged hospital stay, preoperative colonization, and the use of potent immunosuppressive drugs all predispose to the development of postoperative infection. The risk for infection is further increased by augmented immunosuppression used to treat acute and chronic rejection, and bronchial anastomotic problems. Infection accounts for nearly 40% of all deaths in the first year and for about 20% of deaths overall.⁴

Bacterial Infections.

Bacterial infections that occur in the first month following surgery are usually caused by gram-negative organisms (particularly Pseudomonas aeruginosa) and Staphylococcus aureus. In patients with cystic fibrosis, organisms that had previously colonized their upper airways are potential sources of infection. Bacterial infections that occur after discharge from the hospital are usually caused by community-acquired pathogens such as Hemophilus influenzae, Streptococcus pneumoniae, or Legionella species.²³

Symptoms may initially be nonspecific, including deterioration in respiratory function, low-grade fever, and malaise. Leukocytosis is common due to the effects of high doses of corticosteroids and is therefore an unreliable marker of infection. Fulminant pneumonia and septic shock can develop very rapidly, and they carry high mortality rates. The source of infection is usually the lungs, but intravascular catheters are a potential septic source. If infection is suspected, blood cultures (at least two sets from peripheral veins) should be drawn and bronchoscopy performed. All vascular catheters should be removed or resited. Early institution of antibiotics may be lifesaving.

Viral Infections.

Lung transplant recipients are at risk for a wide range of viral infections, including CMV, Epstein-Barr virus, herpes simplex virus, and the respiratory viruses. The risk for viral infection begins about 1 month after transplantation and persists for life. Clinical presentation varies from minor upper respiratory tract infection to systemic viral illness to fulminant respiratory failure requiring mechanical ventilation.

CMV is the most common viral pathogen in lung transplant recipients. Clinical infection can occur due to reactivation of latent disease in an antibody-positive recipient or, more commonly, to new infection in an antibodynegative recipient who has received an organ from a CMV antibody-positive donor. The peak incidence of clinical infection occurs 1 to 12 months after surgery,⁴ typically after cessation of antiviral prophylaxis. CMV infection can cause tracheobronchitis and pneumonitis. Patchy infiltrates may be visible on a chest radiograph but this is a nonspecific finding. The diagnosis is confirmed by identifying viral DNA from blood, from bronchial washings using gene amplification with the polymerase chain reaction, or from typical changes (CMV inclusion bodies) on transbronchial biopsy. Treatment involves 2 to 3 weeks of intravenous ganciclovir followed by oral valganciclovir.

Community-acquired respiratory viruses (respiratory syncytial virus, parainfluenza virus, influenza virus, and adenovirus) are significant causes of morbidity in lung transplant recipients. These viruses are usually diagnosed in samples taken during bronchoscopy that has been performed for clinical indications such as dyspnea or pulmonary infiltrates in chest radiographs. Treatment is usually supportive, although specific antiviral agents can be used if the diagnosis is made early. Infection by community-acquired respiratory viruses has been identified as a risk factor for chronic rejection.⁴¹

Fungal Infections.

Aspergillus species are the most common and lethal fungal pathogens in transplant recipients.²³ These organisms can cause ulcerative tracheobronchitis (particularly in the presence of bronchial anastomotic problems) and pneumonia. Tracheobronchitis presents with fever, cough, wheeze, and hemoptysis. On bronchoscopy, there may be evidence of mucosal ulcerations, pseudomembranes, or frank necrosis. Invasive pneumonia results in severe respiratory failure and is associated with high mortality rates. Infection by Aspergillus species typically occurs within the first 6 months following surgery. Coinfection by CMV also occur.

Treatment of Aspergillus species involves oral itraconazole or voriconazole. Life-threatening infections can be treated with intravenous amphotericin (ideally a liposomal formulation) or with caspofungin, which unlike amphotericin, is not nephrotoxic.

Candida species are normal commensals of the oropharynx and esophagus. Overgrowth of Candida species (oral thrush) in patients receiving antibiotics is common and can be managed with oral nystatin. Identification of Candida species in bronchial washings occurs commonly and is not usually an indication for treatment. However, blood-borne infection by Candida species can cause severe systemic disease (e.g., endocarditis, brain abscesses) and requires antimicrobial therapy. C. albicans usually can be treated with fluconazole, but other species may require a newer triazole agent (e.g., voriconazole) or amphotericin.