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Eur J Cardiothorac Surg 1999;16:546-554
© 1999 Elsevier Science NL
a Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, 30623 Hannover, Germany
b Division of Pulmonology, Hannover Medical School, 30623 Hannover, Germany
Corresponding author. Tel.: +49-511-532-6580; fax: +49-511-532-5404
e-mail: harringer{at}thg.mh-hannover.de
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Abstract |
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 Top Abstract 1. Introduction2. Patients and methods3. Results4. Comments5. ConclusionAppendix AReferences |
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Key Words: Lung • Transplantation • Survival • Bronchiolitis obliterans syndrome
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1. Introduction |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Comments5. ConclusionAppendix AReferences |
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2. Patients and methods |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Comments5. ConclusionAppendix AReferences |
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Our early experience includes 90 patients undergoing 99 operations: 28 heart-lungs (28%), 40 single lungs (40%) and 31 double lungs (31%). The more recent group of transplanted patients (n=168; 183 procedures) demonstrated a significant decrease in heart-lung replacements (n=18, 10%; P<0.0001), slight decrease in single lungs (n=54, 30%; P=0.09), and a consequential increase in double lungs (n=111, 61%; P<0.0001). The proportion of retransplantation remained stable throughout the study period. Nine patients (10%) required a redo-procedure in the early years and 15 patients (9%) in the last 5 years. The underlying indications for different procedures by transplantation period are reported in Fig. 2.
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2.1. Surgical technique and perioperative management
Heart-lung transplantation is usually performed via a median sternotomy, as has been reported elsewhere [9]. More recently, a bilateral anterior thoracotomy in the fourth intercostal space, similar to bilateral sequential lung transplantation, has been used for patients with extensive aortopulmonary collaterals for better exposure of the descending thoracic aorta. Timing of the operation is crucial because explantation of recipient organs can be difficult and time consuming due to extensive adhesions if one or more cardiac operations were performed in the patient's history.
Single and bilateral sequential lung transplantation is performed in a standard fashion [10]. A bilateral anterior thoracotomy in the fourth intercostal space without transection of the sternum has been used in a small number of patients without severe adhesions for double lung transplantation with good success. Utmost care is used to preserve the collateral blood supply to the donor bronchus from the pulmonary artery. Limited dissection of peribronchial tissue, shortening of the donor bronchus up to one cartilage proximal to the upper lobe and careful suture technique (interrupted PDS® sutures: membranous part 4/0, cartilaginous part 3/0) has proven valuable for bronchial healing in our experience. Additionally, an antibiotic/fibrin glue compound has been applied around the bronchial anastomoses in the majority of patients. No routine omental or pericardial wrapping of the bronchial anastomoses has been performed and bronchial arteries were not reimplanted. For improvement of bronchial microcirculation heparin (100 U/kg) was administered prior to crossclamping of the pulmonary artery, has been continued as an intravenous infusion (200 U/kg) for 4 days and was then replaced by subcutaneous injection (15 000 U/day) for 10 days.
In patients without the use of cardiopulmonary bypass, a special challenge for the right-sided graft occurs during the subsequent left-sided pneumonectomy. The transplanted lung is then overflown with the full cardiac output following hours of ischemia increasing the risk for reperfusion injury. We routinely implemented extracoroporeal circulation when the mean pulmonary artery pressure rose>35 mmHg following crossclamping of the left pulmonary artery, despite stable hemodynamics and adequate oxygenation.
Following the operation, the double lumen tube is replaced by a single lumen nasotracheal tube, the patient is bronchoscoped to remove secretions from the lungs and to examine the anastomoses.
Prophylactic administration of broad spectrum antibiotics (currently a combination of tobramycine, ceftazidim and flucloxacillin) was applied for a minimum of 7 days. Thereafter, the antibiotic therapy was adapted according to microbiological analysis of bronchoalveolar lavage. During the last years, all patients inhaled nebulized colistin postoperatively for 2 weeks. Long-term prophylaxis with colistin was continued in patients with evidence of Pseudomonas colonization of the transplanted lungs.
Postoperative CMV-prophylaxis consisted of 5–10 g/day hyperimmunoglobulin for 3 days as well as gancyclovir (10 mg/kg) for 2 weeks. On identification of CMV immediate early antigen (pp65) or suspected CMV infection, a 3-week course with gancyclovir was started.
Fungal prophylaxis included the administration of fluconazol or itraconazol as well as inhaled amphotericine B.
