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Eur J Cardiothorac Surg 2000;18:447-452
© 2000 Elsevier Science NL

Ten years experience with lung and heart–lung transplantation in primary and secondary pulmonary hypertension

^a Department of Thoracic and Cardiovascular Surgery, Friedrich-Schiller-University, D-07740 Jena, Germany
^b Department of Thoracic and Cardiovascular Surgery, Medical School, Hannover, Germany

Received 28 December 1999; received in revised form 19 June 2000; accepted 28 June 2000.

Corresponding author. Tel.: +49-3641-934-801; fax: +49-3641-934-802
e-mail: ulrich.franke{at}med.uni-jena.de

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
Objective: Patients with primary pulmonary hypertension (PPHT) have a worse natural outcome compared with those with secondary pulmonary hypertension in Eisenmenger's syndrome (ES) and chronic pulmonary embolism (CPE). Lung transplantation (SLTx, DLTx, HLTx) still remains the only therapeutical option for patients with this type of endstage lung disease. Methods: From 1988 to 1998, 63 patients underwent lung transplantation for PPHT (n=29, 9 m, 20 f, 2 SLTx, 14 DLTx, 13 HLTx), ES (n=29, 13 m, 16 f, 2 SLTx, 3 DLTx, 24 HLTx) or CPE (n=5, 2 m, 3 f, 1 SLTx, 2 DLTx, 2 HLTx). Groups were comparable for NYHA functional class, preoperative pulmonary arterial pressure, recipient and donor age, ischemic time, necessity and duration of cardiopulmonary bypass and cross-match. Results: The 1-, 3- and 5-year survival was 52, 40 and 35% for the PPHT-group, 83, 78 and 74% for the ES-group and 80, 60 and 60% for the CPE-group, respectively (P=0.026, P=0.033, P=0.082 for 1-, 3- and 5-year survival). Patients following DLTx showed a lower 1-year survival rate as compared with patients after HLTx both in PPHT patients (36 vs. 62%, P=0.091) and in ES patients (67 vs. 83%, P=0.213). The incidence of bronchiolitis obliterans syndrome was 29% at 1 year and 45% at 3 years for the PPHT-group vs. 17 and 65% for the ES-group (n.s. in between groups). Excluding postoperative ventilation time (PPHT-group: 26.8±24.0 days vs. ES-group: 16.1±30.8 days, P=0.011) and a higher incidence of infectious causes of death (PPHT-group n=8 vs. ES-group n=1, P=0.017) groups were comparable with regard to their postoperative courses. Conclusions: It is concluded, that predominantly the underlying primary disease influences graft survival after lung transplantation in patients with pulmonary hypertension compared with all other patient and procedure dependent factors. Lung transplantation in patients with PPHT requires further investigations to achieve results comparable with other indications.

Key Words: Primary pulmonary hypertension • Eisenmenger's syndrome • Chronic pulmonary embolism • Lung transplantation • Heart–lung transplantation • Bronchiolitis obliterans syndrome

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
Single (SLTx), double (DLTx) and heart–lung transplantation (HLTx) are well established therapies in patients with end stage lung disease. However, it has been shown, that the outcome of patients after lung or heart–lung transplantation depends on the underlying diagnosis and the type of procedure applied. This is especially addressed by the adverse outcome of patients with pulmonary hypertension or following after heart–lung transplantation [1].

The survival analysis of patients of our own transplantation program revealed a poor survival of patients with pulmonary hypertension (PHT) compared with patients with cystic fibrosis [2]. Most authors report on PHT in general without a differential analysis of their results [3–7]. However, primary pulmonary hypertension (PPHT) and secondary pulmonary hypertension (SPHT) have to be separated pathogenetically. While PPHT is a well defined diagnosis, in SPHT, Eisenmenger's syndrome (ES) and chronic pulmonary embolism (CPE) are the most common diseases. Comparing the natural course applying medical strategies, patients with ES have a more favorable prognosis than patients with PPHT [8]. So it was the hypothesis of this investigation that ethiology of pulmonary hypertension also influences prognosis after transplantation.

Comparing pulmonary hypertension with other indications, there is a lack of a definite concept regarding the adequate transplantation procedure [9–12]. SLTx as well as DLTx and HLTx are used in these patients. Whereas HLTx is the only reasonable procedure in a lot of cases of Eisenmenger's syndrome due to the concomitant heart defect in primary pulmonary hypertension all three types of lung transplantation are performed.

The aim of this study was the comparison of patients with primary and secondary hypertension undergoing lung transplantation as well as the description of the early and late postoperative follow-up of these patients.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
2.1. Patients
From 1988 through 1998, 70 lung and heart–lung transplantations were performed in 63 patients with pulmonary hypertension at the Hannover Medical School. Six patients underwent a redo-transplantation, one patient a re-redo-lung transplantation. The redo-procedures were not evaluated in this study.

