Clemens Aigner, Doosang Kim, and Walter Klepetko
Lung transplantation is the established surgical treatment modality for end-stage parenchymal and vascular nonmalignant lung diseases. The International Society for Heart and Lung Transplantation (ISHLT) maintains the largest registry worldwide, which covers more than 3,000 transplants annually. The most common indication for lung transplantation has been chronic obstructive pulmonary disease (COPD) for a long time and still represents 34% of the overall worldwide transplant activity. With the introduction of new allocation algorithms such as the Lung Allocation Score (LAS) the percentage of patients transplanted for idiopathic pulmonary fibrosis (IPF) has risen. Cystic fibrosis is the third main indication for lung transplantation. The number of patients with pulmonary arterial hypertension undergoing transplantation has decreased and the preferred type of transplantation is nowadays bilateral lung transplantation. Bronchiectasis, sarcoidosis, retransplantation, connective tissue disease, lymphangioleiomyomatosis, and congenital heart disease are less common indications for lung transplantation.
The percentage of bilateral procedures is constantly increasing and has reached more than 70% of all lung transplant procedures worldwide. In our own center the percentage of bilateral procedures represent more than 90% of the overall lung transplant volume.
The background for this strategy can be found in the persistent survival benefit of bilateral lung recipients compared to single lung recipients. Although a selection bias might play a role in obtaining these superior results, the survival benefit is reproducible in the ISHLT database among patients with different diagnoses and different age groups (Fig. 3.1).
Advanced operative techniques of bilateral transplantation with special importance for pediatric recipients include lobar transplantation or split lung transplantation, which however, should be performed in specialized centers only. In addition, living-related lung donation can be another technical option for bilateral transplantation in selected patients.
There are few absolute contraindications, however, a number of relative contraindications, which vary center wise according to different individual experiences and differences in the availability of donor organs. Absolute contraindications are: Significant systemic diseases, severe extrapulmonary organ dysfunctions, recent malignancies, HIV infection, hepatitis B or C, pan-resistant MRSA or Burkholderia cepacia, active nicotine, and alcohol or drug abuse.
Figure 3.1 ISHLT Registry Slide showing Kaplan–Meier survival for single versus double lung transplantation.
The large number of relative contraindications must be individually judged from case to case: Osteoporosis, muscular or skeletal diseases, extreme cachexy or obesity, long-time corticosteroid therapy, infection with mycobacteria, coronary disease or left ventricular dysfunction, significant peripheral vascular disease, renal insufficiency, severe chest wall deformity, and psychosocial instability.
Pretransplant mechanical ventilation or extracorporeal support was initially considered a contraindication to lung transplantation. However, nowadays new allocation policies and the availability of innovative bridging options allow a safe bridge to lung transplantation in selected patients. The current trend is to keep patients as ambulatory as possible on the device.
The optimal time for listing for lung transplantation is at a stage when survival expectancy with lung transplantation exceeds the survival expectancy without transplantation and the patient is still in a condition to survive the expected waiting period. This implies that the timing of referral and listing for lung transplantation are not only based on recipient factors, but also have to take the organ availability and the allocation system into account. Allocation algorithms vary substantially in different countries. While algorithms based on waiting time only uniformly led to high waiting list mortality and have been abandoned by most countries, nowadays allocation algorithms using the LAS— which takes the expected waiting list mortality and the anticipated 1-year post-transplant survival into account—or center-based allocation are the most common systems in use.
The patient is positioned supine for bilateral lung transplantation with abducted arms and the chest is elevated by inflatable cushions (Fig. 3.2). The entire chest with either one or both groins is scrubbed in the sterile field. This provides access for the thoracic incision as well as for femoral cannulation if required. In this position no additional femoral arterial line to aid in blood pressure monitoring is usually required.
Figure 3.2 Standard position of the recipient for bilateral lung transplantation.
Standard approach to the chest for bilateral lung transplantation is usually the so-called clamshell incision, which combines a bilateral thoracotomy with a transverse sternotomy and ligation of the internal thoracic vessels (Fig. 3.3) and can also be gained by two separate thoracotomies (Fig. 3.4). Some centers also use a median sternotomy, which however, limits access to the posterior hilum.
