The lung is the only organ that is transplanted without its own arterial blood supply. Animal studies have shown a significant decrease in peribronchial tissue tension after lung transplantation, suggesting that the anastomotic site may be highly vulnerable to complications of dehiscence or stenosis due to ischemia.1 Others have suggested that colonization of airways may contribute significantly to peribronchial inflammation and ultimately lead to healing by stenosis.2 Recent reports have also suggested that the degree to which the anastomosis is telescoped to be an important factor.3 Bronchial ischemia and inadequate blood flow to the anastomosis has been touted a major culprit in the pathogenesis of dehiscence and “ischemic stenosis” of the large airways.4,5 Subsequently, omental and/or pericardial wrapping and telescoping of bronchial anastomoses were reported to improve blood flow to the anastomotic site whereas other studies showed no apparent benefit to these approaches.6 Avoidance of massive doses of corticosteroids has dramatically reduced the incidence of dehiscence whereas improvements in surgical technique, postoperative care, lung allograft preservation, and immunosuppression have likely all contributed to the reduction in other airway complications.7 Despite improvements in short-term outcome after lung transplantation, some patients are still devastated by large airway complications of anastomotic and bronchial stenosis, bronchomalacia, and anastomotic dehiscence. Large airway complications are reported to occur in approximately 9% to 20% of all lung transplant recipients.3 The objective of this study was to determine the incidence, associated factors, and clinical outcome in patients requiring intervention for large airway complications in the first 150 consecutive lung transplant recipients at Mayo Clinic, Jacksonville. Modalities of argon plasma coagulation (APC), balloon dilatation, stent placement, and/or retransplantation were employed as therapeutic options.
MATERIALS AND METHODS
All data were analyzed retrospectively from our lung transplant database and from patients' medical records from January 01, 2001 to December 31, 2007 under institutional review board protocol no. 05-004279 and included the first 150 lung transplant recipients at our institution. Lung transplantation was performed in standard fashion.8,9 Bilateral lung transplants were mostly performed by sequential thoracotomy and occasionally by transverse sternotomy (clam-shell incision). Telescopic or end-to-end anastomoses were performed at the surgeon's discretion depending on donor to recipient bronchial size, using 3-0 Prolene in continuous fashion. None of the anastomoses were completed using interrupted sutures. The initial standard immunosuppressive regimen comprised triple therapy with methylprednisolone, later changed to prednisone, cyclosporine, or tacrolimus, and azathioprine or mycophenolate. Sirolimus was not used as part of the initial immunosuppressive regimen. None of these patients received induction therapy. Antibiotic prophylaxis included Cefepime (or Aztreonam in penicillin allergic patients), Metronidazole, and Vancomycin. Intravenous ganciclovir was administered in all patients other than cytomegalovirus donor negative/recipient negative subjects and subsequently switched to oral valganciclovir. Oral itraconazole was continued for at least 6 weeks. Trimethoprim/sulfamethoxazole were routinely started for all nonsulfa allergic patients. Screening bronchoscopy was performed immediately postoperatively, then as needed in the first month and thereafter at 1, 3, 6, 12, 18, and 24 months. Diagnostic bronchoscopy was performed as needed for clinical symptoms, radiographic evidence for infiltrates, and/or decline in forced expiratory volume in 1 second (FEV1), FEF25-75, or oxygen saturation by pulse oximetry. Bronchial dilatation was undertaken as an initial intervention for a significant stricture diagnosed by inability to pass the bronchoscope in the main bronchi (<5.9 mm) or if the stricture was accompanied by clinical symptoms and a fall in spirometry of greater than 10% from baseline values. Stents were placed under deep sedation in the bronchoscopy suite or under general anesthesia in the operating room. Sedation included use of midazolam and fentanyl in accordance with published guidelines, continuously monitoring pulse oximetry, telemetry, and blood pressure at regular intervals.10–13 All procedures were performed through a flexible 5.9-mm bronchoscope. Therapy for anastomotic and bronchial stenosis was initiated with balloon dilatation (C.R.E. Pulmonary Balloon Dilatation Catheter, Boston Scientific, Watertown, MA) with or without additional use of argon plasma coagulation (Erbe Elektromedezin, Tuebingen, Germany), removing necrotic debris using forceps as required. Methodology to use APC in lung transplant recipients has been described elsewhere.14 Endobronchial injection of corticosteroids was carried out after balloon dilatation and APC to reduce the possibility of airway edema. Mucolytics and alpha dornase were not routinely used.
Stenoses to the main bronchi or anastomoses were dilated between 12 and 14 mm and stenoses in lobar segments to a maximum of 10 mm. Patients failing these interventions, and remaining clinically symptomatic, were considered for stent placement. Ultraflex uncovered distal release stents (Boston Scientific, Watertown, MA) were placed according to previously published methods.15,16 If stents were unavoidably placed across the origin to the right upper lobe orifice, a window was created within the stent using APC. FEV1 measurements were obtained as per American Thoracic Society guidelines.17 We obtained surveillance transbronchial biopsies in all lung transplant recipients 10 to 14 days after transplant, at 3, 6, 12, 18, 24 months, and as clinically indicated.
