| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 1998;66:337-346
© 1998 The Society of Thoracic Surgeons
a Divisions of Cardiothoracic Surgery and Pulmonary Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
Address reprint requests to Dr Egan, University of North Carolina at Chapel Hill, 108 Burnett-Womack Bldg, CB 7065, Chapel Hill, NC 27599-7065
Presented at the Forty-fourth Annual Meeting of the Southern Thoracic Surgical Society, Naples, FL, Nov 6–8, 1997.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
Methods. Eight-two patients with cystic fibrosis have undergone bilateral lung transplantation (n = 76) or bilateral lower lobe transplantation (n = 6) since October 1990.
Results. Actuarial survival for the entire cohort is 79% at 1 year and 57% at 5 years. The development of bronchiolitis obliterans syndrome is the leading cause of death after the first year. Freedom from bronchiolitis obliterans syndrome is 84% at 1 year and 51% at 3 years. Pulmonary function tests improve dramatically in recipients. There was no association between death within 1 year and recipient age, weight, graft ischemic time, cytomegalovirus seronegativity, or the presence of panresistant organisms. Similarly, there was no association between the development of bronchiolitis obliterans syndrome within 2 years and ischemic time, number of rejection episodes, cytomegalovirus seronegativity, or the presence of panresistant organisms.
Conclusions. Despite their poor nutritional status and the presence of multiply resistant organisms, patients with cystic fibrosis can undergo bilateral lung transplantation with acceptable morbidity and mortality.
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
As candidates for transplantation, patients with CF pose serious challenges. These patients are generally chronically ill and nutritionally depleted because of the multisystem nature of their disease and its effect on absorption, liver function, and pancreatic exocrine function. The end-stage bronchiectasis and parenchymal destruction of their lungs results in colonization with virulent strains of Pseudomonas and Staphylococcus aureus. Because of repeated exposure to antibiotics, these organisms are frequently resistant to multiple antibiotics and are sometimes panresistant. Even with surgical excision of both lungs, these same organisms are harbored in the upper respiratory tract and sinuses of potential lung transplant recipients.
However, as patients with end-stage lung disease, those afflicted with CF tend to be relatively young and are often highly motivated. Because they have had to cope with a chronic illness, most are able to understand and comply with a complex medical regimen. Despite the multisystem nature of the disease, the extrapulmonary disease is rarely lethal, although end-stage liver disease causing death can occur in some patients with CF.
Because of the existence of two CF centers at this institution (separate adult and pediatric centers), a wealth of expertise in the clinical management of patients with CF, and a substantial research interest in CF, we have had access to a large number of patients with CF as lung transplant candidates at the University of North Carolina at Chapel Hill. Despite our initial concerns that these patients posed high risks for lung transplantation, we have been pleased with the outcome of transplantation in this cohort. As we have gained experience, we have changed our approach to patient selection.
We reported our results of lung transplantation in our first 44 patients with CF undergoing double-lung transplantation, with survival to 4 years [2]. Since then, we have made some changes to our operative technique and immunosuppression protocol and have liberalized selection criteria with respect to antibiotic sensitivity. We have begun to use bilateral lower lobe transplants from living donors for selected patients with CF and have accrued additional data on durability of lung transplantation in this patient population. Herein, we report our results with survival to 7 years.
|
Patients and methods |
|---|
|
TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
Selection criteria
Selection criteria have been published previously [2] and have been modified as experience has accrued. Current criteria are as follows:
As waiting time has increased, we have become increasingly willing to list patients with an estimated life expectancy up to 3 years. Data from a study by Kerem and associates [5] at the University of Toronto suggested that the risk of death due to CF within 2 years began to increase when the forced expiratory volume in 1 second was less than 30% predicted. Because this level of pulmonary dysfunction appears to be an independent predictor of survival, we have encouraged patients with CF whose forced expiratory volume in 1 second decreased to less than 30% predicted to consider transplant evaluation and listing for transplantation in the absence of contraindications.
We have not considered primary referrals on ventilatory support, but have performed transplantation in 8 patients accepted into our program in whom respiratory failure has subsequently developed necessitating mechanical ventilation. Indeed, this has led to bilateral lower lobe transplantations in 3 patients.
We define significant liver dysfunction as the inability to correct prothrombin time to normal with parenterally administered vitamin K, elevated portal venous pressures, or ascites. We define severe diabetes as diabetes that results in a blood glucose level that is difficult to control, or the development of complications attributable to diabetes. Renal dysfunction is considered severe if creatinine clearance is less than 50% predicted.
