Recipients of lung transplantation are surviving longer. As a consequence, complications secondary to the procedure (surgical) or to mandatory lifelong immunosuppression (medical) are becoming increasingly evident. These events can lead to significant morbidity and potential mortality if not managed immediately and appropriately. This chapter addresses the common surgical complications of lung transplantation.

Transplant operations of all types require at minimum two separate surgical procedures: retrieval of the organ from the donor and implantation of the organ into the recipient. A unique exception is the living-related lobar transplantation (see Chap. 96), in which three individuals are susceptible to perioperative complications.¹ Thus technical complications can occur during any phase of the operation, but the recipient always carries the principal burden. Donor procurement is considered less than optimal when there is inadequate harvest of the atrial cuff or iatrogenic injury to the pulmonary artery, pulmonary veins, bronchus, and lung parenchyma. Recipient complications secondary to lung implantation include phrenic nerve injury, hemorrhage, and pulmonary hypertension/hypoxemia.

COMPLICATIONS RELATED TO SUBOPTIMAL DONOR PROCUREMENT

Atrial Cuff and Pulmonary Vein Orifices

Donor procurement is always performed on an emergent basis. Consequently, despite the best efforts of both the heart and lung procurement teams to equitably divide the left atrial cuff and preserve the pulmonary vein orifices, the donor lungs occasionally arrive at the recipient OR in less than optimal condition, with either insufficient left atrial cuff or lacerated pulmonary vein orifices, in particular, the right inferior pulmonary vein. These injuries usually occur as a result of poor visibility or undue haste during division of the left atrial cuff. Laceration of the pulmonary vein orifice is repaired simply by dividing the pericardium overlying the vein and exposing the vessel to the point where it disappears into the lung parenchyma. Small branches of the vein also may require repair if the vein orifice was entered during procurement. These branches should be identified and oversewn to prevent troublesome bleeding after reperfusion.

Casula and colleagues have described a useful technique for augmenting the pulmonary veins with donor pericardium when the left atrial cuff is found to be inadequate.² This method can be used to create a cuff even when the superior and inferior pulmonary veins are completely separated. A running 5-0 polypropylene suture is placed around each vein orifice to tack the intima to the pericardium, thereby creating a "neoatrial cuff." Scissors are used to trim the newly created pericardial cuff and separate it from the other hilar structures. This pericardial cuff substitutes for donor atrium in the atrial anastomosis. Alternatively, donor superior vena cava or redundant donor pulmonary artery can be used for the reconstruction if there is inadequate pericardial tissue.

Pulmonary Artery Injury

The bifurcation of the pulmonary artery always should be taken with the lung graft at the time of procurement. Even when a heart transplant is planned from the same donor, dividing the pulmonary artery at the distal extent of the main trunk proximal to the bifurcation leaves a sufficient and safe length of artery for the heart transplant. Common sites of pulmonary artery injury during donor procurement include the right pulmonary artery as it travels behind the aorta or posterior to the superior vena cava. Because the right pulmonary artery is substantially longer than the left, when injury to this vessel occurs behind the aorta, it rarely requires repair, and the artery simply can be trimmed distal to the laceration. However, when the first branch of the right pulmonary artery is lacerated deep to the superior vena cava, it must be repaired. Usually, the laceration can be repaired with suture, but when reconstruction of the truncus anterior is required, a patch or complete reimplantation may be needed to prevent loss of diameter in the repaired vessel. This sort of repair can be performed with a segment of donor vena cava, azygos vein, or redundant donor pulmonary artery.

Bronchial and Parenchymal Injuries

Injury to the lung parenchyma or main bronchi during procurement is rarely significant. The worst result is a prolonged air leak after implantation, which eventually resolves. Special care should be taken when the implantation is performed with cardiopulmonary bypass because even small parenchymal injuries may lead to endobronchial bleeding under circumstances of profound anticoagulation for bypass.