Primary graft failure was defined as PaO2/FiO2 ratio <200 with radiographic infiltrates (PGD 3).18
Regarding potential risk factors for large airway complications, donor recipient size mismatch, colonization of the airway with fungi or bacteria, ischemia time, episodes of acute rejection, and underlying diagnosis were evaluated. Colonization was defined as recurrence of the same organism on at least 2 occasions from airway cultures in patients without significant clinical symptoms. Days in intensive care unit, days in hospital, and overall survival were evaluated at 1, 2, and 3 years posttransplant. A survival comparison between those with large airway complications requiring intervention and those who did not require intervention was made using the Cox F test and survival data depicted on a Kaplan-Meier curve. Statistical analysis for associations between the need for intervention and associated factors were made using the Fisher exact test. Descriptive statistics and test were used when appropriate.
Transplant recipient and donor characteristics, as well as outcome, are summarized in Table 1. Characteristics of lung transplant recipients requiring intervention (I) versus those who did not (NI) are summarized in Table 2.
APC, balloon dilatation, and stent placement were used on 16%, 15%, and 13% of the entire study population, respectively. APC was used in 95 instances on 24 patients. It was used mainly to ablate small granulomas unrelated to significant airway stenosis on 8 patients once, and multiple times on 16 patients with airway stenosis in preparation for balloon dilatation and/or stent placement. One patient required 21 APC treatments in an attempt to control granulation tissue growing within a stent, and required 30 different balloon dilatations in an attempt to maintain airway patency (case 11, Table 2). A total of 25 (17% of the entire study group) patients required either balloon dilatation or stent placement. Of this group, 23 patients required balloon dilatation to treat airway stenosis affecting the anastomosis and/or main bronchi. Seventeen (74%) of these patients undergoing dilatations ultimately required stent placement. Two patients (cases 2 and 6, Table 2) underwent stent placement without having had prior dilatations. One patient received stents for bronchomalacia and tracheomalacia (case 2, Table 2), and the remaining 19 stent recipients all had circumferential narrowing of the anastomosis and/or large airways distal to the anastomosis after healing of airway necrosis. Nine patients with large airway complications died during the observation period of the study (Table 2). One death was related to the complication of massive bleeding after balloon dilatation. The other 8 deaths were unrelated to airway complications or associated procedures. Seven of these patients had been stent recipients. The median number of days after transplantation to first balloon dilatation and stent placement was 98 days (ranging from 44 to 884 d) and 109 (ranging from 47 to 325 d), respectively. One patient who required multiple bilateral stents has been effectively treated with retransplantation (case 14, Table 2). Twenty-one of 25 patients had FEV1 measured before and 3 months after balloon dilatation with or without stent insertion. FEV1 improved significantly from 1.7±0.6 L to 2.4±0.8 L (P=0.007) whereas FVC was unchanged, measuring 2.8±0.7 L before and 3.0±0.8 L after intervention. Two patients experienced a decline in FEV1 3 months after intervention due to concomitant chronic graft failure and 2 were unchanged.
Of the 13 surviving stent recipients only 4 did not require any further intervention for granulation tissue formation or fungal colonization. Six stent recipients (cases 3, 4, 5, 17, 22, and 23, Table 2) have required follow-up therapy with APC to treat late growth of granulation tissue causing restenosis within the stent. Despite the need to perform occasional APC therapy to keep the stents patent, these patients remain functional. Four patients with stents (cases 2, 5, 9, and 11) required antifungal therapy for recurrent colonization/bronchitis after stent placement, secondary to Aspergillus (3 cases) and Scedosporium apiospermum (1 case).
There was no statistical difference in donor/recipient height difference between transplant recipients not requiring intervention (5±4 cm) and those requiring intervention (6.6±5.5 cm). Colonization with bacteria before intervention (most commonly Pseudomonas aeruginosa in our population group) was associated with an increased relative risk (2.0) for large airway complications but considered not significant (P=0.07, Table 1). Preintervention colonization with fungi (most commonly Aspergillus spp. in our population) did not differ between study groups (Table 1). Mean lung ischemic time was similar at 252±111 minutes and 254±88 minutes for I and NI, respectively. None of the patients required treatment for bronchial dehiscence.
There was no significant difference between NI and I in terms of days in intensive care unit, days on the ventilator, or days in hospital after transplant (Table 1). Survival (Table 1) has been similar for both groups at 1 (88% for I vs. 81% for NI), 2 (74% for I vs. 72% for NI), and 3 years posttransplant (65% for NI and 64% for I).