Mean age of the 24 male and 39 female patients was 31.6±11.2 years, the mean follow-up was 1083±1047 days. The underlying disease was primary pulmonary hypertension (PPHT) in 29 patients, Eisenmenger's syndrome (ES) in 29 patients and CPE in five patients. One patient of the PPHT-group showed histologically a venous-occlusive disease. In the ES-group nine patients had a ventricular and three patients an atrial septal defect. In three cases each a transposition of the great vessels and a combination of ventricular septal defect with pulmonary atresia were the underlying diseases of ES. The remaining patients had an atrioventricular canal (two cases), aortopulmonary window (1) and Karthagener's syndrome (1). Of the CPE-group, three patients underwent prior a thrombendarteriectomy of the pulmonary arteries without success. Patients with primary and secondary pulmonary hypertension were widely homogenously distributed throughout the observation period. With exception of the follow-up the comparison of the disease-groups demonstrated no significant differences as shown in Table 1.

2.2. Surgical procedures
Harvesting of the organs was performed only by members of the own program. It included a bronchoscopy and a actual blood gas analysis under 100% FiO₂ before removal of the donor organs. In all cases we used Euro–Collins-solution for lung preservation [13]. For preservation of the donor heart St-Thomas-solution was administered in the early transplantation period and University of Wisconsin solution in the later one. Transplantations were performed as described previously [14–16]. In HLTx sternotomy was applied. DLTx were performed via an anterior bilateral thoracotomy (clamp shell access) and SLTx via standard posterior lateral thoracotomy. Extracorporeal circulation was used routinely in HLTx and on a patient dependent basis in DLTx and SLTx.

2.3. Postoperative management
All patients were treated with a triple immunosuppressive regiment including cyclosporine, azathioprine and prednisolone. The majority of patients received additionally an induction therapy with antithymocyte globulin (ATG). Episodes of rejection were treated with a 3 day course of methylprednisolone (500–1000 mg/day). After their hospital stay all patients were seen in the outpatient clinic in fixed time intervals. Follow-up was 100%.

2.4. Statistical analysis
Statistical analyses were performed using the SPSS for Windows 9.0 software system (SPSS Inc., Chicago, IL). Continuous variables are expressed as mean±1 SD. Survival and freedom from BOS were analyzed according to the Kaplan–Meier estimate. Evaluation of survival difference between groups, as well as for indications of procedures was conducted by log-rank test. Univariate comparison between alive and deceased patients and between different disease groups for different influencing factors were compared by Kruskal–Wallis test, ² test, Fisher's exact test and Mann–Whitney rank-sum test, where appropriate. Significance was assumed if the P-value was less than 0.05.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
3.1. Survival
The 1-, 3- and 5-year- survival was 68, 59 and 55%, for all patients. Differentiating by the disease groups showed a corresponding survival of 52, 40 and 35% for the PPHT-group, 83, 78 and 74% for the ES-group and 80, 60 and 60% for the CPE-group, respectively (Fig. 1) . The differences between the groups were significantly for the 1-year- (P=0.026) and 3-year-survival (P=0.033). Especially the 30-day-survival rates demonstrated a big difference between the groups (PPHT-group 58%, ES-group 92%, CPE-group 100%, P=0.003). After exclusion of the in-hospital-mortality the prognosis of patients with PPHT was not significantly different compared with patients with ES or CPE (Table 2).

View larger version (15K): [in this window] [in a new window]   Fig. 1. Survival after pulmonary transplantation in patients with pulmonary hypertension.

View larger version (14K): [in this window] [in a new window]   Fig. 2. Survival according to underlying disease and type of pulmonary transplantation.

3.4. Pulmonary artery pressure
Comparison of the postoperative mean pulmonary arterial pressures (PAP) early after transplantation showed no significant differences between the disease groups, whereas the systolic PAP was higher in patients with PPHT (Fig. 3) . However, patients surviving the initial hospital period had both a significantly lower mean and systolic PAP than deceased patients (Fig. 4) .

View larger version (15K): [in this window] [in a new window]   Fig. 3. Mean and systolic PAP in early postoperative course after pulmonary transplantation in patients with ES and PPHT (full-filled signs for systolic pressure, open signs for mean pressure).

View larger version (15K): [in this window] [in a new window]   Fig. 4. Influence of the mean and systolic PAP within the first postoperative days on the hospital mortality of patients after pulmonary transplantation in pulmonary hypertension (full-filled signs for systolic pressure, open signs for mean pressure).

3.6. Cardiac output
The cardiac output did not differ between the disease groups. However, the initial cardiac output of the HLTx patients (6.8 l/min) was higher than that of the DLTx patients (5.0 l/min, P=0.048).

3.7. Ventilation time
The postoperative ventilation time was significantly shorter in the ES-group (16.1±30.8 days, median 3 days) compared with the PPHT-group (26.8±24.1 days, median 20 days) and to the CPE-group (39.8±12.7 days, median 14 days, P=0.011).

3.8. Bronchiolitis obliterans syndrome
Bronchiolitis obliterans syndrome (BOS) was the main cause of death in the long term follow-up. Twelve patients (27%) of the hospital survivors died due to this BOS. The incidence of BOS was 25% for the first year, 16% for the second year, 24% for the third year and 4% for the fourth and fifth year after transplantation. Fig. 5 shows the freedom from BOS for the different groups.

