Balsam
L
Bi
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Yuh
D
Di
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Robbins
R
Ci
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Reitz
B
Ai
. Heart-Lung and Lung Transplantation.
In: Cohn LH, Edmunds LH Jr, eds. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2003:1461-1490.
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Chapter 61 |
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INTRODUCTION |
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HISTORICAL BACKGROUND |
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Long before the first successful human heart-lung transplants were reported, thoracic organ transplantation flourished in the laboratory. In the 1940s, Demikhov developed the first successful method of en bloc heart-lung transplantation in dogs. In his series of 67 dogs, the longest survivor lived for 6 days postoperatively.2 These remarkable studies demonstrated the technical feasibility of heart and lung replacement, yet remained largely unknown in the West until the 1960s. In 1953, Marcus and colleagues at the Chicago Medical School described a technique for heterotopic heart-lung grafting to the abdominal aorta and inferior vena cava in dogs (Fig. 61-1).3 Later studies in the 1960s and early 1970s examined the physiological effect of total denervation on heart and lung function. Discouraging studies by Webb and Howard in 1957 showed failure to resume normal spontaneous respiration following heart-lung replacement in dogs.4 This physiologic phenomenon was confirmed by several other groups doing research in dogs, including Lower et al in 1961.5 Fortunately, later studies in primates by Haglin,6 Nakae,7 Castaneda,8,9 and their colleagues showed that unlike dogs, primates resume a normal respiratory pattern following complete denervation with cardiopulmonary replacement. The 1970s saw the development of improved immunosuppressive medications, particularly cyclosporine, which prevented rejection of primate heart-lung allografts after transplantation. A Stanford series showed survival for well over 5 years after heart-lung allografting in primates.10 In the 1980s, Reitz et al reported a modification to the standard technique of heart-lung replacement, using a retained portion of the right atrium for a single inflow anastomosis instead of separate caval anastomoses (Fig. 61-2).11 This technique preserved the donor sinoatrial node and eliminated the potential for caval anastomotic stenosis. These studies laid the groundwork for a clinical trial of heart-lung transplantation at Stanford University. On March 9, 1981, Reitz et al performed the first successful human heart-lung transplant in a 45-year-old woman with end-stage primary pulmonary hypertension.12
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Experimental lung transplantation developed in parallel with heart-lung transplantation. In 1949, Henry Metras described important technical concepts, including preservation of the left atrial cuff for the pulmonary venous anastomoses and reimplantation of an aortic patch containing the origin of the bronchial arteries to prevent bronchial dehiscence.13 Airway dehiscence was a major obstacle in experimental lung transplantation, and he proposed that preservation of the bronchial arterial supply was critical to airway healing. Unfortunately, this technique was technically cumbersome and never gained widespread popularity. In the 1960s, Blumenstock et al advocated transection of the transplant bronchus close to the lung parenchyma to prevent ischemic bronchial necrosis.14 Additional surgical modifications were developed to prevent bronchial anastomotic complications, including telescoping of the bronchial anastomosis, described by Veith in 1969,15 and coverage of the anastomosis with an omental pedicle flap, described by the Toronto group in 1982.16 Corticosteroids were found to be another contributor to poor bronchial healing,17 so with the introduction of cyclosporine immunosuppression in the 1970s, the stage was set for successful clinical lung transplantation.
The first human lung transplant was described in 1963 by Hardy et al at the University of Mississippi.18 The patient, a 58-year-old man with lung cancer, survived 18 days postoperatively. Over the next two decades, nearly 40 lung transplants were performed without long-term success. In 1986, the Toronto Lung Transplant Group reported the first series of successful single lung transplants with long-term survival.19 Improved immunosuppression, along with careful recipient and donor selection, were pivotal to their success. For patients with bilateral lung disease, en-bloc double lung replacement was introduced by Patterson in 1988.20 This technique was later replaced by sequential bilateral lung transplantation, described by Pasque et al in 1990.21 More recent operative innovations include living lobar transplantation, an alternative to cadaveric bilateral lung transplantation.
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INDICATIONS AND EVALUATION FOR HEART-LUNG AND LUNG TRANSPLANTATION |
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When heart-lung transplantation was introduced in 1982, it provided a lifesaving therapeutic option for patients with end-stage cardiopulmonary disease and end-stage septic lung disease. Since that time, the techniques of single and double lung transplantation have improved considerably, and the indications for combined heart-lung replacement have become fewer. Moreover, donor organ distribution algorithms, which appropriately distribute donor hearts to critical heart recipients, have also limited the availability of heart-lung blocs.
Heart-lung transplant volumes peaked in the late 1990s; in 2001, only 104 operations were performed worldwide.1 The most common indications include congenital heart disease with Eisenmenger's syndrome, primary pulmonary hypertension, and cystic fibrosis. The diagnostic profile of heart-lung transplant recipients reported to the Registry of the International Society for Heart and Lung Transplantation (ISHLT) is shown in Figure 61-3.
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The data regarding the long-term survival benefit of heart-lung transplantation in patients with Eisenmenger's syndrome remains unclear.22 Some data suggests that pulmonary hypertension in these patients has a more favorable prognosis than other types of pulmonary hypertension. There is clear evidence, however, that quality of life is improved by transplantation.23 In patients with simpler cardiac defects, repair of the cardiac defect combined with single or bilateral lung transplantation is another option.
Primary pulmonary hypertension with right-sided heart failure is the second most common diagnosis in heart-lung transplant recipients. Nearly one quarter of patients in the ISHLT registry carry this diagnosis. Recently, there has been a shift toward single and bilateral lung transplantation in this population.24 The shift in paradigm is based on the finding that right heart function often recovers after normalization of pulmonary pressures with lung transplantation. However, in patients with severe right-sided heart failure and primary pulmonary hypertension, heart-lung transplantation is clearly the operation of choice.
The balance of heart-lung transplants are performed for a variety of cardiac and pulmonary diseases. These include cystic fibrosis and other septic lung diseases, severe coronary artery disease with intercurrent end-stage lung disease, and primary parenchymal lung disease with severe right-sided heart failure (e.g., idiopathic pulmonary fibrosis, lymphangioleiomyomatosis, sarcoidosis, and desquamative interstitial pneumonitis).
Septic lung disease was historically a significant indication for heart-lung transplantation. The domino procedure, which emerged in the late 1980s, took explanted hearts from these patients and offered them to a second recipient in need of heart transplantation.25–27 While studies have shown equivalent survival in recipients of domino heart grafts, currently the domino procedure is rarely performed. Instead, bilateral lung transplantation has become the procedure of choice for end-stage septic lung disease.28,29 It avoids the pitfalls of cardiac denervation and graft coronary artery disease that characterize heart-lung transplantation.
Indications for Lung Transplantation
In recent years, the number of lung transplant procedures performed annually has reached a plateau. Worldwide, 1412 lung transplants were performed in 2000. Nearly half were single lung transplants and the remainder were bilateral lung transplants. A small number of living lobar transplants are also being performed annually.1
The primary indications for single lung transplantation are emphysema and pulmonary fibrosis (Fig. 61-4A). Patients with emphysema comprise nearly one half of single lung transplant recipients. In some cases, hyperinflation of the native emphysematous lung may lead to compressive atelectasis and restriction of the donor lung. This may result in a significant ventilation/perfusion mismatch. In such cases, native lung volume reduction can be used to preserve allograft function.30 Some evidence exists that late allograft function may be superior in emphysema patients treated with bilateral rather than single lung transplantation;31 however, given the donor organ shortage, single lung transplantation remains the preferred therapeutic option.
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Less than 3% of all single and bilateral lung transplants are retransplantations.1 Overall, survival is poorer compared to first-time transplantation, though certain subsets of patients perform better than others. The Pulmonary Retransplant Registry has collected data from 230 patients at over 40 centers and has found that 1-year survival of ambulatory, nonventilated patients undergoing retransplantation after 1991 is in fact comparable to first-time transplants.32
Finally, lobar transplantation is another option for end-stage lung disease. Living lobar transplantation was developed by Starnes et al, and has its greatest application in children with cystic fibrosis. The left lower lobe and right lower lobe from two donors are transplanted into the recipient. The procedure is most applicable to children and adults of small stature. Results in children have been superior to cadaveric transplants in terms of long-term survival and freedom from bronchiolitis obliterans syndrome. In adults, results have been comparable to cadaveric transplants.33–35
The primary objective in recipient evaluation is to select individuals with progressively disabling cardiopulmonary or pulmonary disease who still possess the capacity for full rehabilitation after transplantation. It is notable that early attempts in the history of thoracic transplantation were thwarted by selection of critically ill recipients, and it was not until the development of strict recipient selection criteria that heart-lung and lung transplantation were met with success.
