Jose P. Garcia and Ravi Shah
Introduction
The first heart–lung transplant (HLT) was performed at Stanford University in 1981 by Dr. Bruce Reitz. While primary lung and heart transplantation is the mainstay of therapy in patients with advanced cardiac or pulmonary failure, combined heart–lung transplantation remains an option for patients with severe heart–lung failure. Patients with pulmonary hypertension and RV failure (Eisenmenger syndrome), intrinsic pulmonary disease such as cystic fibrosis, or congenital heart disease, which are etiologies that do not permit single organ transplantation are the most common candidates for this procedure. The increased number of transplant centers and their pool of status 1A recipients have made it increasingly difficult to obtain quality heart–lung blocs thus extending the already long waiting period. Also, improved techniques for single- and double-lung transplantation have improved outcomes in patients with end-stage lung disease since the 1990s. These factors have led to a significant decline in the number of combined HLTs performed yearly. Data from the International Society of Heart and Lung Transplantation Registry demonstrates that 4,310 adult individuals had undergone combined heart–lung transplantation before 2012, with between 60 and 100 dual organ transplants per year performed worldwide since 2000 (Fig. 4.1). Despite nearly 36% of dual organ transplants concentrated in seven hospitals (7% of overall transplanting centers) performing 4 to 9 transplants per year, the majority of HLTs occur in low-volume centers, impressing the need for standardized surgical technique and postoperative management to optimize outcomes (Fig. 4.2). This emerging collection of demographic data surrounding heart–lung transplantation has revitalized medical and surgical considerations in this area. In this chapter, we will review published indications and outcomes in combined heart–lung transplantation, and will detail the surgical approach to dual heart–lung transplantation.
INDICATIONS
Nearly 70% of transplant recipients are between 18 and 49 years old (median age 42 years), with the major indication being congenital heart disease or pulmonary arterial hypertension in adults (Table 4.1). Current cumulative survival data between 1982 and 2011 indicate a 3-month survival of 71%, 1-year survival of 63%, and a 10-year survival of 31% with a 10-year median survival for those surviving the first year after transplant (Fig. 4.3). In contrast, the primary indication for pediatric heart–lung transplantation is cystic fibrosis. Of note, data regarding the survival benefit of heart–lung transplantation for Eisenmenger syndrome remains mixed. Although the long-term survival benefit may be debatable, there is a clear improvement in the quality of life in this group of patients that undergo transplant. Over the last 10 years, there has been a decline in HLTs and an increase in double-lung transplants for cystic fibrosis. Experience shows that normalization of pulmonary pressures following lung transplantation allows for significant recovery of the right ventricle. In patients with noncomplex cardiac defects, repair of the defect combined with single- or double-lung transplantation may be a viable alternative. Also, fewer adults in general are requiring HLTs because of new and improved medical therapies. In younger patients with severe right heart failure and severe pulmonary hypertension, combined HLT is still the best option. Combined HLT may yet see more use as more congenital patients are living longer and reaching adulthood.
Figure 4.1 Number of transplants reported by location and year.
Figure 4.2 Average center volume (transplants: January 2000 to June 2012).
TABLE 4.1 Adult Heart–Lung Transplant Diagnosis (Transplants: January 1982–June 2012)
Figure 4.3 Kaplan–Meier survival for all ages (transplants: January 1982 to June 2011).
Patient Selection for Heart–Lung Transplant
As with any surgical procedure or intervention, patient selection is closely linked to outcomes. HLT candidates should meet the established criteria for isolated heart or lung transplantation. The HLT recipient is listed under both heart and lung allocation systems through the United Network for Organ Sharing (UNOS). As in lung transplant, heart–lung candidates are stratified according to their lung allocation score (LAS) and the listing criteria are very similar. In addition, most candidates are New York Heart Association functional class III or IV. The UNOS LAS is meant to allow the sickest patients and the ones with the best chance of recovery post transplant to have priority in receiving organs. The LAS is not comparable to the stratification system used for heart transplant. The LAS also does not clearly reflect the extent of severity of the disease in patients with pulmonary hypertension. These patients may be best served by using the cardiac listing with a special exemption. One criterion that is more stringent in heart–lung than in isolated heart or lung is age. Most centers have an age cut off of 50 years and only a few centers, such as Stanford University, have transplant heart–lung blocs in patients over 60 years of age. With the existing organ shortage, we must do everything possible to ensure a good outcome and prolonged use of the donor organs, especially since each bloc could be used to transplant three different recipients. Another important factor that needs to be considered is recipient–donor size matching. It is critically important not to oversize the heart–lung bloc. As reported by the Papworth Hospital transplant team, attaining predicted total lung capacity at 1 year is to be expected and if not attained then that is suggestive of complications with the transplanted lungs. In the perioperative period, oversizing can lead to tamponade and low cardiac output.
