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Eur J Cardiothorac Surg 1999;14:311-318
© 1999 Elsevier Science NL

Does bronchial artery revascularization influence results concerning bronchiolitis obliterans syndrome and/or obliterative bronchiolitis after lung transplantation?¹

^a Department of Cardiothoracic Surgery, The National University Hospital, RT 2152, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
^b Department of Pathology, The National University Hospital, Rigshospitalet, Copenhagen, Denmark

Received 30 September 1997; received in revised form 14 April 1998; accepted 16 June 1998.

Corresponding author. Tel.: +45 35452627; fax: +45 35452548; e-mail:bar@rh.dk

	Abstract

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Conference... References

 
Objective: To study the frequency of histological obliterative bronchiolitis and clinical bronchiolitis obliterans syndrome after en bloc double lung transplantation with bronchial artery revascularization and bilateral lung transplantation without bronchial artery revascularization. Methods: Primary en bloc double lung transplantation with bronchial artery revascularization using the internal mammary artery as conduit was performed in 62 patients. The frequencies of obliterative bronchiolitis and bronchiolitis obliterans syndrome have been established from transbronchial biopsies and lung function measurements. Results have been analyzed in relation to the arteriographic success of bronchial artery revascularization and have been compared to results from Stanford University obtained through personal communications. Results: Survival after 1, 2, 3, 4 and 5 years was 85, 81, 69, 69, and 69%, respectively. Fifteen patients developed bronchiolitis obliterans syndrome while seven developed obliterative bronchiolitis. Survival was superior for patients with bronchial artery revascularization classified as complete or incomplete bilateral versus incomplete hemilateral, incomplete poor or failed (P=0.016, log-rank test). For patients surviving 3 months post-transplant, the post-operative baseline FEV₁ was lower for patients who later developed bronchiolitis obliterans syndrome compared to patients who did not (P=0.007). The development of bronchiolitis obliterans syndrome and obliterative bronchiolitis were both correlated to observation time post-transplant but not to the number of rejections or infections when corrected for observation time. Conclusions: In a subgroup of lung transplant patients, a process in the transplanted lungs, eventually leading to bronchiolitis obliterans syndrome diagnosis, seems to start in the donor during the transplantation and/or in the early post-operative cause. A comparison with results after bilateral lung transplantation without bronchial artery revascularization suggests that good direct bronchial artery revascularization may postpone the onset of bronchiolitis obliterans syndrome and obliterative bronchiolitis. The positive trend motivates further use of direct bronchial artery revascularization in lung transplantation.

Key Words: Bronchial artery revascularization • Bronchiolitis obliterans syndrome • Obliterative bronchiolitis

	Introduction

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Conference... References

 
Irreversible loss of lung function within a few years remains a frequent problem, and cause of death, after lung transplantation. Most of these patients have bronchiolitis obliterans syndrome (BOS) as defined by the ISHLT formulation [1] and histological evidence of obliterative bronchiolitis (OB) [2]. BOS is defined by irreversible relative loss of lung function and OB by histological changes in the lung tissue. Although most patients with BOS have OB and vice versa, this is not always the case. Loss of lung function may have other obvious mechanical causes like airway obstruction from stenosis or bronchomalacia or resection of lung tissue.

Although chronic rejection is considered the most probable cause of BOS/OB, several factors including infection, rejection, and ischemia may be contributing when BOS/OB develops [3].

When our lung transplantation program was started, the primary argument for performing bronchial artery revascularization (BAR) in LTx was to improve airway healing [4]. In addition, experimental studies found in the literature gave hope that re-establishment of the bronchial circulation in the transplanted lungs would also improve the transplanted lungs' ability to resist infection [5] [6], reduce the number and severity of rejection episodes and, possibly, reduce the incidence and severity of OB [7] [8]. The recent report that successful BAR might even prevent BOS, has increased the interest in the issue [9].