Candidates should have a life expectancy of less than 18 to 24 months despite the use of appropriate medical or alternative surgical strategies. On average, waiting times can be from 6 to 36 months. Unfortunately, mortality while on the waiting list remains nearly 20% for both lung and heart-lung transplant candidates. Therefore, it is imperative that recipients be identified as early as possible within the "transplant window".36
Disabling symptoms prompting consideration for transplantation typically include dyspnea, cyanosis, syncope, and hemoptysis. Most recipients for heart-lung transplantation also fall within New York Heart Association functional classes III or IV.37 Potential recipients are identified by their local primary physicians and referred to transplantation centers for further evaluation. This includes a complete history, physical exam, laboratory tests, specialized studies, and a psychosocial evaluation.
Among most heart-lung transplant programs, the upper recipient age limit is 50 years. For bilateral lung transplantation, the upper limit is 55 years, and for single lung transplantation, it is 60 years. These values represent a relaxation of previous age limits, reflecting the ongoing evolution in recipient selection criteria. Unfortunately, with the expansion of recipient eligibility, the problem of donor organ shortage is further exacerbated.
There are well-established contraindications to lung and heart-lung transplantation (Table 61-1). Significant multisystem disease is a contraindication, though occasionally multiorgan transplants have been performed. Renal dysfunction, active malignancy, infection with HIV, hepatitis B antigen positivity, hepatitis C infection with biopsy-proven liver disease, and infection with panresistant respiratory flora are absolute contraindications. Relative contraindications include active extrapulmonary infection, symptomatic osteoporosis, recent history of active peptic ulcer disease, cachexia or obesity, drug or alcohol abuse, and psychiatric illness or history of medical noncompliance. Cigarette smokers must quit smoking and remain abstinent for several months before transplantation. Patients with previous histories of thoracic surgery are evaluated on a case-by-case basis. In patients requiring systemic corticosteroids, tapering to the lowest tolerable level, preferably below 10 mg/day, is critical to prevent airway healing complications. Finally, mechanical ventilation is generally considered a contraindication to transplantation; repeated studies have shown that these patients have significantly worse immediate and long-term survival after transplantation.38 In addition to meeting these criteria, a stable and supportive socioeconomic environment is an important criterion.
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Tests required for transplant listing are reviewed in Table 61-2. Diagnostic studies that are particularly useful in evaluating potential recipients include full pulmonary function tests, an exercise performance test, electrocardiogram, echocardiogram, 24-hour creatinine clearance, and liver function tests.
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Patients deemed suitable for transplantation during the initial evaluation are subjected to a final phase of testing (see Table 61-2). If accepted by the transplant review committee, they are listed on the national transplant registry on the basis of clinical urgency, time on the waiting list, ABO blood group, and thoracic cage dimensions. Most transplant centers will require patients to reside within several hours of the center by automobile or air charter.
ABO compatibilities are strictly adhered to, because isolated cases of hyperacute rejection have been reported in transplants performed across ABO barriers. Donor-to-recipient lung volume matching is based on the vertical (apex to diaphragm along the midclavicular line) and transverse (level of diaphragmatic dome) radiologic dimensions on chest x-ray, as well as body weight, height, and chest circumference. In practice, matching donor and recipient height seems to be the most reproducible method for selecting the appropriate donor lung size, and the dimensions of the donor lungs should not be greater than 4 cm over those in the recipient. It is possible, however, to downsize donor lungs by lobectomy if needed.
In a series of 82 heart-lung transplants at Papworth Hospital, Tamm et al recorded recipient lung volumes after transplantation and compared them to preoperative and predicted volumes to evaluate the influence of donor lung size and recipient underlying disease.40 The investigators demonstrated that by 1 year after surgery, total lung capacity (TLC) and dynamic lung volume returned to values predicted by the patient's sex, age, and height. They proposed that the simplest method of matching donor lung size to that of the recipient is to use their respective predicted TLC values. Moreover, they concluded that the recipient's predicted lung volumes should be attained by 1 year after transplantation, and that failure to do so suggests possible complications within the transplanted lungs.
In contrast to renal transplantation, HLA matching is not a criteria for thoracic organ allocation. Because only short ischemic times are tolerated by lung and heart-lung blocs, it is not possible to perform this tissue typing preoperatively.41 However, several retrospective studies have been performed to look at the influence of HLA matching on long-term graft survival and the development of obliterative bronchiolitis. Wisser et al examined the relationship between HLA matching and long-term survival in 78 lung transplant recipients.42 They found improved graft survival with matching at the HLA-B locus. In a retrospective study of 74 lung transplant patients, Iwaki et al also correlated improved graft survival with matching at the HLA-B and HLA-DR loci.43 Harjula et al at Stanford evaluated the relationship between HLA matching and outcome in heart-lung transplantation.44 Among 40 heart-lung transplant recipients evaluated, they found a significant increase in graded obliterative bronchiolitis with total mismatch at the HLA-A locus. These studies all suggest that there is a relationship between HLA matching and long-term graft function.
Once an appropriate donor-recipient pairing is made, the recipient is screened for preformed antibodies against a panel of random donors. A percent reactive antibody (PRA) level greater than 25 prompts a prospective specific crossmatch between the donor and recipient. A positive crossmatch indicates the presence of anti–donor circulating antibodies in the recipient that would likely lead to hyperacute rejection of the donor organ. In the event of a positive crossmatch, the donor organ cannot be accepted for that recipient.
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RECIPIENT MANAGEMENT AFTER LISTING |
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Supplemental oxygen is recommended for any patient exhibiting arterial hypoxemia, defined as either an arterial oxygen saturation less than 90% or an arterial Po2 less than 60 mm Hg at rest, during exertion, or while asleep.
For patients with heart failure, standard therapeutic measures are applied, including dietary restrictions, diuretics, and vasodilators. Dietary water and salt restriction as well as diuretic therapy facilitate intravascular fluid management. However, particular care must be exercised when using loop diuretics in patients with underlying pulmonary disease; this class of potent diuretics results in a metabolic alkalosis that depresses the effectiveness of carbon dioxide as a stimulus for breathing. Vasodilators result in afterload reduction, and have been proven to effectively improve functional capacity and prolong survival in patients suffering from severe cardiac failure.45 Commonly used vasodilators include nitrates, hydralazine, and angiotensin-converting enzyme inhibitors.
Despite the clinical heterogeneity among patients with primary pulmonary hypertension, conventional medical therapy targets the sequelae of the pulmonary vascular derangements associated with this disease process. Supplemental oxygen therapy is recommended to eliminate the stimulus for hypoxic pulmonary vasoconstriction and secondary erythropoiesis, thus lessening the burden placed on the right side of the heart and diminishing the likelihood of cardiac arrhythmias. Pulmonary vasodilator therapy is important in the treatment of primary pulmonary hypertension, and includes the use of calcium channel blockers and continuous prostacyclin infusions.46 Because most standard vasodilators have potent systemic effects, careful dosing and follow-up is essential. Approximately 20% of patients with primary pulmonary hypertension will respond to calcium channel blockers, and this favorable response can usually be predicted by the response to short-acting vasodilators during cardiac catheterization, but response to the acute vasodilator challenge does not always predict the response to long-term prostacyclin infusion.
Interstitial lung disease in patients awaiting transplantation results from a wide variety of diffuse inflammatory processes, such as sarcoidosis, asbestosis, and collagen-vascular diseases. Increases in pulmonary vascular resistance leading to right-sided heart failure are thought to result from interstitial inflammatory infiltrates that entrap and eventually destroy septal arterioles, reducing the distensibility of the remaining pulmonary vessels.47 This process, coupled with closure of peripheral bronchioles, results in arterial hypoxemia, which further aggravates pulmonary hypertension. Corticosteroids are the mainstay of treatment in this class of diseases. The adverse effects of steroids on airway healing are well established,17,48 and mandate significant dose reductions in anticipation of heart-lung and isolated lung transplantation.
The multisystem manifestations of cystic fibrosis, particularly chronic bronchopulmonary infection, malabsorption, malnutrition, and diabetes mellitus, pose difficult management problems and require aggressive chest physiotherapy, antibiotics, enteral or parenteral nutritional supplementation, and tight serum glucose control.49
Certain underlying diagnoses are associated with increased rates of pulmonary and systemic thrombosis and embolization. These include dilated cardiomyopathy, congestive heart failure, and primary pulmonary hypertension,47 and most centers recommend routine prophylactic anticoagulation with heparin, warfarin, or antiplatelet agents.