SURGERY
En Bloc Heart–Lung Recovery
All heart/lung recoveries begin with review of all donor data and pertinent tests, which include serologies, blood gases, CXR, bronchoscopy, chest CT and cardiac catheterization if available. ABO blood type and recipient compatibility should be clearly documented. The donor is placed on the OR table in the supine position with the arms tucked at the sides. The donor height is also rechecked for accuracy especially in an en bloc heart–lung recovery, as size matching is critical. Prior to prepping, a bronchoscopy is performed as days may have passed since the initial examination was performed. Throughout the recovery process, it is best to use low-dose vasoconstrictors, such as Neo-Synephrine or vasopressin for hypotension to minimize the amount of crystalloid that is given. The FiO2 is maintained at 40%. The donor is then prepped and draped up to the sternal notch. A midline sternotomy incision is then performed and continued further cephalad than the usual incision for a heart operation to allow for easier dissection and isolation of the suprainnominate proximal trachea, which is an easier approach than between the aorta and the superior vena cava (SVC). The pericardium is incised down the midline and then laterally down both sides at the level of the diaphragm. Sutures are placed along the pericardial edges and a pericardial well is created prior to entering both pleural spaces. The heart and lungs are visually inspected and palpated. If no abnormalities are appreciated, the recipient team is notified and instructed to proceed. The space between the aorta and pulmonary artery is then dissected with the cautery to allow for x-clamping of the aorta. The SVC is dissected free as cephalad as possible and encircled with a suture, which is then tied prior to x-clamping. The azygos vein is divided at this time. The SVC is also dissected free from the underlying right pulmonary artery. The pericardial reflection around the IVC is released to allow for mobilization. The trachea is then identified and dissected above the innominate vein and between the innominate artery and the left common carotid artery. The trachea is encircled with an umbilical tape. When the abdominal team is ready for x-clamping, 300 International Unit /kg of intravenous heparin is administered. A cardioplegia cannula is placed in the ascending aorta approximately 2.5 cm above the aortic valve. This cannula can be left in place and used for further cardioplegia and de-airing at the time of implantation. A pneumoplegia cannula is then placed in the pulmonary artery at the level of the bifurcation, which is then removed at the time of PA transection. A Satinsky clamp is then placed at the base of the left atrial appendage and the appendage is resected. This site will serve as the venting site for the plegia. The SVC is then ligated, making sure there are no central catheters in place. At this time, 500 mcg of PGE-1 is directly injected into the pulmonary artery next to the cannula. The systolic blood pressure will drop precipitously and at least 1 minute is allowed for the PGE-1 to circulate and then the IVC can be transected. The aortic clamp is placed, the Satinsky is removed from the left atrium, cardioplegia and pneumoplegia are initiated and ice is placed on the heart and both pleural spaces. We prefer to administer 2 L of 4°C Plegisol (Hospira, Inc., Lake Forest, IL) for the heart. For the lungs, we administer 60 mL/kg of 4°C Perfadex (Xvivo Perfusion, Inc., Englewood, CO) at a pressure of 10 to 15 mm Hg. The average-sized donor should receive between 4 and 5 L of pneumoplegia. Since the left atrium is not entered, we do not administer retrograde pneumoplegia, as is customarily done in isolated lung transplant. To avoid over distention, lung inflation is maintained at 50% of total lung capacity, airway pressures at less than 20 cm of H2O and FiO2 is maintained at 40%. Once the plegias have been administered, the aorta, pulmonary artery, IVC, and SVC are transected. Inferiorly on the right side, the pericardium is divided down to the esophagus and the dissection is carried cephalad just anterior to the esophagus up to the azygos vein. Once the azygos vein is transected, the dissection can be carried to the site of the umbilical tape on the proximal trachea. This maneuver prevents injury to the right upper lobe bronchus. Similarly, this dissection is performed on the left lung. TA 30 3.5 mm linear stapler (Ethicon, Inc. Somerville, New Jersey) is applied across the trachea and with the lungs partially inflated, the endotracheal tube is retracted and the stapler fired. A second line of staples is applied and then the trachea is divided between staple lines using a knife. The trachea and lungs are separated from the posterior ligaments and the heart–lung bloc is removed from the field (Fig. 4.4). The organs are then placed in Perfadex solution, triple bagged and transported on ice to the recipient hospital.
Figure 4.4 Heart and lung, “en bloc.”
