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Ann Thorac Surg 2009;88:1589-1593. doi:10.1016/j.athoracsur.2009.06.024
© 2009 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Risk Factor Comparison and Clinical Analysis of Early and Late Bronchopleural Fistula After Non-Small Cell Lung Cancer Surgery

Q.V. Jichen, MDa,*, Guangyu Chen, MDb,*, Gening Jiang, PhDa, Jian Ding, Profa, Wen Gao, Profa, Chang Chen, PhDa,*

a Department of Thoracic Surgery, ShangHai Pulmonary Disease Hospital, TongJi University, Shanghai, China
b Department of Clinical Epidemiological Study, Xinhua Hospital, Medical College of Shanghai Jiaotong University, Shanghai, China

Accepted for publication June 9, 2009.

* Address correspondence to Dr Chang Chen, Department of Thoracic Surgery, Shanghai Pulmonary Disease Hospital, TongJi University, 507 ZhengMin Rd, Shanghai, 200433, China (Email: chenlight{at}163.com).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Footnotes
 Acknowledgments
 References
 
Background: We retrospectively analyzed risk factors for late bronchopleural fistula after non-small cell lung cancer (NSCLC) surgery and compared with those for early bronchopleural fistula.

Methods: In all, 6,239 patients with NSCLC who underwent surgery were studied, and clinical risk factors were examined by univariate and multivariate analysis. This study included 23 patients (0.38%) with late bronchopleural fistula and 43 patients (0.65%) with early bronchopleural fistula among all 6,239 patients. Follow-up data were recorded until December 2005 or until death. Statistical significance was calculated using the log rank test.

Results: By univariate analysis, patients with radiotherapy after operation, pneumonia after operation, pneumonectomy, and advanced age were related to higher risk of bronchopleural fistula. In the multiple logistic regression models, both pneumonia and operative procedure were among the independent risk factors of early and late bronchopleural fistula. Early bronchopleural fistula was observed primarily in the aged. Late bronchopleural fistula was associated with postoperative radiotherapy. The average intervals of bronchopleural fistula between pneumonectomy and lobectomy were significantly different. Compared with the mortality rate of late bronchopleural fistula (0%), the mortality rate of early bronchopleural fistula (11.6%) was significantly higher.

Conclusions: There are both similarities and differences between the risk factors for early and late bronchopleural fistula. We should analyze the different reasons for the occurrence of bronchopleural fistula, and adopt different preventive measures. Different follow-up should be provided for the different operations.


   Introduction
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 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Footnotes
 Acknowledgments
 References
 
Bronchopleural fistula (BPF) is a devastating complication after pulmonary resection for primary lung cancer [1]. Although its incidence has decreased over the last few decades from 28% to approximately 4%, this life-threatening complication remains a major challenge for the thoracic surgeon and is associated with high mortality rates. Reducing the potential risks for BPF development is therefore of paramount importance. Just as Algar and colleagues [2] reported, BPF is divided into early and late BPF according to the time of occurrence. Early bronchopleural fistula (EBPF) happens within a month after an operation, whereas late bronchopleural fistula (LBPF) happens after this period. Varoli and colleagues [3] reported that early BPF was associated with perioperative technical error, whereas late BPF was linked to impaired healing of the bronchial stump.

We also speculate that because the time of occurrence of BPF is different, there are different reasons for its occurrence, and that the occurrence of dangerous factors in EBPF and LBPF is also different. This difference should be analyzed, different preventive measures must be developed, and different follow-up procedures should be adopted. In addition, LBPF has been less frequently studied, and fewer systematic analyses of the reasons for its incidence have been reported in the literature. In this study, we have analyzed retrospectively the risk factors for LBPF after 6,239 non-small cell lung cancer (NSCLC) surgeries and compared them with those of EBPF.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Footnotes
 Acknowledgments
 References
 
Between January 1995 and December 2005, 6,239 NSCLC patients underwent surgery with complete resection at the department of thoracic surgery, Shanghai Pulmonary Disease Hospital, China. Our database stored patient information electronically. A telephone questionnaire was conducted with all patients or their family. The study was approved by our Institutional Review Board. Informed consent was not required for this retrospective study.