2.2. Immunosuppression and acute rejection
Standard immunosuppression has been based on cyclosporine A, azathioprine and prednisolone. Cytolytic induction therapy using anti-thymocyte-globulin (ATG, Biotest) was applied during the first 4 years routinely for a period of 3–5 days. Since then its use has been limited to the discretion of the surgeon, usually in selected patients with significant renal dysfunction. Intravenous cyclosporine A is usually administered within 6 hours postoperatively. The initial dose (1 mg/kg) is increased within the following 1–2 weeks up to 10 mg/kg depending on renal and hepatic function. Cyclosporine A serum level (monoclonal assay) is aimed at 220–300 ng/ml for the first year with reduction to 150–200 ng/ml for the following years. Patients also receive 1–2 mg/kg azathioprine with a target white blood cell count of 4000 cells/mm3 or greater. Prednisolone (1000 mg i.v.) is administered intraoperatively followed by three doses of 250 mg at 12 h intervals. Prednisolone maintenance therapy is started on the second postoperative day (initially 0.5 mg/kg and tapered to 0.07 mg/kg within 1 year). More recently, a clinical trial for evaluation of mycofenolic acid as substitute for azathioprine in de novo immunosuppression has been entered, with the results still pending.
Diagnosis of rejection episodes remains still challenging as clinical signs are unspecific and resemble those of infection and preservation injury. Initial treatment of pulmonary rejection episodes follows a regimen of pulsed steroids (3x1000 mg). Repetitive pulsed steroids in combination with monoclonal or polyclonal antibodies were used in case of ongoing or recurrent acute rejection episodes. Concomitantly, various modifications of basic immunosuppresion have been performed in such patients over the years. Currently, cyclosporine and azathioprine are replaced by tacrolimus and mycofenolic acid in patients requiring three or more treatments for acute rejection within the first 6 months.
2.3. Statistical analysis
Continuous variables are expressed as mean plus or minus one standard deviation (SD). Survival after surgery and freedom from BOS were analyzed by Kaplan–Meier method. Evaluation of survival difference between groups, as well as for indications of procedures was conducted by log-rank test. Differences between surgical procedures and outcome in cystic fibrosis and pulmonary hypertension patients were evaluated with Mann–Whitney rank-sum test, 
2 test or Kruskal–Wallis test, where appropriate. Statistical analysis was performed using SPSS for Windows 8.0 software system (SPSS Inc., Chicago, IL). A P-value of <0.05 was considered significant.
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3. Results |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Comments5. ConclusionAppendix AReferences |
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Causes of death in the 90 non-survivors (HLTx: n=19; DLTx: n=37; SLTx: n=34) indicate that infection (n=42) and chronic rejection (n=28) were the major problems. Other causes of mortality are reported in Table 3. Early death (<POD 90; n=36) was caused by infection in 64% of patients followed by cardiac failure (11%) and other causes (14%). Late death (>POD 90; n=54) was due to chronic graft failure in the majority of patients (52%), followed by infection (35%), and other causes (6%). Further analysis did not reveal any significant differences between early and late transplant periods or type of procedure.
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4. Comments |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Comments5. ConclusionAppendix AReferences |
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4.1. Patient selection and choice of procedure
Despite maximal utilization of available organs, which led to a decline in heart-lung replacements, single lung transplantation decreased also in favor of bilateral sequential lung transplantation in recent years. This reflects a change in our institutional policy for preferred procedures in patients with pulmonary hypertension and chronic obstructive lung disease during the last decade. Contrary to the international experience, where the majority of single lung transplantation (55%) are performed for chronic obstructive lung disease [1], we prefer bilateral sequential lung transplantation in the majority of our emphysema patients. It avoids problems with over inflation of the native lung early postoperatively as well as infectious complications during follow-up and minimizes the risk of death due to spontaneous pneumothorax, which has occurred twice in our patients. In emphysema patients a more sophisticated, disease based approach utilizing lung transplantation combined with lung volume reduction surgery might have a significant influence on future patient management [11].