View larger version (15K): [in this window] [in a new window]   Fig. 5. Freedom from BOS (stage I ISHLT-classification) after pulmonary transplantation in pulmonary hypertension.

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

In this study, the survival of all patients with pulmonary hypertension as underlying disease was similar compared with the results of other authors [1,3,4,7]. The 1-year survival rate was 68% and the 5-year survival rate 50% [4,5,7,10]. These results are comparable with the total lung transplant survival of the registry (n=8281) of the International Society of Heart and Lung Transplantation [1].

If patients were analyzed comparing primary and secondary pulmonary hypertension different results were described in the literature. Pasque et al. [10] found a superior survival of patients with PPHT after single lung transplantation (1- and 3-year-survival were 87 and 68%, respectively) compared with all other patients with pulmonary hypertension. In contrast, Kshettry et al. [11] were not able to assess any difference between PPHT and non-PPHT patients.

In our own experience PPHT patients had a significantly impaired prognosis compared with patients with SPHT reflected by a 1-year-survival of 52 vs. 83%.

Various statements have been made concerning the optimal method of transplantation in pulmonary hypertension. Single lung transplantation for pulmonary hypertension was advocated by Pasque et al. [10] and Gammie et al. [7] with equal results compared with double or heart–lung transplantation. Bando et al. [5,12] and Sundaresan [17] prefer double lung transplantation with regard to optimized mid- and long term results. In our own experience we used SLTx very infrequent in patients with pulmonary hypertension. The better results of HLTx did not reach a statistically significance.

Analyzing our patient series, PPHT patients had a significantly higher hospital mortality than patients with SPHT. In the later follow-up we found no significant differences regarding survival. The poor early postoperative survival of PPHT patients was mainly due to a high incidence of infectious death. The significantly longer ventilation time after transplantation might be the cause of this higher incidence of infections. Furthermore, in patients with PPHT we detected a higher systolic PAP within the first days after transplantation, whereas the mean PAP was comparable. Additionally, some of the PPHT patients subsequently showed extraordinary increasing PAP throughout the weaning period from the ventilator, leading to the development of pulmonary edema. As a consequence, we changed our therapeutical regiment to early application of beta-blockers intravenously.

In the long-term follow-up we did not find significant differences for development of BOS between the PPHT-group and the SPHT-group. Also Sudaresan [17] could not detect a correlation between PPHT and the development of BOS. However, Kshettry et al. [11] reported a significantly earlier occurrence of BOS in PPHT patients.

	5. Conclusion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
Lung and heart–lung transplantation has evolved during the last decade to a valuable therapeutic option for patients with terminal pulmonary hypertension. Patients with PPHT demonstrated a more complicated postoperative course as compared with patients with SPHT. The underlying disease seems to influence the survival after lung transplantation in patients with pulmonary hypertension especially in the early postoperative course as reflected by survival curves. Lung transplantation in patients with PPHT requires further improvement to achieve comparable results with other indications. Further studies are warranted to identify the pathophysiological background of this clinical entity.

	Acknowledgments

 
We wish to acknowledge the substantial contribution to these results of various surgeons and pulmonologists working with the Hannover lung transplantation group: H.G. Borst, MD, J. Cremer, MD, H. Fabel, MD, H.G. Fieguth, MD, J. Niedermeyer, MD, H.J. Schäfers, MD, M. Strüber, MD, T.O.F. Wagner, MD.

	Footnotes

 
Presented at the 13th Annual Meeting of the European Association for Cardio-thoracic Surgery, Glasgow, Scotland, UK. September 5–8, 1999.

	Appendix A. Conference discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
Mr J.M. Dark (Newcastle-upon-Tyne, UK): You've demonstrated a reason for the morbidity/mortality in the primary pulmonary hypertension group. I have two questions. Why did they require prolonged ventilation? Were they all pure primary pulmonary hypertension or did some of these patients have other systemic diseases such as various forms of vasculitis or systemic sclerosis? And my final question is, what is your indication for single-lung transplantation in the setting of pulmonary vascular disease?

Dr. Franke: The final question at first. The indication for the single-lung transplantation is not clearly described in our 11-year transplantation collective. The single-lung transplantations were performed in the early years and they have had no special indications. In the Eisenmenger's syndrome group, any patients with corrected anomalies had received a single-lung. Now your first question. We have not seen inflammatory diseases in the primary pulmonary hypertension group. In retrospect we couldn't discriminate these changes in the pathological reports. The cause of death is probably not the long ventilation time. The long ventilation time is a result of something we couldn't describe. It seemed that the postoperative pulmonary arterial pressure is higher in the group of primary pulmonary hypertension compared with the Eisenmenger syndrome group. I believe that the most important thing we have to improve in the next few years is management of the perioperative period in patients with primary pulmonary hypertension.

Mr Dark: So you would recommend heart-lung transplant for all of these patients?

Dr Franke: I think it would be preferable, but we have not enough heart/lungs to perform a heart-lung transplantation in all patients with primary pulmonary hypertension.

	References

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