There was a strong association between a diagnosis of underlying idiopathic pulmonary fibrosis (IPF) and the development of large airway complications after transplantation in this study group (P< 0.0001, Table 1).
Historically, 9% to 20% of lung transplant recipients have required intervention for airway complications3,19,20 and this was consistent in our study group. All anastomoses were performed in the same way, with a continuous, running suture and therefore a comparison between anastomoses performed with running versus interrupted sutures could not be made. Murthy et al3 suggested the only factor associated with large airway complications in their prospective trial was related to size discrepancy between recipient and donor bronchus and therefore the degree to which the airway requires telescoping. They suggested that size matching would be an important clinical consideration to prevent large airway complications. In our retrospective analysis, we therefore analyzed donor and recipient height difference but found this to be similar between the groups. Although the type of suture (continuous, nonabsorbable Prolene in this study) may theoretically contribute to fibrotic healing and stenosis, we were unable to compare suture techniques as all these patients were sutured using the same material and technique. Controversy exists with regard to the type of anastomosis with at least one study challenging the paradigm of telescoping the anastomosis and suggesting that end to end anastomoses may have less airway complications.21 Surgical intervention, such as bronchial sleeve resection was not undertaken for stenosis of airways in any of our patients.22 One patient (case 14) who required interventions with balloon dilatation and multiple stent placements has been successfully retransplanted and has not developed recurrence of airway stenosis 1 year after retransplantation.
Suture dehiscence has been successfully treated by endobronchial stent placement, sometimes allowing for later removal of temporary stents.23,24 None of our patients were treated for dehiscence and all stents in our population were placed with intent to remain permanent. Although we have tried to avoid placing stents by first using balloon dilatation, most (74%) patients with stenosis severe enough to warrant balloon dilatation have eventually required stent placement.
In a series of 35 patients requiring stent placement after lung transplant, Chhajed et al19 suggested that ultraflex stents (n=9) have fewer long-term complications than Gianturco (n=10) or Wallstents (n=16). Although improvement in FEV1 in their series was similar in the 3 groups, according to the authors, none of the patients with ultraflex stents developed mucus plugging or stenosis at the stent ends during a follow-up of 263±278 days. Among our patients, who all received ultraflex uncovered stents, most required some follow-up treatment for airway colonization with bacteria or fungi and/or intervention by APC to treat granulation tissue within the stents.
Speculation concerning the etiology of excessive tissue growth and airway stenosis has centered on possible airway ischemia or inflammation of the airways related to infection or colonization by fungi. Herrera et al2 showed a strong correlation between Aspergillus infection and airway complications but we found no such correlation. Prolonged ischemic time may exert additional stress at the anastomosis site. There was no difference in ischemic time between the 2 groups in our study (Table 1).
Saad et al25 placed 15 stents in 12 patients between 1992 and 2001 and showed no difference in survival between stent recipients and other lung transplant recipients, yet Chhajed et al19 reported significantly worse long-term survival in patients with large airway complications with 1, 3, and 5-year survival rates of 79%, 45%, and 32%, respectively, in patients with large airway complications, compared with 87%, 69%, and 56% in patients without airway complications. Our 1, 2, and 3-year survival rates did not differ between the 2 groups (Figs. 1, 2, Table 1). Follow-up has not been sufficient to comment on survival beyond 3 years at our center.
A diagnosis of IPF was the only factor significantly associated with the development of large airway complications requiring intervention (P<0.0001) in this study group. Every explanted lung in these patients diagnosed with IPF was confirmed to have histologic evidence of usual interstitial pneumonitis. The finding of an association between IPF/usual interstitial pneumonitis and airway stenosis in our lung transplant population may warrant further investigation in a multicenter analysis. To our knowledge this association has not been previously described. The incidence of large airway complications in patients who did not carry a diagnosis of IPF at our center was significantly lower at 4%.
The decision to insert a stent into a lung transplant recipient is not simple. Although most lung transplant recipients with significant stenotic airways will derive symptomatic relief and improved lung function, complications such as stent migration, colonization or infection of airways, increased secretions, or growth of granulation tissue at the site of insertion frequently complicate subsequent management. Therefore, at our center, a stent is being placed only when the stenotic lesion produces significant clinical symptoms, and fails to improve after extensive management, including aggressive treatment of local infection or colonization, repeated attempts to dilate airways with balloon therapy, and/or APC.
In summary, 15% of all lung transplant recipients at our center required balloon dilatation and 13% required stent placement. The majority of patients requiring balloon dilatation (74%) subsequently also required stent placement. The only identifiable factor associated with the development of large airway complications at our center was an underlying diagnosis of IPF.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
bronchoscopy; bronchi; lung transplantation; airway complications; idiopathic pulmonary fibrosis; anastomosis; stents; balloon dilatation; argon plasma coagulation