In patients with pulmonary hypertension our initial approach was heart-lung replacement. Due to severe limitations of available donor organ blocks and following promising reports with single lung transplantation we changed to this procedure but abandoned it shortly thereafter because of the difficult peri- and postoperative course. In single lung transplantation for pulmonary hypertension 90% of cardiac output is directed towards the transplanted lung, because of its lower vascular resistance. Consequently, a ventilation/perfusion mismatch unequivocally will occur during episodes of transplant dysfunction (reperfusion edema, rejection, infection), which is poorly tolerated in our experience. Double lung transplantation achieves better functional recovery and a reduced graft related mortality when compared to single lung transplantation [12]. Yet, this issue is still discussed controversially and neither procedure has emerged as a clearly superior approach in the literature [13]. Our results suggests better survival after heart-lung transplantation for patients with pulmonary hypertension compared to lung transplantation alone. This might reflect a bias in patient selection, as the vast majority of heart-lung recipients were transplanted in the early years of our program. Additionally, severe shortage of donor organs currently prohibits a more liberal use of heart-lung transplantation, as the waiting time for this procedure increased during the decade to almost 3 years now at our center. Comparative waiting time for single or double lung transplantation today is 1 year.
In addition to procedural changes patient selection was influenced during this decade by improvements in medical therapy as well as organ preserving surgical alternatives [14–16]. This stresses the importance of tight interdisciplinary cooperation in the management of these patients. In all patients with pulmonary hypertension referred for transplantation, we currently assess their response to intermittent nebulized prostacyclin before or during enlistment for transplantation with promising results [17]. Furthermore, pulmonary thromboendarterectomy as well as lung volume reduction surgery have broadened surgical therapy and are evaluated as treatment strategies in patients referred for transplantation. Whereas pulmonary thromboendarterectomy is considered treatment of choice in patients with pulmonary hypertension due to thromboembolism, we believe that long-term results of lung volume reduction surgery and clear patient selection criteria are needed to judge the value of this procedure.
4.2. Postoperative management
Contrary to other centers, transbronchial lung biopsies are not performed on a routine basis early after transplantation or during any episode suspicious of lung rejection in our program. Standard bronchoscopy is done in regular intervals in the early postoperative period until endobronchial healing is completed. Thereafter pulmonary function parameters (determined by home spirometry) are used exclusively for further graft surveillance in asymptomatic outpatients. Additionally, in patients with deteriorating lung function in the early as well as late postoperative period bronchoalveolar lavage is performed to exclude infection. Unlike purulent bacterial infections, acutely rejecting lungs often present with small amounts of ubiquitous non-liquid whitish secretions. The material obtained by bronchoalveolar lavage is analyzed for bacterial and viral organisms and fungi. In patients with poor clinical condition, in whom pulmonary infection is unlikely, methylprednisolone is initiated immediately after bronchoscopy. Otherwise, the therapy is withheld until the gram stain and CMV early antigen (pp65) test results are available to exclude an infectious episode as the cause of pulmonary deterioration. Lack of clinical improvement after the first course of steroids in patients with suspected acute rejection represents an indication for transbronchial lung biopsy in our program. For identification of optimal target areas a high resolution CT-scan is performed before biopsy.
Rejection monitoring by routine surveillance lung biopsies is still discussed controversially in the literature and has not proven helpful in the management of stable asymptomatic patients more than 2 years after transplantation [13,18,19]. Similar to others, in our hands routine transbronchial biopsy has achieved a low sensitivity and specificity of the histologic findings in the specimens and very little impact on patient treatment [20]. Whether aggressive treatment of asymptomatic, biopsy proven acute rejection will lead to a reduced prevalence of BOS remains yet to be demonstrated.
Infection represents the major cause of early as well as late death in our patients. This corresponds well with the experience of other centers. Pathogens include bacteria, viruses, fungi and protozoa, with bacterial pneumonia, CMV pneumonitis and invasive aspergillosis being the most problematic [13]. In all our recipients with cystic fibrosis colonization of the transplanted lungs with Pseudomonas strains occurred during 6 weeks postoperatively. In the majority of cases, the bacterial strains had been identified before transplantation [21].
Our causes of early death demonstrate only a small number of early graft dysfunction. This may reflect a liberal acceptance for retransplantation in patients with severe reperfusion injury as well as an intensified postoperative care including NO-inhalation, surfactanct instillation and application of C-1 esterase inhibitor in selected recipients [22]. Additionally, in our last 33 patients modification of lung preservation has been undertaken, changing from modified Euro–Collins to low-potassium-dextran (LPD) solution. Studies from our laboratory as well as from others have suggested an improved post-ischemic lung function following preservation with LPD-solution [23,24]. Thus, a clinical trial has been started recently to further evaluate the potential benefit of this conservation protocol.