In patients with separate bilateral thoracotomies the standard approach on the right side is the fourth intercostal space, which provides excellent access to all hilar structures and gives the opportunity for central cannulation for cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO) whenever necessary. The serratus anterior muscle is divided, while the latissimus dorsi can be left untouched. It is important to open the intercostal muscles from just posterior of the internal thoracic artery to the posterior end of the rib to allow full spreading of the intercostal space without causing rib fractures. On the left side it can be beneficial to choose the fifth intercostal space to facilitate exposure of the left atrium.
The clamshell incision provides the best exposure to both hili and the heart, especially when central cannulation for extracorporeal support is required. The decision whether to use separate incisions or a clamshell incision is based on the individual anatomic situation, especially the size of the recipient chest cavity, the extent of adhesions and whether intraoperative extracorporeal support will be required.
Figure 3.3 Approaches for bilateral transplantation—anterolateral thoracotomy.
Figure 3.4 Approaches for bilateral transplantation—clamshell incision.
Intubation is routinely performed with a left-sided double-lumen tube to allow unilateral ventilation. The choice, which lung is transplanted first depends on donor and recipient issues. The preoperative recipient V/Q scan is an important tool in this decision process. Usually the functionally worse side is transplanted first if the procedure is planned without the use of extracorporeal support. In case of a quality difference between the donor lungs, for example, due to traumatic alterations or other minor impairments, the better lung will be transplanted first. The implantation is performed in a sequential technique.
Recipient pneumonectomy is performed in standard fashion with stapling of the pulmonary artery and pulmonary veins. The bronchus is prepared centrally and opened with a scalpel. Two polydioxanone 4-0 stay sutures are placed at the angles between the cartilaginous and the membranous portion. Thereafter the lung is removed from the chest cavity and the pericardium is opened between the superior pulmonary vein and the phrenic nerve and circumferentially dissected to fully mobilize the left atrium. Thereafter, the pulmonary artery is prepared intrapericardially as central as possible to provide sufficient length for the anastomosis (Fig. 3.5). Once the intrapericardial dissection is completed the posterior mediastinum can be closed with a running PDS 4-0 suture to prevent bleeding from lymph nodes in this area, which is difficult to control after the lung has been implanted. Meticulous hemostasis has to be performed before beginning with the implantation.
Figure 3.5 Right hilum after intrapericardial preparation of the vessels.
Figure 3.6 Bronchial anastomosis using the single running suture technique.
The donor lung is then unpacked and the vessels are prepared and shortened. The pulmonary artery is carefully inspected for any intraluminal embolic material. The bronchus is shortened with only one cartilage ring remaining after the separation of the upper lobe bronchus and careful preservation of the peribronchial tissue. A bacteriologic swab is taken and any residual mucus is removed from the bronchial system. Thereafter the implantation is performed taking care of permanent topical cooling of the donor lung with ice slush. The first step is the bronchial anastomosis, which is performed using a double-armed 4-0 polydioxanone suture, starting at one end of the cartilaginous part, going over the membranous portion in a single running suture technique and then using the same single running suture for the anterior cartilaginous part (Fig. 3.6). In case of a bronchial size mismatch the imbalance is adjusted over the whole circumference. Usually the anastomosis is not covered with any additional tissue.
Thereafter, the left atrium is clamped intrapericardially with a Satinsky clamp. A close surveillance of the hemodynamic situation is warranted at this point. The left atrium is opened and anastomosed at a level where myocardial muscle tissue is present, since at the level of the veins the tissue is too fragile to allow for a safe anastomosis. Usually a 4-0 prolene running suture is used. An everting suture technique providing direct adaptation of donor and recipient endothelium is preferable to minimize the risk of thrombosis (Fig. 3.7). The suture is secured with a clamp but at this stage not yet knotted. The next step is clamping and opening the pulmonary artery. The anastomosis is once more performed in a running technique using a 5-0 prolene suture (Fig. 3.8).