Our observation that the incidence of fractures was high after lung transplantation led to studies of osteoporosis in CF transplant candidates. Severe demineralization is a relative contraindication because the use of steroids after transplantation aggravates osteoporosis and can lead to debilitating spontaneous fractures [6].
Until recently, we considered the emergence of panresistant organisms an absolute contraindication to lung transplantation. However, an analysis of sputum retrieved at the time of transplantation demonstrated that close to 40% of our patients were, in fact, panresistant on the day of transplantation [7]. Subsequent to this analysis, we have considered the emergence of panresistant organisms only a relative contraindication.
The criteria for consideration of bilateral lobe transplantation are that individuals be acceptable candidates for conventional transplantation according to the selection criteria and that they be listed for conventional transplantation. If it is judged that there is little or no likelihood of survival to transplantation because of progressive pulmonary dysfunction, then consideration is given to bilateral lower lobe transplants from volunteer donors. In our experience, the term "living related lobe transplants" is a misnomer, because we have performed this procedure using a spouse and a spouse’s brother, two individuals unrelated to the recipient. Donors must have the same, or a compatible, blood type with normal pulmonary function tests, including blood gases, enjoy good health, be willing to donate with no evidence of coercion, and be large enough that a lower lobe is likely to occupy the recipient’s pleural space. We have required some relationship or emotional attachment to the intended recipient, such as blood relative, spouse, or in-law.
Preoperative management
Listed patients are required to remain physically active and to participate in a pulmonary rehabilitation program of aerobic exercise. When patients accrue enough seniority that they are likely to receive a transplant within 3 to 6 months, we request that they move to the area if they do not live within 2 to 3 hours of our transplant center. Prospective recipients are followed up as outpatients at 3-month intervals. Clinical deterioration often triggers a search for potential living donors.
Anesthetic techniques
Once a prospective donor is identified, the intended recipient is admitted to the hospital and is given bowel preparation with Go-lytely (Braintree Labs, Inc, Braintree, MA) to minimize the risk of distal intestinal obstruction syndrome postoperatively. After induction of general anesthesia, bronchoscopy is undertaken to aspirate purulent secretions from the airway before insertion of a left-sided double-lumen tube. In patients who are too small to accommodate a double-lumen tube, the transplantation is performed with the use of bronchus-blocking balloons. Cardiopulmonary bypass is always available in case of inability to maintain the recipient on one lung during pneumonectomy or implantation, or in case of graft dysfunction after the first lung is implanted.
Antibiotics are administered preoperatively based on antibiotic sensitivities or synergy studies from the most recent sputum cultures, obtained at intervals on an outpatient basis. Recently, in patients who have been demonstrated to have panresistant organisms, ceftazidime and tobramycin are administered systemically.
Operative technique for bilateral lung transplantation
The operative technique of bilateral lung transplantation has been described in detail elsewhere [8]. The patient is placed supine with both arms extended above the head. The chest is entered through a bilateral thoracosternotomy, or "clamshell" incision (Fig 1). A preoperative perfusion scan identifies which lung is the least perfused, and generally this lung is removed first. If the relative perfusion is equal, our preference is to remove the right lung first. Important aspects of technique in patients with CF include division of dense vascular adhesions by electrocautery and awareness of an abundant bronchial arterial blood supply.
|
The donor lung from the appropriate side is brought onto the field and prepared for implantation by excision of excessive donor bronchus to within one or two rings of the upper lobe takeoff. The bronchial anastomosis is the most posterior and is performed first. We prefer to use a running polyglycolic acid suture (3-0 or 4-0 Maxon; Davis & Geck, Danbury, CT) on the membranous airway, and interrupted braided polyglycolic acid suture (Dexon II; Davis & Geck) on the cartilaginous airway. Occasionally, size discrepancies mandate some degree of telescoping of this anastomosis, but we generally prefer to perform an end-to-end anastomosis. We performed omentopexy on the first 56 recipients of double-lung transplants; the last 20 patients have had coaption of peribronchial tissue from the donor to recipient mediastinum, as first described by Noirclerc and colleagues [9]. After completion of the two vascular anastomoses, an attempt is made to remove the air from the pulmonary vasculature by back-bleeding before opening the lung to the circulation. Contralateral pneumonectomy and implantation is then undertaken. Four chest tubes are placed: one curved tube over each diaphragm directed into the gutters bilaterally, and one straight tube directed to the apex on each side. The double-lumen endotracheal tube is replaced with a large bore single-lumen tube, and bronchoscopy is undertaken to aspirate any material that is in the large airways. Cardiopulmonary bypass can easily be instituted through this incision by ascending aorta cannulation and right atrial cannulation with a two-stage venous cannula.