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ORGAN PROCUREMENT AND PRESERVATION |
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Standard criteria have been established for donor selection (Table 61-3).50,51 Donors must have sustained irreversible brain death, but due to the susceptibility of the lungs to edema and infection, particularly in the setting of brain death and trauma, suitable heart-lung and lung blocs are more difficult to obtain than other organs. Less than 20% of organ donors possess lungs suitable for transplantation.
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Absolute contraindications to lung and heart-lung donation include prolonged cardiac arrest, arterial hypoxemia, active malignancy (excluding basal cell and squamous cell carcinoma of the skin), and positive HIV status. For heart-lung donation, severe coronary or structural heart disease and prior myocardial infarction are additional contraindications. Relative contraindications to both lung and heart-lung donation include thoracic trauma, sepsis, significant smoking history, prolonged severe hypotension (i.e., less than 60 mm Hg for more than 6 hours), HBsAg or hepatitis C antibodies, multiple resuscitations, and a prolonged high inotropic requirement (e.g., dopamine in excess of 15 µg/kg/min for 24 hours). It is important to rule out correctable metabolic or physiological causes of cardiac rhythm disturbances and electrocardiographic anomalies (e.g., brain herniation, hypothermia, and hypokalemia).
The last decade has seen a trend toward liberalization of standard donor selection criteria. This strategy, which was initiated in response to the donor organ shortage, has been employed at a large number of transplant centers.52–54 Donors up to age 60 have been used in thoracic transplantation, with good long-term graft survival. However, recent reports from the ISHLT document worse outcomes in recipients of lung allografts from donors over age 55 who had ischemic times longer than 6 to 8 hours.55 In this group of recipients, long-term survival is impaired and the risk of developing bronchiolitis obliterans is increased. A limitation on smoking history is another criterion that has been liberalized. Conventional guidelines limit smoking history to less than 20 pack years, but modified criteria have allowed for a more extensive smoking history, assuming there is no evidence of COPD or other lung disease on screening tests. Other extended criteria include use of lungs from donors whose sputum Gram stain shows presence of bacteria; in these cases, treatment with antimicrobials is initiated in the donor and continued posttransplantation in the recipient. In general, the presence of fungus in donor sputum samples is a contraindication to donation. Some groups have accepted donors with small pulmonary infiltrates on chest x-ray, though clinical correlation is necessary. Others have selectively used donor lungs in patients with Pao2 less than 300 mm Hg on Fio2 of 100%.
Gabbay et al in Australia have adopted an aggressive approach to donor management and "organ resuscitation."54 By manipulating donors with antibiotic therapy, chest physiotherapy, careful fluid management, ventilator adjustments, and bronchial toilet, 34% of donors with an initial Pao2 less than 300 mm Hg on Fio2 of 100% had a rise in their Pao2 and became acceptable donors.
Areas of investigation in the field of donor organ procurement include the use of non–heart-beating donors. In 2001, Steen et al reported on the transplantation of lungs from a non–heart-beating donor into a 54-year-old woman with COPD.56 The functional result has been good during the first 5 months of follow-up. However, ethical, logistic, and scientific questions remain on the use of non–heart-beating donors, and this strategy is far from being widely applicable.
The overriding goal in managing the thoracic organ donor is the maintenance of hemodynamic stability and pulmonary function. Patients suffering from acute brain injury are often hemodynamically unstable due to neurogenic shock, excessive fluid losses, and bradycardia. Donor lungs are prone to neurogenic pulmonary edema, aspiration, nosocomial infection, and contusion. Continuous arterial and central venous pressure monitoring, judicious fluid resuscitation, vasopressors, and inotropes are usually required.
Meticulous fluid management prevents intraoperative blood pressure instability and minimizes the need for inotropes and vasopressors that stress the myocardium. Intravascular volume replacement should be given to maintain the central venous pressure between 5 and 8 mm Hg, though fluids should not be administered at rates far in excess of hourly urine output. In general, crystalloid fluid boluses are to be avoided. Diabetes insipidus is common in organ donors and requires the use of intravenous vasopressin (0.8 to 1.0 unit/h) to reduce excessive urine losses.
To maintain adequate perfusion pressures, dopamine is the standard inotropic agent used, although alpha agonists (e.g., phenylephrine) are often appropriate. Blood transfusions should be used sparingly to maintain the hemoglobin concentration around 10g/dL to ensure adequate myocardial oxygen delivery. CMV-negative and leukocyte-filtered blood should be used whenever possible. Hypothermia should be avoided because it predisposes to ventricular arrhythmias and metabolic acidosis.
With regard to mechanical ventilation, Fio2 values in excess of 40%, especially 100% oxygen "challenges," should be avoided, since these oxygen levels may be toxic to the denervated lung. Ventilator settings should include positive end-expiratory pressures (PEEP) between 3 and 5 cm H2 to prevent atelectasis.
The donor operation is performed via a median sternotomy (Fig. 61-5A). After the sternum is divided, a standard chest retractor is placed, and both pleural spaces are opened immediately with inspection of the lungs and pleural spaces, particularly in cases of trauma. The lungs are briefly deflated, and the pulmonary ligaments are divided inferiorly using electrocautery. After completely excising the thymic remnant, the pericardium is opened vertically and laterally on the diaphragm and cradled during dissection of the great vessels and trachea. The ascending aorta, pulmonary artery, and venae cavae are dissected. Umbilical tapes are placed around the ascending aorta and venae cavae (Fig. 61-5B). The pericardium overlying the trachea is incised vertically, and the trachea is encircled with an umbilical tape between the aorta and superior vena cava at the highest point possible and at least four rings above the carina (Fig. 61-5B). The entire anterior pericardium is excised back to each hilum (Fig. 61-5C).
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For combined heart-lung blocs, the bloc is dissected free from the esophagus commencing at the level of the diaphragm and continuing cephalad to the level of the carina. Dissection is kept close to the esophagus, and care is taken to avoid injury to the trachea, lung, or great vessels. The posterior hilar attachments are divided. The lungs are inflated to a full normal tidal volume, and the trachea is stapled at the highest point possible with a TA-55 stapler (U.S. Surgical, Norwalk, CT), at least four rings above the carina (Fig. 61-5E). The trachea is then divided above the staple line, and the entire heart-lung bloc is removed from the chest.
For separate heart and lung blocs, the donor operation is modified slightly, allowing for in situ separation of the heart from the lungs. After delivery of plegic solutions, the great vessels are divided. The heart is reflected anteriorly and a left atriotomy is performed, leaving a 2-cm cuff of atrium around the pulmonary vein orifices. Once this division is complete, the heart is removed from the chest. The lung bloc is then dissected free along the pre-esophageal plane above the level of the carina. The lungs are inflated and the trachea is stapled at the highest possible point. If needed, the bilateral lung bloc can be further separated into left and right lung blocs. The left atrial cuff containing the orifices of the pulmonary veins is divided in half vertically. The left and right pulmonary arteries are divided at their junction. Finally, the left mainstem bronchus is stapled near its junction with the trachea.
Once removed from the donor, grafts are wrapped in sterile gauze pads and immersed in ice-cold saline at 2°C to 4°C in several sterile plastic bags placed within a sterile plastic container. This, in turn, is placed in an ice-filled chest and transported to the transplant center.
Organ Preservation and Transport
On-site lung procurement was considered essential between 1981 and 1984 due to inadequate lung preservation techniques.57 Since then, active research and clinical experience have produced several different preservation protocols that have permitted distant procurement. Most centers currently tolerate a maximum of 6 to 8 hours of ischemia in lung and heart-lung allografts. This practice is supported by several studies, including independent retrospective studies from the University of Pittsburgh58 and the University of Virginia59 that showed comparable long-term survival and rates of acute rejection and bronchiolitis obliterans among recipients of grafts with over 6 hours of ischemia compared with those with less than 4 or with 4 to 6 hours of ischemia. In animal studies, reports of successful transplantation of lung allografts with cold ischemia times up to 18 hours have been reported. However, it is believed that beyond a certain threshold, organ ischemia will likely lead to primary graft failure and/or impaired long-term function.
The overriding principle in preservation is to minimize injury to the allograft from ischemia and reperfusion.60 Ischemia-reperfusion injury is mediated by reactive oxygen species, which disrupt the homeostatic mechanisms in myocyte and endothelial cells. As receptors for leukocyte adhesion molecules are upregulated and leukocyte chemotactic factors are released, an inflammatory response ensues, leading to cellular injury. Several approaches to minimizing ischemia-reperfusion injury have developed, and these include donor pretreatment, development of specialized preservation solutions, and recipient treatments.