After administering the initial dose of immunosuppression, retro- and antegrade flushing is performed to flush out the preservation solution and de-air the vasculature (Fig. 3.9). Thereafter, the sutures of the artery and atrium are knotted. Protective ventilation without any manual recruitment maneuvers is started at this stage. If the procedure is performed without the use of extracorporeal support, controlled reperfusion for 10 minutes with partial manual compression of the pulmonary artery should be performed to avoid initial volume overload of the newly implanted lung.
Finally hemostasis is performed with special attention to the donor pulmonary ligament and pericardium, which can be the source of substantial bleeding.
After completing the implantation of the first lung the recipient pneumonectomy and implantation of the donor lung is performed in an identical way on the contralateral side.
Figure 3.7 Left atrial anastomosis.
Figure 3.8 Pulmonary artery anastomosis.
Figure 3.9 Flushing the donor lung.
At the end of the operation 24 French drainages are placed in the costodiaphragmatic sinus and toward the apex and the incision is closed. It is beneficial to insert an additional small drain, which can be left in place to avoid basal fluid collection without compromising mobilization of the patient after the standard chest drains are removed.
The routine use of intraoperative extracorporeal support in bilateral lung transplantation remains an area of controversy. Some centers routinely perform all bilateral procedures on extracorporeal support, with the intention to avoid uncontrolled reperfusion of the first implanted lung and the advantage of intraoperative hemodynamic stability.
Other centers prefer to use extracorporeal support only when it becomes absolutely necessary, for example, in patients with pulmonary hypertension or whenever insufficient oxygenation on single lung ventilation or hemodynamic instability exists. Before pneumonectomy is performed on the first side the pulmonary artery can be manually compressed for 3 to 5 minutes to assess the cardiocirculatory situation. If hemodynamic instability is observed or pulmonary artery pressure approaches levels of systemic pressure, extracorporeal support is indicated. If the procedure is performed without support and the first implanted lung shows signs of poor initial graft function or developing reperfusion oedema immediate installation of extracorporeal support prior to pneumonectomy of the second is warranted to avoid additional damage to the newly implanted lung, which is otherwise exposed to the entire cardiac output during this phase.
The most common intraoperative support device still is CPB. However, an increasing number of institutions start adopting to use heparine-coated ECMO instead of CPB, which avoids full heparinization and therefore, leads to a reduced turnover of blood. In our institution ECMO is the standard support device since 2001. With CPB, a bilateral pneumonectomy can be performed prior to the implantation and both donor lungs can be reperfused at the same time. With ECMO a sequential approach is mandatory. The flow rate has to be chosen to maintain a pulsatile pulmonary blood flow, which can be monitored by the pulmonary artery pressure curve and the end-tidal CO2. If the flow is too high the entire cardiac output is bypassed by the lung, which then suffers from a second warm ischemia, which has to be avoided. Intraoperative extracorporeal support can be provided either by central or peripheral cannulation.
The decision whether to prolong the ECMO support in the postoperative period is taken after an initial stabilization phase. Factors influencing this decision are the quality of the donor organ, high-risk recipients especially with elevated pulmonary artery pressure as well as an intraoperative situation with low or continuously decreasing oxygenation index especially if combined with a high or rising pulmonary artery pressure. ECMO support is gradually reduced and if the ECMO can be removed, the patient is decannulated and the venous and arterial tubes of the ECMO are connected with each other and the ECMO system is left sterile at the table circulating in it until the patient leaves the operating room. This provides the possibility to reinsert the same ECMO system in the groin for prolonged support in case of deteriorating graft function. In our center postoperative extracorporeal support is liberally applied, especially in patients with pulmonary hypertension.