We have previously reported a BAR success rate of 93% after en bloc double lung transplantation with BAR and, in the majority of cases, the BAR was complete or incomplete bilateral according to our classification system [10]. Our 2 year patency of BAR with the internal mammary artery conduit was 100% and the bronchial vascularity was unchanged or even improved after 2 years compared to 1 month post transplant [11]. That the bronchial artery supplies all parts of the lungs was demonstrated when complete or incomplete bilateral BAR was present [12].

In this paper the effect of BAR on the frequency of OB and BOS after clinical lung transplantation has been studied.

	Materials and methods

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In Copenhagen, en bloc double lung transplantation with BAR has been the most common method of lung transplantation for any indication. All double lung transplantations were performed en bloc with the best possible BAR. BAR has also been applied in SLTX and HLTX, but the number of patients is smaller and the mean follow-up is shorter.

Patients
Between June 1992 and July 1997, 66 DLTxs with BAR were performed at our institution. Four patients were excluded from this study: one emergency DLTx performed at a remote hospital on a patient on ECMO, one combined liver and lung transplantation, one re-transplantation after a previous single lung transplantation and one patient who committed suicide 2 months post-transplant.

Out of the 62 patients included in the study, 28 were female and 34 were male. The mean age was 46 years (range 18–63 years). The indications for lung transplantation were: emphysema due to 1-antitrypsin deficiency (n=36); chronic obstructive pulmonary disease (n=11); primary emphysema (n=2); cystic fibrosis (n=9); primary pulmonary hypertension (n=2); chronic pulmonary artery embolism (n=1) and Eisenmenger's syndrome (n=1).

Donor selection
Donors were selected using the following criteria: no lung disease; P_aO₂10–12 kPa with a FiO₂ of 40% and PEEP 5 cm H₂O (depending on the cause of death, age and smoking history); no major changes on chest X-ray and no clinical evidence of invasive pulmonary infection.

Matching included the following criteria: ABO compatibility; negative test for lymfocytotoxic antibodies in the recipient or negative cross-match; size matching based on recipient diagnosis; calculated and measured TLC and chest X-ray and finally CMV mis-match was avoided, but was not considered an absolute contraindication.

Operative techniques
The donor lungs were perfused with modified EuroCollins solution and were removed en bloc with the descending aorta and the esophagus.

All recipients were operated through a median sternotomy using cardiopulmonary by-pass, systemic cooling to 25°C and cardiac fibrillation. The left internal mammary artery was anastomosed to as many as possible (mean 1.9 orifices; range 1–4 orifices) of the bronchial artery orifices identified in the donor descending aorta (mean 2.23 orifices/patient; range 1–5 orifices). The operative technique and anatomical findings have been published [4] [10].

Immunsuppression
Peri-operatively a quadruple immunsuppression therapy was employed:

Antithymocyte globulin (r-ATG, Merieux) induction was given for 2–7 days. Methylprednisolone (Solu-Medrol^®, Upjohn), and azathioprin (Imurel^®, Glaxo–Wellcome) were given peri-operatively and ciclosporine was started on post-operative days 1–4 (Sandimmune^® or Neoral^®, Sandoz).

A traditional triple drug regimen including ciclosporin, azathioprin, and prednisolone (Prednisolone^®, Nycomed DAK) was used for maintenance.

Acute rejection was treated with 1 g of methylprednisolone daily for 3 days most often followed by prednisolone 0.5–1 mg/kg per day, tapered during 14 days to the maintenance dose of 0.1 mg/kg per day.

Antibiotic prophylaxis
Ceftriaxon (Rocephalin^®, Roche) and fusidin (Fucidin^®, Leo) were given in the first 3–5 days. Trimethoprim-sulfomethoxazole (Sulfotrim^®, GEA) was used as prophylaxis against toxoplasmosis and pneumocysts. Aciclovir (Zovirax^®, Glaxo–Wellcome) was given for 3 months after the transplantation up until one year ago. During the last year, it has been replaced by ganciclovir (Cymevene^®, Roche) to include CMV prophylaxis. In addition, CMV prophylaxis with ganciclovir (Cymevene^®, Roche) was most often given to CMV positive patients during treatment of rejection.