Hypothermia is considered by many to be the most important method of organ preservation. It works by reducing the tissue's metabolic demand by up to 99%. In a small number of centers, hypothermic preservation includes donor core cooling on CPB. Universally, hypothermia is employed during explantation, storage, and implantation. During explantation, organs are flushed with cold plegic solutions (between 0°C to 10 °C, depending on the institution and solution employed). They are stored at 0°C to 10°C, and during implantation, they are covered with gauze soaked in saline slush or recipients are cooled through CPB. The optimal temperature for flush and storage of organs remains unknown, but common practice is to rely on ice bath temperature for convenience.
Heart-lung and lung blocs are typically preserved with a cold pulmonary artery flush in conjunction with standard crystalloid cardioplegic arrest. A variety of crystalloid flush solutions are used worldwide, and they can be divided into two categories based on their electrolyte compositions: intracellular and extracellular. Intracellular solutions contain moderate to high concentrations of potassium and little calcium and sodium; Euro-Collins, University of Wisconsin (UW), and Cardiosol are examples. Extracellular solutions contain high concentrations of sodium and low to moderate concentrations of potassium; low-potassium dextran solution is an example. While Euro-Collins is the most frequently used preservation solution, data comparing the merits of the various solutions is sparse and for now inconclusive.
Prostaglandins are commonly used for donor pretreatment and as an additive in pulmonary flush solutions. PGE1, a vasodilator, is given to counteract reflex pulmonary vasoconstriction resulting from the cold flush and to permit uniform distribution of the perfusate throughout the lung. Experimental studies also suggest that PGE1 treatment may minimize reperfusion injury through its anti-inflammatory properties.61
Another commonly used donor pretreatment strategy is steroid treatment. Experimental evidence suggests that donor lymphocytes may play a role in ischemic lung graft injury, so methylprednisolone is given intravenously to the donor to inactivate them.
Experimental studies suggest that lung graft function is improved when the explanted organ is inflated, when 100% oxygen is used for inflation, and when the lung is transported at 10°C.62 Research in the field of lung preservation has recently focused on the role of various flush and storage solution additives, such as antioxidants, which may act as free radical scavengers. Other additives that have been shown to decrease reperfusion injury in research models include nitric oxide donors and phosphodiesterase inhibitors. Additional areas of research interest include the development of leukocyte depletion strategies, examining the role of gene therapy in modifying donor organ susceptibility to ischemia-reperfusion injury, and the development of colloid-based perfusates.
These preservation techniques, coupled with streamlined donor and recipient protocols, have permitted procurements as far as 1000 miles from the transplant center. Extensive communication and coordination must be maintained between the organ procurement agency, donor and recipient operative teams, medical centers, and abdominal procurement teams.
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RECIPIENT OPERATION |
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Anesthetic monitoring includes arterial pressure monitoring, pulse oximetry, continuous electrocardiography, pulmonary artery catheter monitoring, temperature monitoring, and urine output monitoring. The use of double-lumen endotracheal tubes is particularly helpful, allowing for single lung ventilation during certain portions of the dissection. Large bore intravenous lines are placed for volume infusion. Transesophageal echocardiography is often performed during the procedure.
The recipient is positioned supine on the operating table. The chest is entered through a median sternotomy, a sternal retractor is placed, and both pleural spaces are opened anteriorly from the level of the diaphragm to the level of the great vessels (Fig. 61-6A). Any pleural adhesions are divided using electrocautery. In patients in whom dense pleural adhesions are anticipated, such as those with previous thoracotomies or cystic fibrosis, a bilateral "clamshell" thoracotomy is performed. Combined with the use of perioperative antifibrinolytic therapy (e.g., aprotinin) and an argon beam coagulator, this approach improves exposure and facilitates both lysis of adhesions and hemostasis.
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After fully heparinizing the recipient, the ascending aorta is cannulated near the base of the innominate artery, and the venae cavae are individually cannulated laterally and snared. Cardiopulmonary bypass with systemic cooling to 28°C to 30°C is instituted, and the heart is excised at the midatrial level. The aorta is divided just above the aortic valve, and the pulmonary artery is divided at its bifurcation (Fig. 61-6C). The left atrial remnant is then divided vertically at a point halfway between the right and left pulmonary veins.
The posterior edge of the left atrial and pulmonary venous remnant is developed in a manner that allows the left inferior and superior pulmonary veins to be displaced over into the left chest. Following division of the pulmonary ligament, the left lung is moved into the field, allowing full dissection of the posterior aspect of the left hilum, being careful to avoid the vagus nerve posteriorly. Once this is completed, the left main pulmonary artery is divided (Fig. 61-6D), and the left main bronchus is stapled with a TA-30 stapler and divided. The same technique of hilar dissection and division is repeated on the right side (Fig. 61-6E), and both lungs are removed from the chest.
The native main pulmonary artery remnant is removed, leaving a portion of the pulmonary artery intact adjacent to the underside of the aorta near the ligamentum arteriosum to preserve the left recurrent laryngeal nerve. Attention is then turned to preparing the distal trachea for anastomosis. The stapled ends of the right and left bronchi are grasped and dissection is carried up to the level of the distal trachea. Bronchial vessels are individually identified and carefully ligated. Patients with congenital heart disease and pulmonary atresia or severe cyanosis secondary to Eisenmenger's syndrome may have large mediastinal bronchial collaterals that must be meticulously ligated. Perfect hemostasis is necessary in this area of the dissection, because it is obscured once graft implantation is completed. Once absolute hemostasis is achieved, the trachea is divided at the carina with a no. 15 blade. The chest is now prepared to receive the heart-lung graft.
The donor heart-lung bloc is removed from its transport container and prepared by irrigating, aspirating, and culturing the tracheobronchial tree and by trimming the trachea to leave one cartilaginous ring above the carina. The heart-lung graft is then lowered into the chest, passing the right lung beneath the right phrenic nerve pedicle. The left lung is then gently manipulated under the left phrenic nerve pedicle (Fig. 61-6F). The tracheal anastomosis is performed using continuous 3-0 polypropylene suture (Fig. 61-6G). The posterior membranous portion of the anastomosis is performed first, followed by completion of the anastomosis anteriorly. The lungs are then ventilated with room air at half-normal tidal volumes to inflate the lungs and reduce atelectasis. Topical cooling with a continuous infusion of cold Physiosol into both thoraces is begun. To augment endomyocardial cooling and to exclude air from the graft, a third cold "bubble-free" line is placed directly into the left atrial appendage.
Next, the bicaval venous anastomosis is performed. The recipient inferior vena cava is anastomosed to the donor inferior vena cava-right atrial junction with a continuous 4-0 polypropylene suture. At this point the patient is rewarmed toward 37°C, and the superior vena caval and aortic anastomoses are performed end-to-end with continuous 4-0 polypropylene sutures (Fig. 61-6H). After the ascending aorta and pulmonary artery are cleared of air, the aortic cross-clamp and caval tapes are removed. The left atrial catheter is removed, and the atrium is allowed to drain. The amputated left atrial stump is oversewn, and the pulmonoplegia infusion site on the pulmonary artery is closed. The heart is defibrillated, and the patient is gradually weaned from cardiopulmonary bypass in the standard fashion. Methyprednisolone (500 mg) is administered to the recipient following heparin reversal with protamine sulfate.
PEEP at 3 to 5 cm H2O and an Fio2 of 40% are maintained. As in cardiac transplantation, isoproterenol (0.005 to 0.01 µg/kg/min) is usually initiated on graft reperfusion to increase the heart rate to about 100 to 110 bpm and to lower pulmonary vascular resistance. Temporary right atrial and ventricular pacing wires are placed. Right and left pleural chest tubes (right angle) are placed along each diaphragm, as well as one mediastinal tube. The chest is closed in the standard fashion. Finally, the double-lumen endotracheal tube is exchanged for a single-lumen tube and the tracheal anastomosis is checked endoscopically before transporting the patient to the intensive care unit.
Lick et al at the University of Texas and the University of Arizona have recently described an interesting alternative to the standard technique in which the pulmonary hila are placed anterior to the phrenic nerves and direct caval anastomoses are used whenever feasible.63 This modification obviates extensive dissection of the phrenic nerves and posterior mediastinum, decreasing the likelihood of phrenic and vagus nerve injury. Furthermore, the posterior mediastinum can be inspected more easily for bleeding after implantation by rotating the heart-lung bloc anteriorly and medially while still on bypass.