We have frequently encountered donors who were "too large" for the recipients with CF, who tend to be of small stature. When, in the judgment of the operating surgeon, the donor lungs are too large, they are downsized (by resection) after completion of the transplantation. Eleven patients with CF have undergone this form of pneumoreduction consisting of right middle lobectomy, nonanatomic lingulectomy, or both. An analysis of this practice demonstrated no adverse impact on outcome [10].
Operative technique for bilateral lobe transplantation
The technique of recipient pneumonectomy is identical to that decribed above, except for division of the airway on the right side. We have elected to divide the upper lobe airway with a TA stapler and then divide the bronchus intermedius of the recipient, performing the anastomosis of the donor right lower lobe to the recipient bronchus intermedius. The bilateral lower lobe transplantation is always performed on cardiopulmonary bypass, which is instituted before pneumonectomy is undertaken (Fig 2).
|
After the left lower lobe is implanted, cardiopulmonary bypass flow is reduced to allow some flow through the newly engrafted organ, while attention is directed to right pneumonectomy and, subsequently, lobe implantation. In general, we prefer the larger donor to be the right lower lobe donor, because the right lower lobe is usually smaller than the left lower lobe. A preoperative computed tomographic scan helps to identify anatomic problems on the right side that might preclude the safe separation of lower lobe from middle lobe in the donor.
Principles of early postoperative management
Patients are ventilated until they are able to maintain adequate gas exchange and tidal volumes. Perioperative analgesia is facilitated by the placement of a thoracic epidural catheter if coagulation factors are normal. Otherwise, intravenous patient-controlled administration of morphine is used. Aggressive pulmonary toilet, including vigorous chest physical therapy and early ambulation, is a cornerstone of early postoperative management. Early function of the engrafted lungs can be altered by graft dysfunction due to reimplantation response or infection. Overwhelming graft dysfunction has led to urgent retransplantation in 3 patients with CF, with two successful outcomes, but is no longer practical because of the change in the United Network for Organ Sharing algorithm for lung donor placement.
Immunosuppression
Immunosuppression is based on cyclosporine, azathioprine, and steroids. Cyclosporine and azathioprine administration is begun intravenously in the operating room. For the first 55 transplantations, the early use of steroids was avoided, and antilymphocytic therapy was used. This consisted of University of Minnesota ALG or Atgam (Upjohn Pharmaceuticals, Kalamazoo, MI). For the last 27 patients, no cytolytic therapy has been used, and prednisone has been started in the operating room (125 mg every 8 hours for three doses) followed by Solu-Medrol, 0.5 mg/kg in divided doses twice a day (Upjohn). Episodes of acute rejection are treated with bolus doses of methylprednisolone for 3 days, initiated at 15 mg/kg of Solu-Medrol. Recently, patients who have recurrent acute rejection episodes or development of bronchiolitis obliterans syndrome are switched from azathioprine to mycophenolate mofetil (Cell-Cept, Hoffman LaRoche, Nutley, NJ) and from cyclosporine to FK506 (Tacrolimus, Fujisawa, Dierfield, IL).
Before the introduction of Neoral (Sandoz, Basel, Switzerland), the microemulsion formulation of cyclosporine, we routinely used ketoconazole or diltiazem to increase cyclosporine levels in patients with CF. Because the rate and extent of cyclosporine absorption from the microemulsion formulation are greater compared with the conventional formulation in patients with CF [11], we have found this to be necessary in only a small number of patients with CF [12].
Late postoperative management
After discharge from the hospital, patients are required to record their temperature daily and perform daily spirometry with either a hand-held spirometer (Microdirect, Auburn, ME) or the Datalog (Datalog, Stillwater, MN) system, which sends a copy of the spirometry via modem to the nurse-coordinator. Bronchoscopy is performed usually within the first few weeks during hospitalization, and again 1 and 3 months after transplantation, and then every 3 months for the first year, or when clinically indicated to investigate a fever, a reduction in airway flows, or a pulmonary infiltrate on a chest radiograph.