Bronchoscopic examinations
Bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies (TBB) was performed routinely every 14th day during the first 2 months, and repeated at 3, 6, 12, 18 and 24 months and then once a year. Additional bronchoscopic examinations, including BAL and TBB, were performed whenever clinically indicated. The threshold for performing extra bronchoscopies was low.

Lung function
Routine lung function measurements were done every week until the 14th post-operative week, then every second week until 6 months, then every month until 12 months and, after the first year, every 6 months. Forced expiratory volume in the first second (FEV₁) and forced vital capacity (FVC) were measured on a calibrated dry wedge spirometer (Vitalograph^®, Buckingham, UK) and at least two technically correct forced maximal expiratory maneuvers with a variation less than 5% in FEV₁ were obtained. The highest values were used for further calculations.

Furthermore, FEV₁ and FVC were measured in daily monitoring by the patients, using a Micro Spirometer S01 MK2 (Micro Medical^®). When the patients recorded a decline in FEV₁ to 90% (approx.) of the usually measured value he/she was advised to contact the hospital for further examinations, usually including bronchoscopy with BAL and TBB.

BOS was defined as an irreversible loss of FEV₁ to 80% of post-operative baseline FEV₁, according to the ISHLT working formulation [1]. Patients with BOS were identified by reviewing FEV₁ measurements.

Evaluation of BAR success
To evaluate the result of the BAR, all patients routinely had a cinematographic mammary-bronchial arteriography performed approximately 1 month (1 day to 5 months) after the transplantation. Using the Seldinger technique, the tip of a 6F Cordis internal mammary catheter (no. 532 623) was introduced into the origin of the left mammary artery under fluoroscopic control. Using hand injection of 6–8 ml of contrast medium (Ultravist 370 mg I/ml) a series of cinematographic recordings was made in the anterior-posterior, lateral, 45° left anterior oblique, and 45° right anterior oblique projections.

The arteriographic success of BAR was classified according to our previously published classification [10]:

Complete BAR: Clear visualization of bronchial arteries on the/both transplanted side(s). Each lobe is supplied by at least one lobar ramus.

Incomplete bilateral BAR: Visualization of bronchial arteries on two transplanted sides but one or more lobar rami are missing.

Incomplete hemilateral BAR: Clear visualization of bronchial arteries on only one out of two transplanted sides.

Incomplete poor BAR: Sparse visualization of bronchial arteries in one or two transplanted side(s).

Failed BAR: No visualization of bronchial arteries.

Using this classification system, it was possible to distinguish two separate groups of patients.

One group (complete BAR or incomplete bilateral BAR) had clear bronchial arteries visualized close to the central and intermediate sized bronchi and bronchial arteries followed most lobar and segmental bronchi. Airway or lung parenchyma ischemia was considered unlikely in these patients.

The other group (incomplete hemilateral, incomplete poor and failed BAR) was missing revascularization of major bronchial arteries and most likely had airway and lung parenchyma ischemia in one or both lungs.

In the following we will evaluate and discuss our results based on this subclassification.

Histological evaluation
All TBB samples were processed immediately by a microwave oven technique and analysed and reported within 3–4 h. At least three biopsies of at least 6 mm³ each were required. The revision of the 1990 working formulation for the classification of pulmonary allograft [13] were used for the morphologic evaluation. All tissue specimens were reviewed by the same pathologist (C.B. Andersen).

Statistics
Survival data and freedom from BOS/OB have, whenever possible, been evaluated using the Kaplan–Meier product limit method. Comparisons between groups have been made using the log-rank test. Other comparisons between independent groups have been made using the Mann–Whitney U-test.

	Results

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Follow up
Follow up is complete up to 61 months, so far reached by only two patients.