If possible, the lung with the least function determined by preoperative ventilation-perfusion scan is selected for replacement. The patient is placed in a standard thoracotomy position, with access to the groin should CPB be needed. A posterior lateral thoracotomy is made at the level of the fourth or fifth intercostal space. Adhesions are lysed and the hilar dissection is performed. The pulmonary artery, the superior and inferior pulmonary veins, and the mainstem bronchus are isolated. A trial occlusion of the pulmonary artery is used to determine whether the procedure will be tolerated without CPB. If it is tolerated, the pulmonary artery is ligated and divided distal to the upper lobe branch. The pulmonary veins are also ligated and divided. The mainstem bronchus is stapled and divided, and the native lung is explanted.
The donor lung is removed from its transport container and prepared for implantation. The donor bronchus is opened and secretions are aspirated and cultured. The bronchus is trimmed, leaving two cartilaginous rings proximal to the orifice of the upper lobe. Any remaining pericardial and lymphatic tissue is removed, and the left atrial cuff is trimmed as needed. The donor lung is then placed in the recipient's chest and covered with saline slush and iced laparotomy pads.
The sequence of anastomoses is a matter of preference, though most perform the deepest anastomosis (the bronchial anastomosis) first and then proceed to the more superficial ones. The bronchial anastomosis is fashioned with 4-0 polypropylene suture. We favor a continuous suture technique; alternatively, the membranous portion can be sewn with interrupted suture. Alternatively, the entire anastomosis can be sewn with a running suture. Variations on the end-to-end bronchial anastomosis include the use of a telescoping technique, in which the donor bronchus is intussuscepted into the recipient bronchus, and the placement of an omental pedicle flap around the anastomosis. These techniques were developed to prevent bronchial anastomotic dehiscence but are now rarely performed.
Once the bronchial anastomosis is complete, attention is then turned to making the pulmonary venous anastomosis. A side-biting clamp is applied to the left atrium to include the pulmonary veins. The recipient pulmonary vein stumps are opened and the intervening atrial tissue is cut. This creates a cuff that is anastomosed to the donor atrial remnant using continuous 4-0 polypropylene suture; this suture is not tied down until reperfusion. Donor and recipient pulmonary arteries are anastomosed with 5-0 polypropylene suture. Upon graft inflation, kinking can occur if the arteries are left too long, so they must be carefully trimmed to an appropriate length before fashioning the anastomosis. The pulmonary artery anastomosis is de-aired. The lung is inflated, and the pulmonary artery clamp is temporarily released to allow flushing of air through the atrial suture line, and the left atrial clamp is removed to allow retrograde de-airing of the atrial anastomosis. The pulmonary venous anastomosis is then secured.
After hemostasis is ensured, apical and basal chest tubes are inserted. The ribs are reapproximated and the chest is closed in a standard fashion. The double-lumen endotracheal tube is exchanged for a single-lumen tube and bronchoscopy is performed to evaluate the bronchial anastomosis.
Bilateral Lung Transplantation
Bilateral lung transplantation is performed as sequential single lung transplants. The patient is positioned supine and a bilateral anterior thoracosternotomy (clamshell) incision is made at the level of the fourth intercostal space. The lung with the least amount of function (as determined by a preoperative ventilation-perfusion scan) is removed first and replaced with an allograft as described for single lung transplantation above. Once ventilation and perfusion are established in the first allograft, the second native lung is explanted and the second allograft is implanted. Bilateral chest tubes are placed and the chest is closed. Bronchoscopy is performed to evaluate the bronchial anastomoses.
Many centers use CPB routinely during bilateral lung transplantation. It allows for improved exposure, shorter graft ischemic times, controlled reperfusion, and the use of leukocyte-depleting filters. Because the risk of bleeding may be increased with CPB, strategies have been developed to minimize the chance of hemorrhage. These include the routine use of aprotinin and heparin-coated CPB circuits, as well as the availability of an argon beam coagulator.
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Interesting corollaries to the clinical benefits of heart-lung and isolated lung transplantation are the structural and functional aspects of the transplanted heart-lung or lung bloc (Table 61-4).
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Clinical Management in the Early Postoperative Period
The acute postoperative management for heart-lung and isolated lung graft recipients centers around careful fluid and ventilatory management. Simply put, the primary objective in the immediate postoperative period is to maintain adequate perfusion and gas exchange in the recipient while minimizing intravenous fluid administration, cardiac work, and barotrauma.
Upon completion of the transplant, the patient is transported to the intensive care unit (ICU), where cardiac rhythm and arterial and central venous pressures are monitored. Strict isolation precautions, previously enforced to reduce the incidence of infection in these immunosuppressed patients, are no longer required; simple handwashing is now considered sufficient.
Approximately 10% to 20% of heart-lung graft recipients experience some degree of transient sinus node dysfunction in the immediate perioperative period, often manifested as sinus bradycardia, which usually resolves within a week. The use of bicaval venous anastomoses has been reported to lower the incidence of sinus node dysfunction and improve tricuspid valve function.67 Because cardiac output is primarily rate dependent after heart-lung transplantation, the heart rate should be maintained between 90 and 110 bpm during the first few postoperative days using temporary pacing or isoproterenol (0.005–0.01 µg/kg/min) as needed. Although rarely seen, persistent sinus node dysfunction and bradycardia may require a permanent transvenous pacemaker. The systolic blood pressure should be maintained between 90 and 110 mm Hg using afterload reduction in the form of nitroglycerin or nitroprusside if necessary. Renal-dose dopamine (3–5 µg/kg/min) is used frequently to augment renal blood flow and urine output. The adequacy of cardiac output is indicated by warm extremities and a urine output great than 0.5 mL/kg/hr without diuretics. Cardiac function generally returns to normal within 3 to 4 days, at which time parenteral inotropes and vasodilators can be weaned.
In the heart-lung graft recipient, several factors may contribute to some form of depressed global myocardial performance in the acute postoperative setting. The myocardium is potentially subject to prolonged ischemia, inadequate preservation, or catecholamine depletion prior to implantation. Hypovolemia, cardiac tamponade, sepsis, and bradycardia may also be contributory and should be treated expeditiously if they are present. A Swan-Ganz pulmonary artery catheter should be used in cases of persistently abnormal hemodynamics.
Ventilatory management is a key element in the postoperative management of both heart-lung and isolated lung graft recipients. Barotrauma and high airway pressures that might compromise bronchial mucosal flow should be avoided. Lower tidal volumes and flow rates may be necessary to limit peak airway pressures to less than 40 cm H2O. Upon arrival to the ICU, an anteroposterior chest x-ray is obtained, and the ventilator is typically set to an Fio2 of 50%, tidal volume of 10 to 15 mL/kg, an assist-control rate of 10 to 14 breaths per minute, and PEEP of 3 to 5 cm H2O. These settings are adjusted every 30 minutes to achieve an arterial Po2 greater than 75 mm Hg on an Fio2 of 40%, an arterial carbon dioxide pressure (Paco2 between 30 and 40 mm Hg, and a pH between 7.35 and 7.45. Pulmonary toilet with endotracheal suctioning is an effective means of reducing mucous plugging and atelectasis. Ventilatory weaning is initiated after the patient is deemed stable, awake, and alert. Usually, weaning is accomplished through successive decrements in intermittent mandatory ventilation rate followed by a trial of continuous positive airway pressure. Once ventilatory mechanics and arterial blood gases are deemed acceptable, the patient is extubated. This usually occurs within the first 24 hours after transplantation. Subsequent pulmonary care consists of vigorous diuresis, supplemental oxygen for several days, continued aggressive pulmonary toilet and incentive spirometry, and serial chest x-rays.
A diffuse interstitial infiltrate is often found on early postoperative chest x-rays. Previously referred to as a reimplantation response, this finding is better defined as graft edema due to inadequate preservation, reperfusion injury, or early rejection.68 It appears that the degree of pulmonary edema is inversely related to the quality of preservation. Judicious administration of fluid and loop diuretics is required to maintain fluid balance and minimize this pulmonary edema.
Early lung graft dysfunction manifested by persistent marginal gas exchange without evidence of infection or rejection occurs in less than 15% of transplants.69 This primary graft failure is often the result of ischemia-reperfusion injury and is manifested histologically by diffuse alveolar damage. Of course, technical causes of graft failure, such as pulmonary venous anastomotic stenosis or thrombosis, must always be considered. In cases of persistent severe pulmonary graft dysfunction refractory to mechanical ventilatory maneuvers, extracorporeal membrane oxygenation (ECMO)70 and inhaled nitric oxide71 have been used successfully to stabilize gas exchange in several patients. In others, urgent retransplantation has been performed.