4.3. Bronchiolitis obliterans syndrome
The most important factor limiting long-term survival and quality of life after lung transplantation is chronic allograft rejection. Histologically, bronchiolitis obliterans (a diffuse, concentrical, luminal narrowing of the terminal bronchioli) is the characteristic finding in the lungs resulting clinically in a progressive loss of vital capacity and FEV1 with an obstructive airflow pattern. Transbronchial biopsies achieve low sensitivity and specificity so that spirometric parameters are used to define BOS after exclusion of acute rejection, infection and airway stenoses [25,26]. Our data indicate that 5 years following lung transplantation 55% of patients demonstrate clinical evidence of chronic rejection. Frequent acute rejection episodes could be identified as the most significant risk factor for development of BOS in several reports [13,27,28]. Additionally, CMV pneumonitis may be a predisposition for BOS but its significance is still discussed controversially. A possible mechanism of CMV infection for BOS development is the induced upregulation of MHC class II antigens in the transplanted lungs, making them more prone to acute rejection episodes [29]. Preventive measures other than aggressive treatment of acute rejection episodes and CMV pneumonitis and – probably – CMV prophylaxis are currently not evident [13]. Once BOS is diagnosed augmentation and modification of basis immunosuppression is empirically performed by most transplant centers including corticosteroids, polyclonal and monoclonal antibodies, methotrexate, tacrolimus, mycofenolic acid, aerolized cyclosporine and total lymphoid irradiation with modest and often transient improvement of lung function similar to our experience [13]. Mean survival rates after diagnosis were 66% at 1 year and 37% at 5 years in a Stanford series, with the majority of patients dying of pneumonia [28]. With improved early results and a continuous increase in successful transplantation the question of retransplantation ultimately rises for these patients [30]. Due to its amplification of donor organ shortage and still inferior outcome when compared to first time transplants this issue is discussed highly controversial [31]. In our opinion, absence of other therapeutical options as well as acceptable survival rates makes lung retransplantation a therapeutical option in selected patients with end-stage BOS.
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5. Conclusion |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Comments5. ConclusionAppendix AReferences |
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Acknowledgments |
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Footnotes |
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Appendix A |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Comments5. ConclusionAppendix AReferences |
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Dr. Harringer: In the subanalysis of these 21 patients, 1- year survival in this group is just below our regular 1- year survival, ranging around 70%. I think one critical factor for retransplantation is that these patients are in a fairly well nutritional status and that they go ambulatory into retransplantation. If you wait too long these patients will deteriorate so dramatically that your results will not be acceptable. So far, our patient group is very small, and it does not correspond to the IHLST experience. It is very difficult to predict which of these patients will develop BOS again once they are retransplanted. We have seen patients who developed it very early and we have seen patients who did well for 5, 6 years and still are doing well after retransplantation.
Dr. Varela (Madrid, Spain): What is your current preservation protocol, and for patients with pulmonary hypertension, what kind of pulmonary transplant do you favor?
Dr. Harringer: Right now we have switched our preservation protocol from Euro–Collins to low-potassium dextran solution. We are currently evaluating the low-potassium dextran solution in a clinical study protocol. We think that the reperfusion edema and reperfusion injury has decreased dramatically compared to Euro–Collins solution. With regard to pulmonary hypertension, our experience with single lung transplantation and pulmonary hypertension is bad. So we do as a routine procedure bilateral sequential lung transplantation in these patients.
Mr. Murday (London, England): To examine survival you need to have some comparison, some group of patients with whom you can compare survival without transplantation. Of course that has always been a great difficulty. I think to date there isn't anything in the published literature that really demonstrates an improved survival with lung transplantation, although it is something many of us would accept as being the case. Can you tell us how your survival data compares with any control group, for example, waiting list mortality?
Dr. Harringer: There was a very nice paper published in Lancet in January this year demonstrating that for the patient group of pulmonary fibrosis and for cystic fibrosis there is definitely a survival benefit with lung transplantation. In the same study there was no survival benefit for the patients with emphysema on the waiting list. Despite survival, you also have to keep in mind that you achieve an extreme improvement with regard to physical fitness and life quality in these patients. So I think the issue with the emphysema patients is not yet settled, but for cystic fibrosis and for pulmonary fibrosis patients, there is a significantly improved course with lung transplantation compared to the patients on the waiting list.
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References |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Comments5. ConclusionAppendix AReferences |
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stage I ISHLT-classification) after pulmonary transplantation at Hannover Medical School. Error bars represent 1 SD.