The lung parenchyma can sustain atraumatic injury if there is a technical problem in the delivery of the flush solution used to cool and preserve the lungs during extracorporeal ischemia. Injuries of this type can have grave consequences. Inadequate flushing of the lungs can lead to profound ischemia-reperfusion injury and poor initial graft function. We experienced an extreme example of ischemia-reperfusion injury in a bilateral lung transplant performed in a patient with cystic fibrosis. On routine postoperative perfusion scan, no flow was observed perfusing the left lung (Fig. 98-1). A pulmonary arteriogram demonstrated a patent anastomosis without evidence of technical flaws to account for the absent blood flow in the lung (Fig. 98-2). Reexploration revealed an edematous ischemic lung with severe reperfusion injury that necessitated removal of the graft. Analysis of this case revealed that the flush of preservative solution had been preferentially and exclusively directed down the right pulmonary artery, thus exposing the left lung to a no-reflow phenomenon as a consequence of severe ischemic injury.

COMPLICATIONS RELATED TO RECIPIENT EXPLANT

Phrenic Nerve Injuries

Dense adhesions present at the time of explantation can increase the risk of bleeding as well as injury to the phrenic and left recurrent nerves. These adhesions are most common in patients with septic lung diseases (e.g., cystic fibrosis and bronchiectasis) and patients who have had previous thoracic surgery. Particularly dense adhesions have been seen in emphysema patients who have undergone previous lung volume-reduction surgery. In a multicenter experience of 35 lung transplant patients who had previously undergone lung volume-reduction surgery, phrenic nerve injury was recorded in two patients (5.7%).³ We have noted that the phrenic nerve often adheres to the lung volume-reduction surgery staple line, making dissection of the phrenic nerve both tedious and dangerous. To avoid injury to the phrenic nerve in these patients, we leave the staple line, along with a small amount of residual lung tissue, attached to the phrenic nerve and use a lung stapler to divide the densely attached tissue. Electrocautery to take down mediastinal adhesions should be avoided because it greatly increases the risk of phrenic nerve injury.

If one of the phrenic nerves is injured, little can be done to remedy the situation acutely. The consequences are not as dire with a bilateral transplant, which mitigates the impact of unilateral phrenic injury. The redundant lung ensures an overall satisfactory outcome, and consequently, this complication is often underreported. When the phrenic nerve is injured during a unilateral transplant, the benefit of the transplant is greatly diminished. It has been exceedingly rare in our experience or in the reported literature for a patient to require diaphragmatic plication after lung transplantation.

Hemorrhage

Hemorrhage was once a common complication after lung transplantation. Indeed, in the early experience of some programs undertaking heart-lung and en bloc double-lung transplants, approximately 25% of patients required reoperation for postoperative hemorrhage. Improved technique and perioperative care have reduced the incidence of hemorrhage. Posterolateral thoracotomy for single-lung transplantation and the clamshell and sternal-sparing clamshell incisions for bilateral lung replacement provide superb surgical exposure.^4,5 Aprotinin administration reduces intraoperative and postoperative bleeding, especially in patients with extensive pleural adhesions requiring cardiopulmonary bypass.

Pulmonary Hypertension and Hypoxemia

Persistent pulmonary hypertension and unexplained hypoxemia can occur as a result of stenosis at the pulmonary artery anastomosis. A nuclear perfusion scan that demonstrates less than anticipated flow to a single-lung graft or unequal distribution of flow in a bilateral lung recipient can suggest this problem. Occasionally, transesophageal echocardiography can visualize a stenotic vascular anastomosis. Contrast angiography should be performed in any patient for whom there is such a concern. At the time of angiography, the pressure gradient across the pulmonary artery anastomosis should be determined. A gradient of 15–20 mm Hg is commonly encountered, especially in single-lung recipients, in whom most of the cardiac output may be directed to the transplanted lung, or in bilateral recipients, who have a high cardiac output. The need for anastomotic revision is dictated by the clinical situation. Dramatic reduction in flow should not be accepted because the donor bronchus is totally dependent on pulmonary arterial collateral flow.

Compromised flow across the atrial anastomosis also can occur as a result of unsatisfactory anastomotic technique. Impaired venous outflow results in elevated venous pressure and ipsilateral pulmonary edema. Pulmonary artery pressures remain unexpectedly high in this situation, and flow through the graft is less than expected. Transesophageal echocardiography is often used to assess patency and flow through the atrial anastomoses. Contrast studies may be helpful in demonstrating a reduced level of flow through the anastomoses. Open exploration occasionally is necessary to confirm the diagnosis and conduct appropriate repair.