Expedient removal of vascular lines has been shown to reduce the incidence of line sepsis. Pleural and mediastinal chest tubes are removed when drainage has fallen to less than 25 mL/h. For heart-lung graft recipients, pacing wires are removed between 7 and 10 days after transplantation, provided that pacing is not required. After several days, barring significant complications, the patient is transferred from the ICU to a standard cardiothoracic surgical ward for the remainder of the hospital stay.
Immunosuppressive Management: Early and Late Postoperative Regimens
For heart-lung and lung graft recipients, immunosuppression begins intraoperatively and is continued for the patient's lifetime. The conventional triple-drug combination consists of cyclosporine, azathioprine, and prednisone. Initially, high doses of these drugs are given, and they are later tapered for chronic administration. A typical dosing protocol employed at Stanford University Hospital is outlined in Table 61-5. Cyclosporine is initiated in the early postoperative period, initially intravenously (0.05–0.1 mg/kg/h) and subsequently orally when oral intake is well established (5–10 mg/kg/d in two divided doses). Dosing is titrated to maintain a trough serum concentration between 150 and 250 ng/mL in the first few weeks after transplantation and from 100 to 150 ng/mL thereafter. Azathioprine is administered intravenously at 4 mg/kg preoperatively and subsequently maintained at approximately 2 to 3 mg/kg/d. Azathioprine dosages are adjusted to maintain the white blood cell count greater than 4000 cells/mm3. Methylprednisolone is administered intraoperatively at graft reperfusion (500 mg intravenously) and then continued for the first 24 hours at 125 mg intravenously every 8 hours. Steroids are then suspended for 2 weeks, based on experimental and clinical evidence that they impede bronchial anastomotic healing. After 2 weeks, prednisone is started at a daily oral dose of 0.6 mg/kg and gradually tapered over the next 3 to 4 weeks to 0.1 to 0.2 mg/kg/d.
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Many centers have added prophylactic induction therapy to the standard triple-drug regimen. This includes the use of OKT3, antithymocyte globulin (RATG and ATGAM), and daclizumab. OKT3 is a murine monoclonal antibody preparation that recognizes the CD3 antigen of human T cells. RATG and ATGAM are polyclonal anti–T cell antibody preparations. Daclizumab is a monoclonal antibody preparation that blocks IL-2-dependent activation of human T cells by binding to their IL-2 receptors. Use of these agents may reduce the rate of acute pulmonary rejection, but may also predispose to infection. Several retrospective and prospective studies have compared the efficacy of all or some of these induction agents. Palmer et al found a decreased incidence of acute rejection in lung transplant recipients receiving RATG induction and conventional triple-drug therapy when compared to patients receiving triple-drug therapy alone.74 Barlow et al found that the incidence of acute pulmonary rejection was significantly lower in recipients induced with RATG compared with those induced with OKT3; in addition, there was a trend toward decreased infection rate in the RATG group when compared to the OKT3 cohort.75 Brock et al performed a prospective nonrandomized trial comparing OKT3, ATGAM, and daclizumab as induction agents in 87 lung allograft recipients.76 Among all groups, they found comparable freedom from acute rejection and bronchiolitis obliterans syndrome and comparable long-term survival. However, daclizumab was associated with a lower rate of infections. Unfortunately, the follow-up for the daclizumab cohort was only 7 months, whereas the other cohorts were followed for 2 years. Long-term follow-up will be important in ascertaining which induction therapy is optimal in heart-lung and lung allograft recipients. Moreover, because of the increased risk of infection with some agents and an association with increased risk of development of posttransplant lymphoproliferative disorder, induction agents should be used with caution.
Judicious doses of immunosuppressives are usually well tolerated by patients; however, each is associated with side effects. Cyclosporine is commonly associated with nephrotoxicity, hypertension, hepatotoxicity, hirsutism, and an increased incidence of lymphoma. The primary toxicity of azathioprine is generalized bone marrow depression, which manifests as leukopenia, anemia, and thrombocytopenia. Steroids are associated with a myriad of side effects, including the development of cushingoid features, hypertension, diabetes, osteoporosis, and peptic ulcer disease. Initial doses of OKT3 and antithymocyte globulin can be associated with a "cytokine release syndrome"; significant hypotension, bronchospasm, and fever can result. Therefore, patients receiving these induction agents are premedicated with acetominophen, antihistamines, and corticosteroids, and are monitored closely. Interestingly, daclizumab is not associated with the cytokine release syndrome.
Antiviral and antifungal prophylaxis are important components of postoperative management in heart-lung and lung transplant recipients. Cytomegalovirus prophylaxis (CMV) with ganciclovir is employed by many centers in any CMV-positive recipient and in any CMV-negative recipient receiving an allograft from a CMV-positive donor. Ganciclovir is typically given for a several week course, and can be associated with leukopenia. Some patients may require G-CSF if their white blood cell count falls below 4000. Fungal prophylaxis against mucosal Candida infection includes use of daily nystatin swish and swallow. Pneumocystis carinii prophylaxis consists of trimethoprim-sulfamethoxazole or aerosolized pentamidine. In the immediate postoperative period, Aspergillus colonization is inhibited by the use of aerosolized amphotericin B. For Toxoplasma-negative recipients of grafts from Toxoplasma-positive patients, pyrimethamine prophylaxis is maintained for the first 6 months after transplantation.
Graft Surveillance: Patient Follow-Up Schedule
Routine clinical follow-up for heart-lung and lung allograft recipients is required to monitor graft function and modify immunosuppressive regimens. Regular surveillance protocols have been developed to monitor graft function, and these typically consist of serial pulmonary function tests, arterial blood gases, and bronchoscopic evaluation at 2 weeks, 4 to 6 weeks, 12 weeks, and 6 months after transplantation, and yearly thereafter. Transbronchial biopsies are obtained from each transplanted lung, and lavage specimens are submitted for staining (i.e., Gram, fungal, acid-fast bacillus, and silver), culture, and cytology. Surveillance endomyocardial biopsies are performed at 3 months and then annually in heart-lung graft recipients.
In addition to routine surveillance, follow-up is often needed to address changes in clinical status. Complications related to transplantation are many, and these must be addressed carefully and expediently to prevent long-term graft failure.
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Perioperative hemorrhage is an infrequent but significant cause of early death in heart-lung and lung transplantation. Much of this stems from operating in the midst of dense adhesions from previous operations or the inflammatory response to chronic lung infection. As mentioned previously, meticulous attention to hemostasis is mandatory, and all available means should be used to achieve a dry field on completing the operation.
ABO matching of donor and recipient has decreased the rate of hyperacute rejection. This complication, which is almost universally fatal, is mediated by preformed antibodies in the recipient that recognize antigens on the donor vascular endothelium. This humoral immune response results in activation of inflammatory and coagulation cascades, and results in extensive thrombosis of graft vessels and subsequent graft failure.68 To reduce the incidence of hyperacute rejection, a prospective crossmatch should be performed in recipients with a PRA greater than 25%.
Early Graft Dysfunction and Primary Graft Failure
Graft dysfunction in the first few days after transplantation is common. It has often been referred to as the "reimplantation response" and is manifested by abnormal lung function, pulmonary edema, and pulmonary infiltrates on chest x-ray. This phenomenon is thought to be linked to ischemia and reperfusion. It may also be related to allograft contusion, inadequate preservation, or use of cardiopulmonary bypass during transplantation. While most cases are mild and resolve with supportive care, some progress to primary graft failure. The rates of primary graft failure following lung and heart-lung transplantation are reported between 10% and 15%; treatment may include the use of ECMO and inhaled nitric oxide (NO). Unfortunately, primary graft failure is associated with a mortality of over 60%.69
As in cardiac transplantation, the majority of acute rejection episodes occur within the first year after transplant. From 1981 through 1994 at Stanford University, acute lung rejection (either isolated or simultaneous with heart rejection) occurred in more than 67% of heart-lung patients within the first year.77 Similar rates of acute rejection have been reported among isolated lung transplant recipients. Despite its prevalence, death is very rarely a direct consequence of acute rejection. It is recognized, however, that the number and severity of acute rejection episodes is a risk factor for the ultimate development of obliterative bronchiolitis.