Recipient Explant
The recipient is placed in the supine position on the OR table with the arms tucked to the side, after monitoring lines and a transesophageal echocardiography probe have been placed. The major goals in explanting the heart and lungs are to avoid injury to the phrenic, vagi, or the recurrent laryngeal nerves and to leave a hemostatic operative field. A midline sternotomy or clamshell incision is made and the heart is exposed. As a significant number of recipients have congenital disease, it is not unusual for this to be a redo sternotomy and standard precautions should be taken. Once the heart has been mobilized, the pleural spaces are entered and any adhesions are taken down with a cautery. The left and right phrenic nerves are mobilized leaving a minimum of 2 cm of pericardium above and below the nerve as a pedicle (Fig. 4.5). Heparin 300 International Unit/kg is administered and the aorta and venae cavae are cannulated for cardiopulmonary bypass. The patient is cooled to 32°C. Tourniquets are placed around both the IVC and SVC and are snared after the initiation of cardiopulmonary bypass. At the appropriate time, an aortic x-clamp is placed and a cardiectomy is performed in standard fashion. The aorta, PA, IVC, and SVC are transected and only the posterior wall of the left atrium is left behind (Fig. 4.6). Alternatively, if a right atrial to right atrial anastomosis is to be performed, then the IVC and SVC are left intact. With the heart removed from the field, the posterior wall of the left atrium is divided midline. The pulmonary veins on the left side are mobilized circumferentially (Fig. 4.7) and then the PA and bronchus are mobilized in similar fashion (Fig. 4.8). The inferior pulmonary ligament and any remaining attachments are transected and the left lung is removed from the field. The right hilum is dissected and removed from the field after the ligament attachments have been transected. The trachea should be transected two rings proximal to the bifurcation of the bronchi and the bronchial stumps resected. Lastly, the remaining pulmonary artery is removed, leaving behind a small area adjacent to the ligamentum arteriosum to prevent recurrent laryngeal nerve injury (Fig. 4.9). Posteriorly, care should be taken not to injure the vagi nerves. Meticulous hemostasis should be performed prior to beginning the implantation.
Figure 4.5 Mobilization of phrenic nerves.
Recipient Implant
Once the ABO compatibility is confirmed, the donor heart and lung bloc is removed from the transport container and brought on to a sterile back table. The trachea is transected one cartilaginous ring above the carina. The tracheobronchial tree is irrigated and aspirated and cultures are sent for microbiology. The bloc is then brought into the chest and with gentle manipulation, the right lung is passed beneath the right phrenic nerve pedicle (Fig. 4.10). In similar fashion, the left lung is passed under the left phrenic nerve pedicle. The membranous tracheal anastomosis is performed using continuous 3-0 PDS suture. The posterior membranous portion can be performed using a running suture or with interrupted sutures while the cartilaginous trachea is anastomosed with interrupted sutures (Fig. 4.11). Once the tracheal anastomosis has been completed, gentle ventilation with room air and half-normal tidal volumes are initiated to reduce atelectasis. Topical cooling of the lungs with iced saline is continued during this time. Next, the IVC and SVC anastomoses are performed in sequential fashion using a continuous 4-0 polypropylene suture. Once the cavae have been anastomosed, the patient is rewarmed to 37°C. Lastly, the ascending aorta anastomosis to the donor aorta is carried out using 4-0 polypropylene suture in end-to-end continuous fashion. Prior to removing the clamp, the left atrium venting site must be closed with running 4-0 polypropylene suture. The aorta and pulmonary artery are then de-aired and the aortic x-clamp is removed. Prior to removing the aortic cross clamp, 1,000 mg of Solu-Medrol is administered. The heart is defibrillated as needed. The patient is then gradually separated from cardiopulmonary bypass after an appropriate reperfusion period has passed (Fig. 4.12).
Figure 4.6 Recipient cardiectomy for bicaval implant.
Figure 4.7 Posterior left atrial wall is divided and left pulmonary veins are mobilized posteriorly and circumferentially.
Figure 4.8 Left bronchus and left PA are dissected free from attachments to allow for transection.
Figure 4.9 Remnant of main pulmonary artery is left behind in the area of ductus ligament to prevent injury to recurrent laryngeal nerve.
Figure 4.10 Heart and lungs are placed in chest passing each lung under the phrenic nerves.
Figure 4.11 Tracheal anastomosis.
Once the patient is off bypass, the lungs are ventilated using low PEEP in the 3 to 7 cm of H2O range and the FiO2 is set at 40%. If the heart rate is too slow, atrial and ventricular pacing wires are placed and the heart is paced at 100 to 110 bpm. Thoracostomy tubes are placed in both apices and over both diaphragms. The chest is closed in standard fashion, once adequate hemostasis has been achieved. After the drapes have been removed and the patient is hemodynamically stable, the double-lumen endotracheal tube is exchanged for a single-lumen tube. A bronchoscopy is then performed to inspect the tracheal anastomoses and to remove any blood or mucus in the bronchial tree.