POSTOPERATIVE COMPLICATIONS

Sternal Complications

The bilateral transsternal thoracotomy provides excellent exposure to the hila and pleural spaces, but problems have been reported with poor sternal healing. Brown and colleagues⁶ report an institutional prevalence of 36% for sternal disruption in transverse bilateral thoracosternotomy for lung transplantation, and they cite disruption rates of 20–60% at centers worldwide. Lung transplant recipients are particularly prone to poor sternal healing (Fig. 98-3) owing to their debilitated state and the routine use of postoperative corticosteroids.⁴ Sternal override is a common complication that results from a tendency of the distal sternum to angulate and displace anteriorly, a translational movement that is not prevented by the sternal wires. The addition of coaxial stabilization, either with long, thin Kirschner wires or with short, stout Steinmann pins placed within the cancellous bone of the sternum, reduces the incidence of sternal override and translational movement at the bony closure. However, these wires have a tendency to migrate, causing other problems (Fig. 98-4). We have removed numerous wires that have migrated from the sternum to various locations in the body. Such retrievals require interventions of various complexity, ranging from the administration of local anesthetic to liberate a wire that has eroded through the anterior chest wall to a laparoscopic procedure under general anesthesia to remove a Kirschner wire from the pouch of Douglas. Deep sternal wound infection is an additional serious complication of transverse sternotomy. We have encountered this problem in several patients, and it has required operative and bedside wound debridement with additional antibiotics and a prolonged hospital stay. The estimated prevalence for all sternal closure complications in our historical control group is 34%. We routinely avoid sternal division and have found that adequate exposure in most circumstances can be provided by bilateral anterior thoracotomies alone. Additionally, in rare selected patients, we also advocate modified approaches such as a combined left posterolateral and right anterior thoracotomy to optimize the left hilar exposure without the need for sternal division or separate positioning, preparation, or draping.

Primary Graft Dysfunction

Primary graft dysfunction is one of the most important complications of lung transplantation and represents a common cause of early mortality and prolonged ICU stay. The frequency of primary graft dysfunction at our institution is 23%.⁷ The impact of primary graft dysfunction is enormous. Patients experiencing initial graft dysfunction at our institution had a mortality of 28.8% compared with 4.2% in patients without the condition.⁷

Primary graft dysfunction is commonly referred to as ischemia-reperfusion injury. A number of factors such as poor preservation techniques, prolonged ischemic time, and unsuspected donor lung pathology such as contusion, pulmonary thromboembolism, or aspiration all play a role in the development of primary graft dysfunction. Additionally, we have reported a statistically significant difference in the distribution of primary graft dysfunction according to underlying diagnosis leading to transplantation. There appears to be more primary graft dysfunction in patients transplanted for pulmonary hypertension and less in patients transplanted for emphysema. Hyperacute rejection is exceedingly rare, but it must be a consideration in cases of early severe lung dysfunction. Ischemia-reperfusion injury is characterized by noncardiogenic pulmonary edema and progressive lung injury over the first few hours after implantation (Fig. 98-5). Pathologically severe ischemia-reperfusion injury has the appearance of diffuse alveolar damage. Regardless of cause, it is important to establish a diagnosis of early graft dysfunction and to rule out other treatable conditions. We perform open lung biopsy at the time of implantation if graft dysfunction is immediately apparent in the OR. Serologic evaluation for anti-human leukocyte antigen antibodies also may reveal evidence of hyperacute rejection in some patients.

In recent years, severe reperfusion injury has not been a common experience. Superior strategies of lung preservation have evolved.⁸ It is clear from experimental^9,10 and clinical work¹¹ that the low potassium dextran solution provides superior protection compared with the high potassium solution used previously. In addition, experimental work suggests that adding nitric oxide to the flush solution at the time of harvest provides a preservation advantage.¹² On the other hand, lung hyperinflation can produce a striking model of postreperfusion pulmonary edema. Therefore, we are particularly careful to avoid lung hyperinflation during harvest and storage of the donor lungs. Each of these factors has contributed to a reduction in the frequency of ischemia-reperfusion injury.

The notion of controlled reperfusion was used originally to reduce cardiac dysfunction after reperfusion of acutely ischemic myocardium at the time of coronary artery revascularization. Recently, the clinical use of controlled reperfusion, combined with leukocyte depletion,¹³ has shown promise as a preventive strategy for ischemia-reperfusion injury.