In the early posttransplant period, the diagnosis of acute rejection is often based on clinical parameters. Symptoms and signs of rejection include fever, dyspnea, impaired gas exchange manifested by a decrease in arterial Po2, a diminished forced expiratory volume during 1 second (FEV1, a measure of airway flow), a fall in vital capacity (VC), and the development of a characteristic bilateral interstitial infiltrate on chest x-ray (Fig. 61-9A). After the first postoperative month, the chest x-ray is frequently normal during episodes of acute rejection, placing greater emphasis on other clinical parameters of rejection.
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Acute lung rejection is characterized histologically by lymphocytic perivascular infiltrates (Fig. 61-10). A histologic grading scheme for acute lung rejection was developed by Clelland and Colin81 and is presented in Table 61-6; a similar scheme was also developed by the Lung Rejection Study Group.78
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As in cardiac transplantation, efforts are being made to develop noninvasive ways of diagnosing early acute lung rejection. Loubeyre et al at the Hospital Cardiovasculaire et Pneumologique report an association between "ground-glass" density areas seen on high-resolution computed tomography (HRCT) and histologically diagnosed acute lung rejection in heart-lung transplant recipients.83 They found that ground-glass opacities on HRCT had a sensitivity of 65% for detecting lung rejection and a specificity of 85% for detecting an acute lung complication.
Treatment strategies for rejection involve augmentation of immunosuppression. At most institutions, the timing and severity of rejection episodes dictate therapy. A typical algorithm is shown in Figure 61-11. Rejection episodes that are graded moderate or severe are treated with a "steroid pulse" (intravenous methylprednisolone 500-1000 mg/d for 3 consecutive days), followed by augmentation of the oral prednisone maintenance dose to 0.6 mg/kg/d. This maintenance dose is then tapered to 0.2 mg/kg/d over 3 to 4 weeks. Clinical and radiographic improvement (see Fig. 61-9B) following steroid therapy is often rapid and dramatic and is considered confirmatory of rejection. Mild episodes are treated initially with an increased oral prednisone dose, followed by a gradual taper over 3 to 4 weeks. Transbronchial biopsies are repeated 10 to 14 days following antirejection therapy to assess efficacy. Recurrent rejection episodes may be treated by a second steroid pulse and taper. Acute rejection refractory to steroid therapy may be treated with antilymphocyte preparations. Alternatively, primary immunosuppression may be switched from cyclosporine-based therapy to tacrolimus-based therapy. Finally, in especially difficult persistent cases of rejection, total lymphoid irradiation (TLI) may be useful.84
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Chronic lung allograft rejection poses the greatest limitation to the long-term benefits of lung and heart-lung transplantation. Chronic lung rejection most commonly presents as obliterative bronchiolitis (OB). It was first noted as a pulmonary corollary to chronic cardiac rejection (cardiac graft atherosclerosis) in recipients of heart-lung transplants.85 Later, obliterative bronchiolitis was shown to occur in recipients of isolated lung transplants as well. The onset of OB typically occurs after the first 6 months to 1 year after transplantation. Its incidence increases steadily thereafter. Recent data demonstrate that 70% of heart-lung and lung graft recipients are diagnosed with OB by the fifth postoperative year.86
Transbronchial biopsies are the "gold standard" for diagnosing OB. The sensitivity of transbronchial biopsy for detecting OB has been reported between 17% and 87%.80,87 The diagnostic yield of the biopsy procedure is related to the number of specimens taken, and current recommendations are that at least 5 specimens be taken from each transplanted lung. Clearly, OB is a patchy process and therefore a large number of samples will be falsely negative.
OB is a histologic diagnosis and is characterized by dense eosinophilic submucosal scar tissue that partially or totally obliterates the lumen of small (2 mm) airways, specifically the terminal and respiratory bronchioles (Fig. 61-12). The physiologic consequences are decreased arterial Po2, FEV1, FEF25–75[forced expiratory flow at 25% to 75% (midrange) of lung volumes], and FEF50/FVC (ratio of FEF50 to forced vital capacity). A characteristic "bowing" of the expiratory limb of the flow-volume loop has also been associated with OB. Clinical symptoms may be nonspecific, and include cough and dyspnea with or without exertion. The term bronchiolitis obliterans syndrome (BOS) was developed to refer to patients who have clinical manifestations of obliterative bronchiolitis with or without proven histologic characteristics. A standardized working formulation for the clinical staging of BOS was established by the ISHLT and is based on the ratio of the current FEV1 to the best posttransplant FEV1. Patients with a decline of 20% or greater in their FEV1 (in the absence of infection or other process) are diagnosed with BOS, irrespective of pathologic evidence of obliterative bronchiolitis (Table 61-7). 88
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With regard to the etiologies of OB, experimental and clinical evidence points to injury of the bronchial epithelium by one or more mechanisms. These include infection (particularly CMV), chronic inflammation stemming from impaired mucociliary clearance, and immunologic mechanisms.68 These insults result in airway epithelial damage and a subsequent exaggerated healing response. Along with this injury, there is increased expression of major histocompatibility class II antigens in the bronchial epithelium. In a recent meta-analysis, Sharples et al89 found that acute rejection is a risk factor for later development of OB. In keeping with this finding is the association between BOS and decreased levels of immunosuppression (as may occur with noncompliance). Lymphocytic bronchitis and bronchiolitis were also closely associated with development of OB. CMV pneumonitis, other pulmonary infections, and HLA mismatching have been linked to the development of OB in small retrospective studies. Novick et al recently reported on the relationship between OB, donor age, and graft ischemic times.55 Using data from the ISHLT registry, they found a higher rate of OB at 3 years in recipients of grafts from donors over 55 who were also subjected to 6 to 8 hours of ischemia.
The current management of OB hinges on prevention, close surveillance, and immediate therapeutic intervention when patients are symptomatic or when asymptomatic physiologic changes occur. Patients are encouraged to perform incentive spirometry to prevent microatelectasis of lungs deprived of native innervation, bronchial circulation, and normal mucociliary clearance mechanisms. Moreover, all recipients are instructed to contact their transplant center or primary physician when respiratory tract symptoms develop so that pulmonary function tests can be performed. Any alteration in FEF25–75or FEF50/FVC or specific changes in the flow-volume loop are an indication for bronchoscopy with bronchoalveolar lavage and transbronchial biopsy, especially in the absence of infectious bronchitis or pulmonary edema.
Augmentation of immunosuppression is the mainstay of therapy for BOS. The prednisone dose is increased to 0.6 to 1.0 mg/kg/d and slowly tapered to 0.2 mg/kg/d while concomitantly optimizing cyclosporine and azathioprine dosing. Ganciclovir is reinstituted during treatment for those patients at risk of reactivation CMV infection, and antimicrobial therapy is directed against any organisms isolated from bronchoalveolar lavage. Follow-up pulmonary function tests are performed. Pulmonary function can be stabilized in most patients, but significant improvement is uncommon. Unfortunately, relapse rates are greater than 50% and progressive pulmonary failure or infection due to increased immunosuppression are the most common causes of death in lung transplant patients after the second year. Among 89 heart-lung and 13 bilateral lung recipients who underwent transplantation at Stanford University between 1981 and 1995, a 5-year survival rate of 49% among recipients diagnosed with OB (n = 59) was noted compared to 74% among recipients without OB (n = 43). The 1-, 3-, 5-, 8-, and 10-year actuarial survival rates following the diagnosis of OB were 74%, 50%, 43%, 23%, and 11%, respectively, with a median survival of 3 years following diagnosis.
Retransplantation is the only option for terminal respiratory failure secondary to OB. While survival for patients undergoing retransplantation for OB is better than for those undergoing retransplantation for other reasons, it is still worse than survival of first-time transplant recipients. Among heart-lung recipients with OB, Adams et al at Harefield Hospital noted worse survival rates if combined heart-lung replacement, as opposed to isolated lung replacement, is performed on retransplantation.90 They also noted that the absence of preformed antibodies, retransplantation at least 18 months after the original transplantation, and negative preoperative sputum cultures were associated with improved survival after retransplantation. Novick et al recently reported results from the Pulmonary Retransplant Registry.32 They reviewed survival rates in 237 patients who underwent pulmonary retransplantation between 1985 and 1996. At 1, 2, and 3 years after retransplantation, survival was 47%, 40%, and 33%, respectively. Survival was higher in nonventilated ambulatory patients and their freedom from OB was comparable to first-time transplant recipients. The authors conclude that pulmonary retransplantation should be performed only in carefully selected recipients who have a reasonable likelihood of long-term survival.