Survival
For the 62 studied DLTx patients from Copenhagen, 1, 2, 3, 4 and 5 year survival was 85, 81, 69, 69, and 69%, respectively. Three patients received a single lung retransplantation and two of these patients are still alive ( Fig. 1 ).

View larger version (17K): [in this window] [in a new window]   Fig. 1. Survival (including re-transplantation) after primary DLTx with attempted BAR (n=62) (Kaplan–Meier).

View larger version (25K): [in this window] [in a new window]   Fig. 2. DLTx with BAR cumulative proportion surviving (without re-transplantation) (Kaplan–Meier) with complete/incomplete BAR versus incomplete hemilateral/poor/failed BAR.

For patients surviving 3 months or more post-transplant (n=42) who did not develop BOS, the mean (±SEM) post-operative baseline FEV₁ was 94.0±3.3% of the expected normal FEV₁. This was significantly better than the post-operative baseline FEV₁ of patients who later had BOS diagnosed (P=0.007, Mann–Whitney U-test). In this group (n=15), the post-operative mean (±SEM) baseline FEV₁ was only 76.6±6.1% of expected normal FEV₁.

For patients who developed BOS, the onset time was not significantly different for patients with arteriographically complete or incomplete bilateral BAR, compared to patients with incomplete hemilateral, incomplete poor or failed BAR, although there was a trend ( Fig. 3 ).

View larger version (24K): [in this window] [in a new window]   Fig. 3. BOS in relation to success of BAR (Kaplan–Meier).

Following development of BOS and OB, three patients have had a right single lung retransplantation performed 1.8, 3.6 and 4.9 months post-transplant.

Including all patients, Kaplan–Meier plots have been made for patient survival ( Fig. 1) and freedom from BOS and OB ( Fig. 4 ).

View larger version (15K): [in this window] [in a new window]   Fig. 4. Freedom from OB and BOS after DLTx with attempted BAR (n=62).

Infection
For patients developing BOS and/or OB the mean number (±SD) of treated lung infections per observation year was 2.29±3.06, while for patients not developing BOS or OB the mean number of treated lung infections per observation year was 2.10±3.72. This difference was not statistically significant (Mann–Whitney, P=0.34). No patient developed lung abscesses.

	Discussion

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Conference... References

 
Irreversible loss of lung function (BOS) remains a major problem after lung transplantation. We have found it relevant to study the possible impact of successful re-establishment of the bronchial artery blood supply. We have compared the results regarding survival, BOS, and OB after DLTx with good bronchial artery blood supply to all parts of the airways and lung parenchyme (complete or incomplete bilateral BAR) to results after DLTx with probable ischemia (incomplete hemilateral/poor or failed BAR) and, furthermore, to results after bilateral lung transplantation without BAR.

The histological diagnosis of OB
The observed relatively low frequency of OB in our material made us speculate whether this was real or if our TBB sampling routine could be insufficient. In this study, 3 biopsies and a size of 6 mm³ for each biopsy have been minimum requirements for a TBB to be considered adequate. Out of the seven cases of OB, the diagnosis was made on open lung biopsies or from removed lungs in four cases, from TBBs in two cases and at autopsy in one case. TBBs can be false negative due to inadequate tissue sampling. If the tissue volume is too small (i.e. biopsies are too few or too small) existing OB may not be diagnosed [14]. In 1988 Higenbottam et al. [15] found TBB sensitivity to be 84% when at least four biopsies were taken. Cagle et al. found that 62% of TBBs from OB patients were negative when only one tissue sample was taken per patient or when the tissue biopsy size was 1.44 mm³ on average [14]. Since July 1993, Stanford University has improved the TBB sensitivity to 71.4% by taking 8–10 biopsies from different lung lobes. This improvement in sensitivity seems quite small and remains lower than the sensitivity previously found by Higgenbottam et al. [15]. However, it remains a possibility that we underestimate the number of OB patients in our material when compared to Stanford.