Statistics
Data are presented as mean ± standard error. Actuarial survival and actuarial freedom from bronchiolitis obliterans were calculated using the Kaplan-Meier method and are presented as freedom from death or freedom from development of bronchiolitis obliterans, respectively, with 95% confidence intervals. For factors influencing the development of bronchiolitis obliterans syndrome or for poor early outcome, contingency tables were analyzed using a Statview program (Abacus Concepts, Berkeley, CA), with a 
2 statistic calculated on a Macintosh II F-X personal computer (Apple Computer, Inc, Cupertino, CA).
|
Results |
|---|
|
TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
|
|
|
|
Actuarial freedom from bronchiolitis obliterans syndrome is depicted in Figure 4. Bronchiolitis obliterans syndrome is defined as a reduction of more than 15% from the baseline forced expiratory volume in 1 second [12]. For purposes of this analysis, patients who died of causes other than bronchiolitis obliterans syndrome were censored at the time of their death. By 3 years, more than half of the living recipients had some degree of bronchiolitis obliterans syndrome. As is apparent from Table 3, there were 12 deaths from bronchiolitis obliterans syndrome. In 3 of these, lack of compliance contributed substantially to the development of chronic rejection. Three other patients have undergone retransplantation because of end-stage lung disease due to bronchiolitis obliterans syndrome. One of these patients died of cytomegalovirus pneumonia after the second transplantation, but the other 2 remain alive and well at 36 and 2 months after retransplantation. The longest survivor has no evidence of recurrent bronchiolitis obliterans syndrome at 36 months. Four other patients with CF are currently listed for retransplantation because of bronchiolitis obliterans syndrome.
|
|
Posttransplantation lymphoproliferative disorder (lymphoma) has been lethal in 2 patients, but has been successfully treated by reduction of immunosuppression in 4 other patients. One of these later died from bronchiolitis obliterans syndrome. This abnormality is associated with Epstein-Barr virus seronegativity in recipients [14].
The incidence of airway complications in this population has been gratifyingly infrequent. Airway dehiscence developed in 4 patients. In 1 it was contained and went on to heal with no sequelae. In 2 it was associated with a mediastinal abscess; one dehiscence healed spontaneously after percutaneous drainage of the mediastinal abscess. The other patient had a sleeve right upper lobe resection that resolved the airway problem, but he died of a panresistant Burkholderia cepacia pneumonia. A fourth patient had dehiscence of the airway anastomoses that communicated with the pleural spaces. He had renal failure and died of fungal sepsis before the airway dehiscences became clinically problematic. Two other patients have required placement of stents in the bronchus intermedius because of stenosis of this segment of airway. No anastomotic strictures have been seen.
One patient, who underwent nonanatomic stapling of the lingula and right middle lobe and nonanatomic resection of the apices of both upper lobes because the donor was substantially larger, had to be returned to the operating room for prolonged air leak from two of the staple lines on the right side.
Despite the prevalence of bronchiolitis obliterans syndrome, pulmonary function tests in survivors are dramatically improved and allow most long-term survivors to enjoy unlimited levels of activity without oxygen. Spirometric results after transplantation are depicted in Figure 5.
|
When a similar analysis was undertaken for the development of bronchiolitis obliterans within 2 years, recipient age appeared to be a potentially significant issue. Of 49 patients who could be evaluated at 2 years for the presence of bronchiolitis obliterans syndrome, 22 met the criteria, with a mean age of 21.1 years, as opposed to 27 patients who did not have bronchiolitis obliterans syndrome, with a mean age of 27.7 years. This difference in age was statistically significant by unpaired t test (p < 0.005). The clinical significance of this is unclear and invites further study.
Of particular interest was the failure of panresistant organisms to auger a poor outcome. The actuarial survival out to 3 years for patients whose organisms were panresistant on the day of transplantation compared with those patients who had sensitivies in vitro to at least one antibiotic is depicted in Figure 6. It is clear from this figure that the presence of panresistant organisms on the day of operation does not in any way predict a poorer outcome. Ten patients in this series were colonized with B cepacia at the time of transplantation.
|
|
Comment |
|---|
|
TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
The first published report of heart–lung transplantation for a patient with CF came from Harefield Hospital [18]. Initial experience with heart–lung transplantation for patients with CF in North America was discouraging. A 1-year actuarial survival of 42% was reported for 33 patients with CF undergoing heart–lung transplantation at 14 centers in North America between October 1983 and August 1990 [19]. Results with this procedure were better in European centers, with Yacoub and colleagues [18] reporting four operative deaths among 27 patients with CF, and the group from Papworth Hospital in Cambridge reported a 1-year actuarial survival of 73% in 32 patients undergoing heart–lung transplantation for CF [20]. The first report of double-lung transplantation for patients with CF came from the University of Toronto, where the first 17 patients with CF had a 1-year actuarial survival of 58% [21]. Shennib and colleagues [22] reported on the combined experience of double-lung transplantation for CF at the Montreal General Hospital in Montreal, Canada, and the St. Marguerite Hospital in Marseilles, France. Their 25 recipients had an operative survival of 76% and a 1-year actuarial survival of 64%.