In cases of established ischemia-reperfusion injury, proper treatment includes diuresis and maximal ventilatory support without introducing additional ventilator-induced injury. In most cases, the reperfusion injury resolves over 24–48 hours. We have shown previously that inhaled nitric oxide is beneficial in severe reperfusion injury because it decreases pulmonary artery pressure and improves the PaO₂:FIO₂ ratio.¹⁴ More recently, inhaled prostacyclin has been investigated and shows promise as an economic alternative to nitric oxide.¹⁵

While standard intensive ventilatory and pharmacologic interventions generally suffice, severe graft dysfunction or coexisting cardiac failure may require extracorporeal membrane oxygenation (ECMO) support. We have reported on the use of ECMO after lung transplantation¹⁶ and have found satisfactory results when the lung failure occurs immediately after transplantation (<24 hours). The etiology of graft failure in these patients was reperfusion lung injury. The frequency of reperfusion injury severe enough to warrant this therapy is less than 3% of all transplant operations. When the deterioration occurs beyond the first 24 hours, it is often multifactorial and is associated with lasting pathologic changes in the pulmonary parenchyma that are less likely solved by temporary ECMO support. An alternative approach to severe, reversible allograft dysfunction is reported by Eriksson and Steen,¹⁷ who have used core cooling successfully to reduce oxygen requirements and avoid ECMO, giving a chance for the lung to heal. As a last resort, acute retransplantation may be lifesaving. In our series, we have performed six retransplants emergently for primary graft failure⁷ (Fig. 98-6).

Airway Complications

Airway complications formerly were a major cause of morbidity and mortality after pulmonary transplantation. In the current era of transplantation, airway complications remain a source of morbidity but do not appear to be associated with poorer survival.⁷ Using standard methods of implantation, the donor bronchus is rendered ischemic, without reconstitution of its systemic bronchial artery circulation. The donor bronchus relies on collateral pulmonary artery blood flow during the first few days after transplantation. It has been demonstrated that pulmonary collateral flow contributes substantially to bronchial viability at the level of the distal bronchus and lobar origin. A shortened donor bronchial length (i.e., two rings proximal to the upper lobe takeoff) reduces the length of donor bronchus dependent on collateral flow. Superior preservation, improved sepsis prophylaxis, and better immunosuppression have reduced the incidence of airway complication. In a review of our experience, Date and colleagues¹⁸ reported a reduction of the prevalence of anastomotic complications from 14% to 4%. Across our entire series, the rate of airway anastomotic complications is 9.3%.⁷

Airway anastomotic complications include strictures, dehiscences, and malacia, with strictures representing the most common problem. Airway complications can be identified in a number of ways. Routine postoperative bronchoscopic surveillance generally provides early evidence of an anastomotic complication. On occasion, CT scan, performed for some other indication, demonstrates an unexpected airway stenosis or dehiscence. In fact, we learned that CT scanning is a useful diagnostic tool for evaluating documented or suspected donor airway complications (Fig. 98-7). Late airway stenoses generally manifest with symptoms of dyspnea, wheeze, or decreased forced expiratory volume in 1 second (FEV₁). Bronchoscopic assessment confirms the diagnosis (Fig. 98-8).

A normal bronchial anastomotic suture line demonstrates a narrow rim of epithelial slough that ultimately heals. On occasion, one can observe patchy areas of superficial necrosis of donor bronchial epithelium. These areas are generally of no concern and will heal eventually without causing problems. Minor degrees of bronchial dehiscence also have little long-term consequence. Membranous wall defects generally heal without any airway compromise, whereas cartilaginous defects usually result in some degree of late stricture. Significant dehiscence (>50% of the bronchial circumference) may result in compromise of the airway. This problem should be managed expectantly by mechanical debridement of the area to maintain satisfactory airway patency. A stent can be placed only if the distal main airway remains intact. Occasionally, a significant dehiscence results in direct communication with the pleural space, resulting in pneumothorax and a significant air leak following chest tube insertion. If the lung remains completely expanded and the pleural space is evacuated, the leak will seal ultimately, and the airway may heal without significant stenosis. Similarly, a dehiscence may communicate directly with the mediastinum, resulting in significant mediastinal emphysema. If the lung remains completely expanded and the pleural space is filled, adequate drainage of the mediastinum can be achieved by placing a drain in close proximity to the anastomotic line by way of mediastinoscopy. This step also will result in satisfactory healing of the anastomosis, often without stricture.