The association of acute rejection with OB/BOS
When reviewing the time-period during which the major FEV₁ decline occurred in the patients with BOS, we noticed that very often the lung biopsies demonstrated episodes of mild rejection without additional symptoms. Although we found that the development of OB and BOS were both correlated to the observation time but not to the number or severity of rejections, episodes of mild rejection may still be part of, or trigger, the process/response eventually leading to OB, as earlier described by other investigators [16] [17]. From this perspective, it may be relevant to consider augmentation of the immunosuppression also when minor rejection is incidentally found [18].

Lung function
It is an important observation that for patients surviving 3 months or more post-transplant, the post-operative baseline FEV₁ was significantly better for those who did not develop BOS than for those who later had BOS diagnosed. This indicates that the process eventually leading to BOS is initiated very early after the transplantation, during the transplantation or possibly already in the donor, limiting the post-operative improvement in FEV₁ during the first post-operative months and eventually leading to progressive loss of lung function. Factors possibly of importance are, donor related lung injury (infection, trauma), method of preservation, ischemia (pre- and post-transplant), re-implantation injury, acute rejection and infection.

We have used the ISHLT definition [1] to define BOS. Although this definition is easy to use, it may not always reflect the clinical picture. In one patient, who later had BOS diagnosed, the baseline FEV₁ was 131% of expected normal and, at the time BOS was diagnosed, FEV₁ was still 101% of expected normal and the patient has remained asymptomatic. Likewise seven patients from the group that did not have BOS diagnosed had baseline FEV₁ of 41–76% of expected normal. Three of these patients died after 0.3, 2.3 and 2.4 years without developing BOS, as defined by ISHLT, or OB at autopsy, although lung function was never satisfying. Other authors have found that FEV at FVC₅₀ is a more sensitive indicator for the early detection of BOS [19].

Since we have found very few publications providing information about the number of patients free from OB and/or BOS after a given time post-transplant, we have chosen to compare our results to the results published [20] and OB data obtained by personal communications with Stanford University. All patients from Stanford University have received bilateral lung transplantation with two main bronchus anastomoses and no BAR. We have compared the OB frequency in patients with complete or incomplete bilateral BAR (n=51) to the OB frequency in patients with bilateral lung transplantation without BAR (n=88) ( Fig. 5 ). Comparing the `freedom from OB' curves from Stanford and Copenhagen it looks like there is a difference in OB development until 3.5 years but, due to the fact that two out of the three patients from Copenhagen with a follow-up longer than 3.5 years have developed OB, there is no significant difference between the curves (P=0.23, log-rank test). Stanford University has previously published an actuarial analysis of LTx patients free from BOS and/or OB, including only LTx patients surviving 3 months post transplant and observed for a minimum of 15 months before the data analysis [20]. Using the same inclusion criteria for patients from Copenhagen with complete or incomplete BAR our actuarial curve of patients free from OB and/or BOS seems to be better ( Fig. 6 ) but we are not able to apply any statistical analysis, since we do not have all the raw data from Stanford University available. Out of 184 LTx performed at Stanford University between 1981 and 1996, 26 consecutive LTx patients with 6 years of observation have been plotted. Possible explanations for the apparent difference in freedom from BOS and OB could be based on geographical, ethnic and microbiological differences between the institutions. It looks, however, as if the development of BOS and/or OB is delayed for 2 years or more in the Copenhagen patients with good BAR compared to the patients from Stanford University.

View larger version (16K): [in this window] [in a new window]   Fig. 5. Freedom from OB in patients with bilateral lung transplantation without BAR (Stanford University) versus DLTx with complete/incomplete bilateral BAR (Copenhagen University Hospital) (Kaplan–Meier, log-rank tests).