Accelerated graft coronary artery disease (CAD) or graft atherosclerosis is another major obstacle to long-term survival in heart-lung transplant recipients. Significant graft CAD resulting in diminished coronary artery blood flow may lead to arrhythmias, myocardial infarction, sudden death, or impaired left ventricular function with congestive heart failure. Classic angina due to myocardial ischemia is usually not noted in transplant recipients because the cardiac graft has been denervated. Multiple etiologies for graft CAD have been proposed, but they all focus on chronic, immunologically mediated damage to the coronary vascular endothelium. In fact, elevated levels of antiendothelial antibodies have been correlated with graft CAD. Unlike coronary artery occlusive disease in the native heart, which tends to be more focal in nature, transplant atherosclerosis represents a more diffuse vascular narrowing extending symmetrically into distal branches. Histologically, transplant arteriopathy is characterized by concentric intimal proliferation with smooth muscle hyperplasia (Fig. 61-13).
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Percutaneous transluminal coronary angioplasty and coronary artery bypass grafting have been used to treat discrete proximal lesions in some cases of graft CAD; however, the only definitive therapy for diffuse disease is retransplantation. Effective prevention of graft CAD will rely on development of improved immunosuppression, recipient tolerance induction, improved CMV prophylaxis, and inhibition of vascular intimal proliferation.
Improvements in surgical technique and posttransplant management have resulted in a relatively low incidence of airway complications after heart-lung and lung transplantation. Kshettry et al at the University of Minnesota report an airway complication rate of 15% in lung transplant recipients.92 The avoidance of perioperative steroids has long been considered important in preventing airway complications; however, recent experimental and clinical evidence suggests that the detrimental effect of steroids may be overestimated.93 The most common airway complications are partial anastomotic dehiscence and stricture. Such complications are usually diagnosed by bronchoscopy. Airway dehiscence is treated by reoperation or close observation and supportive care. Strictures are treated by balloon or bougie dilatation, often with stent placement.
Bacterial, viral, and fungal infections are leading causes of morbidity and mortality in both heart-lung and lung transplant recipients. The rate of infection is higher in this transplant group than in other solid organ transplant recipients; this may be related to the lung allograft's direct exposure to airway colonization and aspiration, as well as its impaired cough reflex and mucociliary clearance. The risk of infection and infection-related death peaks in the first few months after transplantation and declines to a low persistent rate thereafter. Between 1981 and 1994 at Stanford, only 20% of heart-lung transplant recipients were free from infection 3 months after transplantation. In a retrospective analysis of 200 episodes of serious infections occurring in 73 heart-lung recipients at Stanford between 1981 and 1990, Kramer et al94 found that bacterial infections accounted for half of all infections; fungal infections accounted for 14%; and CMV was the most common viral agent, comprising 15% of viral infections and occurring primarily in the second month after transplantation. Other viral infections (i.e., herpes simplex, adenovirus, and respiratory syncitial virus) were less common. Five percent of infections were attributed to Pneumocystis carinii, typically occurring 4 to 6 months after transplantation, and 2% were due to Nocardia, generally appearing after the first year. There was no significant difference in the incidence of infections between patients receiving triple-drug or double-drug (cyclosporine and prednisone) immunosuppression. Infectious mortality comprised 40% of all deaths.
Posttransplant infections can be classified broadly into those that occur early or late after transplantation. Early infections, occurring in the first month after transplantation, are commonly bacterial (especially gram-negative bacilli) and manifest as pneumonia, mediastinitis, catheter sepsis, and urinary tract and skin infections. In the late posttransplant period, opportunistic viral, fungal, and protozoan pathogens become more prevalent. The lungs, central nervous system, gastrointestinal tract, and skin are the usual sites of invasion.
Bacterial infections, particularly caused by gram-negative bacteria, predominate during the early postoperative period. Between 75% and 97% of bronchial washings obtained from donor lungs before organ retrieval culture at least one organism.95 Posttransplant invasive infections frequently are caused by organisms cultured from the donor. Conversely, bacterial infections developing in patients with septic lung disease, particularly cystic fibrosis, most commonly originate from the recipient's airways and sinuses. Treatment of bacterial infections generally involves characterization of the infective agent (e.g., cultures, antibiotic sensitivities), source control (e.g., catheter removal, debridement), and appropriate antibiotic regimens.
CMV infection presents either as a primary infection or as reactivation of a latent infection; it occurs most often at 1 to 3 months after transplantation. By definition, primary infection results when a previously seronegative recipient is infected though contact with tissue or blood from a seropositive individual. The donor organ itself is thought to be the most common vector of primary CMV infections. Reactivation infection occurs when a recipient who is seropositive prior to transplant develops clinical CMV infection during immunosuppressive therapy. Seropositive recipients are also subject to infection by new strains of CMV.
Clinically, CMV infection has protean manifestations, including leukopenia with fever, pneumonia, gastroenteritis, hepatitis, and retinitis. CMV pneumonitis is the most lethal of these, with a 13% mortality rate, while retinitis is the most refractory to treatment. Diagnosis of CMV infection is made by direct culture of the virus from blood, urine, or tissue specimens, by a 4-fold increase in antibody titers from baseline, or by the characteristic histologic changes (i.e., markedly enlarged cells and nuclei containing basophilic inclusion bodies). Most cases respond to ganciclovir and hyperimmune globulin.
The significance of CMV as an infective agent becomes clear when one realizes that it is implicated as a trigger for accelerated graft CAD96 and OB,89 as well as an inhibitor of cell-mediated immunity. CMV-negative donors comprise less than 20% of the donor organ pool and, because of organ scarcity, most transplant centers perform transplants across CMV serologic barriers using ganciclovir and/or hyperimmune globulin prophylactic protocols in CMV-positive donors and/or recipients. A recent study by Valantine et al in 80 heart-lung and lung transplant recipients found that the combined use of ganciclovir and hyperimmune globulin was superior to ganciclovir alone as prophylaxis for CMV; moreover, the ganciclovir/hyperimmune globulin cohort had longer survival at 3 years and greater freedom from obliterative bronchiolitis.97
Invasive fungal infections peak in frequency between 10 days and 2 months after transplantation. Treatment consists of fluconazole, itraconazole, or amphotericin B. Reichenspurner et al have reported that the actuarial incidence and linearized rate of fungal infections after heart, heart-lung, and lung transplants performed at Stanford University were significantly reduced in recipients who received inhaled amphotericin prophylaxis.98
Pneumocystis carinii pneumonia has been prevented effectively in lung and heart-lung transplant patients since the institution of prophylaxis with oral trimethoprim-sulfamethoxazole or inhalational pentamidine for sulfa-allergic patients.
Infection prophylaxis in heart-lung and lung recipients is comprised of vaccinations, perioperative broad-spectrum antibiotics, and long-term prophylactic antibiotics. Pretransplant inoculations with pneumococcal and hepatitis B vaccines, as well as DPT boosters, are recommended. Perioperative antibiotic regimens vary widely between transplant centers; however, first-generation cephalosporins (e.g., cefazolin) or vancomycin are commonly used. Long-term prophylaxis typically includes nystatin mouthwash, trimethoprim-sulfamethoxazole, aerosolized amphotericin B, and antivirals such as acyclovir or ganciclovir.
The incidence of neoplasia is higher in transplant recipients than in the general population.99 Undoubtedly, this is due to chronic immunosuppression. Recipients are predisposed to a variety of tumors, including skin cancer, B-cell lymphoproliferative disorders, carcinoma in situ of the cervix, carcinoma of the vulva and anus, and Kaposi's sarcoma. On average, tumors appear approximately 5 years after transplantation.1
The incidence of B-cell lymphoproliferative disorders in transplant patients is a staggering 350 times greater than that seen in the normal age-matched population. Posttransplant lymphoproliferative disorder (PTLD) has been reported in 6% of lung transplant recipients.100 PTLD most commonly occurs within the first year after transplantation, and has been associated with Epstein-Barr virus infection. Treatment consists of reduction in immunosuppression and administration of an antiviral agent such as acyclovir or ganciclovir, with a response rate of 30% to 40%.
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1 antitrypsin deficiency; CF = cystic fibrosis; COPD = chronic obstructive pulmonary disease; IPF = idiopathic pulmonary fibrosis; Misc = miscellaneous; PPH = primary pulmonary hypertension. (Adapted from Hosenpud JD, Bennett LE, Keck BM, et al: The Registry of the International Society for Heart and Lung Transplantation: Eighteenth Official Report—2001. J Heart Lung Transplant 2001; 20:805 with permission from Elsevier Science.)