A high incidence of postoperative airway dehiscence has been reported recently with the early use of sirolimus (Rapamune, Rapamycin, Wyeth Laboratories, Philadelphia, PA, and Certican, RAD, Everolimus, Rapamycin derivative, Novartis, East Hanover, NJ) in lung transplant recipients.¹⁹ In a series of 15 patients treated in the early postoperative period with sirolimus, 4 experienced anastomotic dehiscences, and 3 of these 4 patients died. The use of sirolimus in the early posttransplant period should be discouraged.

Anastomotic Stenosis

Chronic airway stenoses can present significant management problems. A right main bronchial anastomotic stricture generally is managed easily by repeated dilation and ultimate placement of an endobronchial stent. There is usually sufficient length to place a right main bronchial orifice stent without impinging on the right upper lobe bronchus. On the left side, however, strictures can be somewhat more difficult to manage. Dilating the distal left main bronchus is technically more difficult because of the angulation of the left bronchus. In addition, the lobar bifurcation immediately distal to the usual site of anastomosis does not provide a suitable length of bronchus distal to the stricture for placement of large-caliber dilating bronchoscopes. Finally, Silastic stents placed across a distal left main bronchial anastomotic stricture may occlude the upper or lower lobe orifice as the stent bridges the stricture.

Silastic stents are tolerated exceptionally well. However, patients may require daily inhalation of N-acetylcytene to maintain the patency of the stent. DeHoyos and Maurer²⁰ reported dramatic improvement in pulmonary function with the Silastic stent. Fortunately, most stents are required only temporarily. After several months, the stent may be removed, and most stented anastomotic strictures maintain satisfactory patency after the stent has been removed.

Self-expanding metal stents have benefited from impressive technological improvement in recent years. These stents are available in a wide variety of lengths and diameters and are exceptionally easy to insert. In rare situations, when the airways distal to anastomotic stricture are too small to accept a Silastic stent or when a Silastic stent will obstruct one bronchus while stenting another, the use of a self-expanding metal stent may suit the purpose perfectly. The only caveat is that granulation tissue will rapidly overgrow an uncovered metal mesh stent, sometimes making it impossible to remove.

A recent addition to this armamentarium is a self-expanding plastic stent without interstices that permit ingrowth of granulation tissue. This stent (Poly-Flex, RUSCH, www.ruesch.de) appears to incorporate the best aspects of the two predecessor stents in a single useful device (Fig. 98-9). Long-term data concerning stability and function of these stents are lacking. For additional information on the use of upper airway stents, readers are referred to Chapter 47.

Anastomotic Infections

Because of the inherent ischemia occurring at the bronchial anastomosis after lung transplantation, fungal infections may develop at this site. Aspergillus and Candida have been identified as potential pathogens that can cause life-threatening bronchial anastomotic infection²¹ (see also Chap. 90). Nunley and colleagues²² identified 15 (24.6%) saprophytic fungal infections involving bronchial anastomoses in 61 recipients. Most of these infections were due to the Aspergillus spp. Stenotic airway complications were seen more frequently in recipients with anastomotic fungal infections (46.7%) compared with those without (8.7%). Specific complications from fungal infections that arose at the bronchial anastomosis included bronchial stenosis, bronchomalacia, and fatal hemorrhage. A number of interventions, including bronchial stenting, balloon dilation, electrocauterization, laser debridement, and radiation brachytherapy, have been used to treat these complications. Additionally, in the series by Nunley and colleagues, three fatalities were associated (4.9%) with saprophytic bronchial anastomotic infections.