Size-reduced Lung Transplantation
In case of a pronounced size mismatch between donor and recipient or if the donor organ is found to be unexpectedly large during the retrieval process various options are available to downsize donor lungs to overcome size discrepancies. In case of a minor size mismatch of up to 20% TLC nonanatomical simple wedge resections are an effective tool to tailor the donor lung. The most accessible target areas for these resections are the middle lobe on the right side and the lingula on the left side. In case of a more pronounced size discrepancy, lobar transplantation becomes an option. The division of the lobes is performed at the back table immediately prior to the implantation to allow the most accurate size matching. The parenchyma of the donor lung is subdivided by standard stapler devices after identification of the artery in the interlobar fissure. The arterial branches are ligated, the veins and the bronchus are divided and after complete excision of the lobar carina, the lobes are separated and the implantation is performed in standard fashion. Polydioxanone 5-0 instead of 4-0 is used for the bronchial anastomosis. Lobar transplantations can be performed using all combinations of lobes, with the exception of a right upper lobe in combination with the middle lobe, which should be avoided since it requires leaving a bronchial stump, which is at high risk for dehiscence.
All of these techniques can also be applied to accept oversized donor organs for urgent pediatric or small adult recipients.
After uneventful bilateral transplantation early weaning and extubation should be the goal in patients with parenchymal lung disease. In patients operated for vascular lung disease weaning should not be precipitant due to the changes in the postoperative hemodynamic situation and the risk for left ventricular failure. To avoid fluid overload, infusions should be minimized and intravenous drips concentrated. Blood pressure is to be supported by catecholamines at low doses rather than by volume loading.
After extubation of the patient, early mobilization is crucial. Physiotherapy plays an important role in secretion clearance and should be started as early postoperative as possible. Usually patients can be discharged from the ICU 1 or 2 days after successful extubation.
Bronchoscopies are performed routinely on the first postoperative day, immediately before extubation and surveillance bronchoscopies start 1 week postoperative. Additional bronchoscopies are performed upon clinical necessity.
Since wound healing is decelerated due to the high doses of immunosuppression required, sutures and staples must not be removed before the 12th postoperative day. A lung function test and a computed tomography of the chest are performed before discharge of the patient.
After uneventful postoperative course patients can usually be discharged 3 weeks postoperative and subsequently spend 4 weeks at a rehabilitation centre.
Primary Graft Dysfunction (PGD)
PGD describes the development of a noncardiac pulmonary oedema caused by acute lung injury within the first 72 hours after transplantation. Differential diagnoses include venous obstruction and hyperacute rejection. The definition is based on the chest x-ray and pulmonary gas exchange and three degrees of severity are differentiated. Donor and recipient factors might contribute to the development of PGD, which occurs in up to 50% of patients. In most patients it is a mild and transient form; however, it can result in severe gas exchange impairment similar to ARDS. Treatment consists of negative fluid balance, increased positive end-expiratory pressure, vasodilators, protective lung ventilation, and in severe cases the use of venoarterial ECMO. Acute retransplantation for PGD has poor results and is not recommended.
Airway complications are nowadays very rare due to improved surgical technique and preservation strategies. Bronchial dehiscence is hardly seen any more in experienced centers. Bronchial stenosis can occur due to shrinking at the anastomotic site with incidence rates reported between 1% and more than 10%. Therapy of choice is balloon dilatation or insertion of a stent via rigid bronchoscopy. Granulation tissue can be removed via surgical or laser ablation. Bronchial stenosis can also be observed distal to the anastomosis, especially in the intermediate bronchus, which is most likely due to an ischemia fostered by denudation of the affected part of the bronchial system.
Hyperacute rejection is a rare event due to careful evaluation prior to transplantation and crossmatching between donor and recipient. Preformed antibodies against HLA or ABO blood group donor antigens cause a fulminate humoral reaction against the donor vascular endothelium within minutes to hours after implantation of the graft. Hyperacute rejection has an unfavorable prognosis concerning recipient survival.
Acute rejection episode have the highest incidence in the first 6 months postoperatively and have a broad spectrum of clinical presentation ranging from completely asymptomatic patients to severe dyspnea, cough, fever, and respiratory failure. Radiography is not infrequently unspecific, though perihilar or interstitial infiltrates and pleural effusions may be indicators. Diagnosis is usually established by transbronchial biopsy. Severity is classified into four grades (A0 to A4) according to the Society for Heart and Lung Transplantation.