View larger version (13K): [in this window] [in a new window]   Fig. 6. Actuarial freedom from OB and/or BOS 0–5 years for patients surviving 3 months and with a minimum of 15 months observation time, from Stanford [20] (bilateral lung transplantation without BAR, n=26) and Copenhagen (DLTx with complete/incomplete bilateral BAR, n=38).

View larger version (21K): [in this window] [in a new window]   Fig. 7. Survival (without re-transplantation) of patients surviving 3 months post-transplant with/without BOS/OB.

	Conclusions

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Conference... References

 
In a subgroup of lung transplanted patients, the process eventually leading to the bronchiolitis obliterans syndrome diagnosis seems to start very early, possibly already in the donor, during the transplantation, and/or in the early post-operative period.

Good, complete or incomplete bilateral bronchial artery revascularization may postpone the onset of OB. Longer follow-up in a larger number of patients is needed to verify this effect.

The positive trend motivates further use of direct bronchial artery revascularization in lung transplantation.

	Acknowledgments

 
The study has been performed with financial support from The Danish Research Council.

	Footnotes

 
Presented at the 11th Annual Meeting of the European Association for Cardio-thoracic Surgery, Copenhagen, Denmark, September 28 – October 1, 1997.

	Appendix A. Conference discussion

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Conference... References

 
Dr F. Ciullit (Sheffield, UK): Do you think that your results could be influenced by the quality of the organ that you are transplanting; have you looked at any donor variables such as the anatomy of the bronchial arteries, the ischemic time and the cause of death of the donor? I would also like you to comment on the complications that you encountered by doing the bronchial artery revascularization. Were there any bronchial healing problems or bleeding problems and was there an increase in the warm ischemic time of those organs that were revascularized compared to those that were not?

Dr Nørgaard: Concerning the donors and the anatomy of the donors, I think we received the same kind of donors as any other transplant center throughout Europe at least, and probably throughout the United States as well. The usual cause of death is intracerebral hemorrhage. We are very rarely able to use organs from donors that have died due to trauma.

I expect that our ischemic time is comparable to other centers, meaning that we get organs not only from Denmark but also from all of Scandinavia, and we have sometimes received organs from Czechoslovakia as well. So I think our ischemic time is probably comparable to other places, but I have not looked into these data.

You also wanted me to comment on the complications after bronchial artery revascularization. Concerning healing, the only patients that we encountered healing problems with were the patients that had a failed bronchial artery revascularization. You probably know that we use tracheal anastomosis, approximately one ring above the primary carina and, in three patients, the bronchial artery revascularlzation failed. The patients survived, but two of them had to be left-lung pneumonectomized due to stenosis of the left main bronchus, but they survived for more than 2 years. One was later re-transplanted and is still alive. In other patients where we had what we classify as a poor bronchial artery revascularization we found Aspergillus growth and we suspect that this disease is in some way connected with ischemia of the bronchial tree.

We have only re-operated for bleeding in five cases out of the first 50 double-lung transplantations we performed. Three of these were related to the bronchial artery revascularization, while the other two were bleeding from other sources. So we do not think bleeding is a major problem, but, of course, as in any surgical maneuver, if you do not do it well you have bad results, including bleeding.

You also asked me about the warm ischemic time. We did not do this from the beginning, but what we do now is, we perform the bronchial artery revascularization as the first anastomsis when the lungs are placed in the recipient, meaning that the lungs will slowly warm up from the 0°C or 1°C they are kept at. We have been a bit worried about this because it may warm the tissue without really revascularizing all the tissue. However, this has not been a problem as far as we have been able to recognise.

Dr A. Haverich (Hannover, Germany): Were there three re-transplant procedures or three of them performed as single-lung transplants in the cohort of double-lung transplants?

Dr Nørgaard: These patients were first double-lung transplanted and later they were right single-lung transplanted.

Dr Haverich: In all three of them the underlying cause for the re-transplant was obliterative bronchiolitis?

Dr Nørgaard: Yes, it was bronchiolitis obliterans syndrome in all three.

	References

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Conference... References

 

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