If bronchoscopic inspection reveals extensive anastomotic pseudomembranes, a biopsy of the site should be performed to rule out an invasive fungal infection. The optimal treatment of bronchial anastomotic fungal infection is unknown. Success has been reported with a combination of systemic and inhaled antifungal agents. The addition of the inhaled antifungal therapy seems to be justified because aerosolization permits direct drug delivery to the poorly vascularized anastomosis. It also may be necessary to debride the site.^23,24

PLEURAL SPACE COMPLICATIONS

Hyperinflation

When undersized lungs are used in recipients, the airway pressure may increase when suction is applied to the chest tubes.²⁵ The negative pleural pressure presumably inhibits elastic recoil of the lung, leading to detrimental hyperinflation. With hyperinflation, the alveoli do not decompress completely when the patient exhales, resulting in an increase in functional residual capacity. As more mechanical breaths are delivered, a stacking of the breaths occurs, and the lungs function on a flatter portion of the volume-pressure curve. In extreme cases, the residual functional capacity leads to detrimental alveolar hyperexpansion and hemodynamic instability. Awareness of the potential for acute hyperinflation should invoke preventive measures such as avoiding chest tube suction or water seal while the patient is on positive-pressure ventilation.

Pneumothorax

Pneumothorax is encountered primarily in two circumstances. This first is the development of insignificant pneumothoraces in patients with obstructive lung disease, either emphysema or cystic fibrosis, who have undergone bilateral replacement and have received lungs smaller than the pleural space into which they have been implanted. Often a minimal degree of bilateral pneumothorax occurs subsequent to chest tube removal. In general, these pneumothoraces can be ignored. The pleural air will resorb eventually, and any remaining space will fill with fluid. Pneumothorax can occur as a result of airway dehiscence with communication into the pleural space. This is a rare occurrence and is usually readily managed by intercostal tube drainage with appropriate reexpansion of the underlying lung.

Pleural Effusion

Pleural effusions are common, particularly in recipients with a lung volume that is somewhat smaller than the pleural space. A sympathetic effusion will occur in association with underlying pulmonary infection or rejection. These effusions, as with others, generally clear with appropriate therapy of the underlying parenchymal condition.

Empyema

Pleural empyema is an uncommon complication, but its occurrence is associated with significant mortality. Spontaneous empyema is rare. It is more common for an empyema to develop after prolonged air leak owing to an open lung biopsy that has been performed on a patient receiving high-dose corticosteroids. Persistent air leak and failure to achieve reexpansion of the lung and subsequent pleurodesis give rise to a chronic pleural space that will become infected eventually. Nunley and colleagues performed a retrospective review of 392 transplant recipients and found empyema documented in 14 patients (3.6%).²⁶ In this series, empyemas tended to occur early in the posttransplant period. Four patients with empyema (28.6%) died secondary to infectious complications. No single predominant organism was isolated from the empyemic fluid, which had gram-positive, gram-negative, and saprophytic organisms. There was no relationship between the development of an empyema and the type of transplant performed or whether the transplant was done for a septic or nonseptic lung diagnosis.

We have treated a number of patients who developed empyemas with open drainage or rib resection or by creating a Clagett window or Eloesser flap. Of note, an empyema rarely occurs as a result of bronchial dehiscence in communication with the pleural space.

OTHER COMPLICATIONS

Gastroesophageal Reflux

One complication of lung transplantation that is currently receiving significant attention because of its association with chronic lung rejection is gastroesophageal reflux disease. Although prevalent in end-stage lung patients, its occurrence increases after lung transplantation, for multiple reasons. Nissen fundoplication has been used successfully to treat lung transplant patients with documented gastroesophageal reflux. This surgical procedure is associated with significant improvements in lung function, particularly if performed before the late stages of the bronchiolitis obliterans syndrome.

SUMMARY

Complications occur commonly in lung transplant recipients because of their general debilitation and the requirement for lifelong immunosuppression. Prevention and early recognition of these complications are important to control morbidity and mortality in this high-risk population. Focusing on complications can benefit the conduct of the initial surgery as well as identify areas that warrant high priority for future investigation.

EDITOR'S COMMENT

In the acute phase after lung transplantation, pulmonary dysfunction can be associated with an interesting mix of potential technical and biologic causes. Pulmonary edema apparent within the first hour generally reflects technical issues (e.g., venous narrowing or atrial torsion) or hyperperfusion of the first lung during sequential single lung transplants. In contrast, the ischemia-reperfusion response is generally delayed and occurs approximately 4 hours after transplantation. In the absence of a serologic mismatch, immune-mediated pulmonary edema rarely occurs within the first several days of transplantation.

–SJM

REFERENCES