Despite the potential for increased perioperative morbidity and mortality, patients with CF can undergo lung transplantation with a low perioperative mortality. There is evidence of increasing enthusiasm for double-lung transplantation for patients with CF. According to the Registry of the International Society for Heart and Lung Transplantation, 38% of the 1,667 double-lung transplant procedures reported to the Registry were performed for CF [23]. Our observation that long-term survival is unrelated to the existence of panresistant organisms may allow this therapy to be extended to this group of patients with CF who were previously not considered candidates in most centers. We are still concerned about performing bilateral lobe transplantation in panresistant recipients because of our perception that infectious complications in recipients would be more difficult to treat and our desire to avoid futile operations in willing donors. Nonetheless, 3 of our 6 recipients of bilateral lobes had panresistant organisms at the time of operation.
Bronchiolitis obliterans syndrome remains a serious problem affecting half of the long-term survivors of lung transplantation, but is not uniformly lethal. It would appear that in selected patients, retransplantation may be an option. Our philosophy with regard to retransplantation is that potential recipients should be evaluated using the same selection criteria as those used for first-time transplant patients. Many individuals in whom bronchiolitis obliterans syndrome develops are not candidates for retransplantation because of inadequate renal function or the emergence of other comorbidities, such as severe osteoporosis or unwillingness to undergo the procedure a second time.
A more vexing problem for patients with CF is the inadequate supply of donors. In our experience, death on the waiting list occurs more frequently than death after lung transplantation from all causes. Although bilateral lobe transplantation may be an option for some patients with CF, it is not practical for many because of their size or the inability to identify two appropriate donors.
Options to address the issue of death on the waiting list may include a more fair distribution of organs. Unfortunately, any change in organ distribution algorithms will likely mean that patients with other diagnoses will be deprived of lungs. Although xenografts hold promise to resolve the donor shortage, there are still substantial—and, at present, insurmountable—immunologic barriers [24]. Other approaches may be to attempt to salvage donor lungs that are dysfunctional. An improved understanding of graft dysfunction in brain-dead individuals may make this approach practical. Another option, which has been the focus of investigation in our laboratory, is the possible use of lungs retrieved from circulation-arrested cadavers for transplantation [25–27].
We conclude that bilateral lung transplantation is a reasonable and durable option for patients with CF who have end-stage lung disease. Despite an intuitive bias, antibiotic sensitivities do not play a role in predicting outcome. We hope that strategies to increase the pulmonary donor pool will enable more CF lives to be extended and will reduce the number of deaths on the transplant waiting list, while a better understand of bronchiolitis obliterans syndrome and the immunology of lung transplantation offers the promise of reduced deaths after transplantation.
|
Acknowledgments |
|---|
|
TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
|
References |
|---|
|
TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  G Meachery, A De Soyza, A Nicholson, G Parry, A Hasan, K Tocewicz, T Pillay, S Clark, J L Lordan, S Schueler, et al. Outcomes of lung transplantation for cystic fibrosis in a large UK cohort Thorax, August 1, 2008; 63(8): 725 - 731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W Chalermskulrat, N Sood, I P Neuringer, T M Hecker, L Chang, M P Rivera, L J Paradowski, and R M Aris Non-tuberculous mycobacteria in end stage cystic fibrosis: implications for lung transplantation Thorax, June 1, 2006; 61(6): 507 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Reed General thoracic surgery and the Southern Thoracic Surgical Association: the second 25 years Ann. Thorac. Surg., November 1, 2003; 76(90050): S14 - 16. [Full Text] [PDF]
|
|
|
|
 |
|
 T.M. Egan, F.C. Detterbeck, M.R. Mill, M.S. Bleiweis, R. Aris, L. Paradowski, G. Retsch-Bogart, and B.S. Mueller Long term results of lung transplantation for cystic fibrosis Eur. J. Cardiothorac. Surg., October 1, 2002; 22(4): 602 - 609. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Vricella, J. M. Karamichalis, S. Ahmad, R. C. Robbins, R. I. Whyte, and B. A. Reitz Lung and heart-lung transplantation in patients with end-stage cystic fibrosis: the stanford experience Ann. Thorac. Surg., July 1, 2002; 74(1): 13 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. ARIS, J. C. ROUTH, J. J. LIPUMA, D. G. HEATH, and P. H. GILLIGAN Lung Transplantation for Cystic Fibrosis Patients with Burkholderia cepacia Complex . Survival Linked to Genomovar Type Am. J. Respir. Crit. Care Med., December 1, 2001; 164(11): 2102 - 2106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Date, M. Yamashita, I. Nagahiro, M. Aoe, A. Andou, and N. Shimizu Living-donor lobar lung transplantation for primary ciliary dyskinesia Ann. Thorac. Surg., June 1, 2001; 71(6): 2008 - 2009. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