Long-term survival after lung transplantation is still mainly limited by the development of chronic lung allograft dysfunction (CLAD). The irreversible decline in FEV1 caused by a fibroproliferation narrowing of the lumen of the small airways has been defined as bronchiolitis obliterans syndrome (BOS). In some patients a predominantly restrictive type of allograft function is observed. Risk factors include prior acute rejection episodes, especially late recurrent or refractory rejections, lymphocytic bronchitis or bronchiolitis, cytomegalovirus infections, insufficient immunosuppression, HLA mismatches, and eventually airway ischemia. Symptoms are unspecific, patients usually report about insidious dry or productive cough and dyspnea. Different treatment strategies are used including augmentation of the immunosuppression, switching from cyclosporin A to tacrolimus or sirolimus, cytolytic therapy, and photopheresis. Treatment usually slows but does not terminate functional decline. Retransplantation is a viable option in selected patients.
Due to the immunosuppression defense mechanisms are diminished and therefore, infections pose a great risk to transplant recipients. The permanent exposure of the transplanted organ to the outside environment and the impairment of cough reflex and mucociliary clearance make lung transplant recipients especially prone to infectious problems.
Bacterial infections are the most common infections in the first 2 postoperative months. Broad-spectrum antibiotics are applied prophylactically in the early postoperative phase. Additional antibiotics are administered according to culture and bacterial sensitivity data.
Viral infections are almost solely from the herpes group viruses, with cytomegalovirus (CMV) being the predominant source of infection. Infections may occur due to reactivation of the virus or as primary infections mainly in the constellation of a CMV negative recipient who receives a graft from a CMV positive donor. Symptoms are nonspecific and frequently accompanied by leucopenia. Treatment of choice is currently ganciclovir or valganciclovir. In addition, CMV hyperimmunglobulin (IgM) has been proven beneficial. All patients are routinely screened for CMV infection at every outpatient follow-up appointment.
Fungal infections occur mainly during the first 2 months after transplantation with Aspergillus species and Candida species being the predominant pathogens. Treatment of manifest infection is performed by administration of IV antifungal agents according to the underlying subtype.
Protozoan infections, especially with Pneumocystis carinii or Toxoplasma gondii are usually prevented by lifelong administration of trimethoprim/sulfametrol.
Patients with bilateral lung transplantation show better long-term survival rates compared to single-lung recipients across all indications in the ISHLT registry. These differences might be influenced by a selection bias, however, are consistently reproducible. Survival statistics provided by the ISHLT report overall 1-year, 3-year, and 5-year survival rates of 79%, 63%, and 52% respectively. However, there has been a significant rise in survival rates in the most recent period. In our center a perioperative 30-day survival of 95.8% can be achieved with bilateral lung transplant procedures. Long-term survival according to the ISHLT registry is 57% for bilateral recipients at 5 years, compared to 48% for single-lung recipients. Even better results can be achieved in high volume centers with 5-year survival rates approaching 70%.
Quality of life is markedly improved after lung transplantation. Independence from oxygen insufflation with diminished dyspnea, improved sleep, improved mobility, and energy to accomplish activities of everyday life all collude for improved quality of life. Three years after transplantation according to ISHLT more than 40% of the patients are full- or part-time employed. Yet with development of chronic lung allograft this trend reverses, though most patients remain active despite the development of CLAD.
Significant evolvements over the last two decades have taken place in the field of lung transplantation. Bilateral transplantation has become the procedure of choice for all indications. The surgical technique has been standardized and is performed in a similar fashion throughout the world with remaining variation in details of the procedure.
Despite the fact that lung transplantation remains to be a technically demanding procedure, mortality and morbidity directly related to the surgical technique can be minimized by meticulous surgical performance and experience. The long-term survival results of bilateral lung transplantation are uniformly superior to those of single lung transplantation making it the preferred approach. Technical refinements in combination with advances in organ preservation and immunosuppression have contributed to improved long-term survival during the last decades.
Recommended References and Readings
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