POSTOPERATIVE MANAGEMENT
Acute postoperative complications are usually evident while the recipient is still in the operating room. Common complications include bradycardia secondary to sinus node dysfunction and occurs in 10% to 20% of cases, although this usually resolves within a week. It is rare that a permanent pacemaker is required. As with isolated heart transplantation, the use of bicaval anastomosis has been reported to reduce the incidence of sinus node dysfunction and tricuspid regurgitation. Atrial and ventricular pacing wires should be used to increase the heart rate to 100 to 110 bpm as cardiac output is largely dependent on heart rate in the HLT patient. If needed, isoproterenol (0.005 to 0.01 ug/kg/min) can be used to increase heart rate and decrease pulmonary pressures. If the myocardial function is decreased, we either use epinephrine (1 to 3 mcg/min) and milrinone (0.1 to 0.5 mcg/kg/min) or dobutamine (1 to 5 mcg/kg/min). If the patient is vasodilated then we start vasopressin and titrate to 0.04 units/min and then add norepinephrine (1 to 10 mcg/min) if further vasoconstriction is needed. If hypertension is experienced, then we use Nipride (10 to 150 mcg/min) or nitroglycerin (10 to 300 mcg/min) to maintain a systolic blood pressure between 90 and 110 mm Hg as we do with all postcardiotomy patients. If a coagulopathy persists after the protamine has been administered, it should be aggressively treated with fresh frozen plasma, platelets, and cryoprecipitate as needed. Vitamin K (phytonadione) or DDAVP (Desmopressin) may also be considered. The patient should not leave the operating room if significant blood loss is ongoing.
Figure 4.12 Heart–double-lung transplant.
Morbidity and Mortality
The most common complications after HLT are hypertension, renal dysfunction, hyperlipidemia, diabetes, coronary artery vasculopathy, and bronchiolitis obliterans. Early mortality (within 30 days to 1 year) after heart–lung transplantation is most commonly related to noncytomegaloviral infections, primary graft dysfunction, or surgical/technical complications. After 1 year, infectious complications, bronchiolitis, and graft failure are the predominant source of death. Donor age (higher), transplant center volume (lower), and indication for transplantation remain significant predictors of 1-year mortality post dual organ transplant. Rejection is still commonly seen during the first year post transplant occurring in approximately 70% of recipients. Of note, rejection in the lungs is seen more frequently than in the heart. For this reason, most centers rely on transbronchial biopsies rather than endomyocardial biopsies (Table 4.2). Even if lung biopsies are positive, endomyocardial biopsies remain negative. If a significant decline in heart function is noted, then endomyocardial biopsies are warranted. The Harefield Hospital group has also reported that improved survival is seen in retransplant patients who do not have preformed antibodies, sputum bacteria, and are out further than 18 months post the initial transplant.
Coronary vasculopathy is still a major factor in decreasing long-term survival in HLT recipients, although seen less commonly than in isolated heart transplant. Angina is rarely seen in these patients because the heart is denervated but other signs and symptoms consistent with coronary insufficiency can be seen such as myocardial infarction, impaired left ventricular function, arrhythmias, congestive heart failure, and sudden death. The vasculopathy has been attributed to immune-mediated injury to the coronary vascular endothelium. Although the etiology of this vasculopathy appears to be multifactorial, cytomegalovirus (CMV) infection may play a more dominant role. HLT recipients should undergo coronary angiograms on a yearly basis. Also, intracoronary ultrasound can be used as a tool in assessing diffuse disease. In the setting of discrete proximal lesions, coronary bypass grafting and percutaneous angioplasty have both been employed.
TABLE 4.2 Adult Heart–Lung Transplant Cumulative Morbidity Rates in Survivors within 1- and 5-Year Post-Transplant (FoIIow-ups: April 1994–June 2012)
TABLE 4.3 Adult Heart–Lung Transplant Cause of Death (Deaths: January 1992–June 2012)
As with any organ transplant, infection is commonly seen and a common reason for hospital readmission. In the Stanford University experience, approximately 80% of recipients had some type of infection at 3 months post transplant. About half of these infections are bacterial and only 10% to 15% were found to be fungal. CMV is the most common viral infection and usually occurred in the first 2 months post transplant.
With regard to recipient mortality, early death is usually attributed to graft failure and technical issues. Late death is due largely to non-CMV infection and bronchiolitis obliterans. Acute rejection is a cause of death in less than 2% of cases whether early or late (Table 4.3).
CONCLUSIONS
Although significant improvements have been made in HLT outcomes, further advances must be made if this surgical option is to be used more frequently. It is clear that for younger patients with end-stage heart and lung disease, HLT improves greatly the quality of life. Nonetheless, obstacles that will need to be overcome include graft rejection and a limited donor pool. We remain hopeful that xenotransplantation will become a viable option in the future solving the organ shortage issue. Also, improvement of immunosuppression and organ preservation techniques may also improve outcomes. The use of ex vivo technology also shows promise in improving organ preservation.
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