Tracheal tumors (n = 23), lung metastasis (n = 76), and small-cell lung cancers (n = 106) were excluded. Nineteen percent were lost to follow-up. The patient population consisted of 1,214 females and 5,025 males. Their ages ranged from 12 to 80 years, with an average of 55 ± 9.67 years. These patients with NSCLC had squamous cell carcinoma (n = 3,687), adenocarcinoma (n = 2,359) or adenosquamous carcinoma (n = 183), and large cell carcinoma (n = 10). According to the Classification of Malignant Tumours (TNM) [4], 1,917 patients were in stage I, 1502 in stage II, 2428 in stage III, and 392 in stage IV. This was a retrospective review, and the NSCLC surgery was an anatomic resection inclusive of lobectomy or greater. Operative mode meant method of operation. The following surgical procedures were performed: right lobectomy (n = 2,730), left lobectomy (n = 1,725), sleeve lobectomy (n = 334), left pneumonectomy (n = 771), and right pneumonectomy (n = 679).

After 1995, we routinely performed bronchial stump coverage using intercostal muscle, mediastinal fat pad, phrenic pedicle, azygos vein, or other tissues. Coverage of the stumps in these cases was recommended for safe pulmonary resection. All patients had complete resection of their lymph nodes.

Examination of the pathology specimens was carried out by the same pathologist. The staging system was estimated according to the American Joint Committee on Cancer (AJCC) classification.

The group in whom were discovered any lymph nodes of 1 cm on computed tomography or who belonged to stage IIIB/IV were treated with conventional radiotherapy, three-dimensional cardiac resynchronization therapy, 1 month after the operation. A linear accelerator (Siemens MD2813; Siemens, Beijing, China) was used. Radiation was given by 6 mV X-ray. Starting doses ranged from 40 to 60 Gy, given in 2 Gy fractions. Target volumes included the primary tumor and any nodes 1 cm on computed tomography. Clinically uninvolved nodal regions were not included purposely.

The diagnosis of BPF was suggested clinically, confirmed by radiographic studies and bronchoscopy. Postoperation BPFs were given immediate chest tube drainage before rethoracotomy to prevent aspiration pneumonia of the nonoperated side. Antibiotic therapy was routine for all patients.

Study variables included age (less than 60 years = 0; 60 years or more = 1), sex (female = 0; male = 1), side, malnutrition, preoperative chemotherapy, pulmonary function, postoperative pneumonia, radiation after operation, chemotherapy after operation, interval between the first resection and BPF, TNM stage, tumor histology, and mode of pulmonary resection (lobectomy = 1, pneumonectomy = 0), operative findings, surgical procedure, duration of postoperative ventilation, and long-term mortality. Follow-up data were recorded until December 2005 or until death. Death associated with BPF was defined as death within 30 days after the occurrence of BPF or before hospital discharge.

Patient data were reported as medians and ranges for quantitative variables, and as absolute and relative frequencies for qualitative variables. The effects of risk factors on endpoints were evaluated using Student's t test and Fisher's exact test in the univariate analysis, and multiple logistic regression in the multivariate analysis. The Kaplan-Meier method was used to calculate expected survival rates; operative mortality was included in this analysis. Statistical significance was calculated using the log rank test. A p value less than 0.05 was considered significant. Data processing and analysis were done using the Statview software package version 5 (Abacus Concept, Berkeley, CA).


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Footnotes
 Acknowledgments
 References
 
General State of Health
Late bronchopleural fistula
This study included 23 patients (0.38£¥) with late bronchopleural fistula, among all 6,239 patients, and consisted of 2 females and 21 males. These patients with LBPF had left pneumonectomy (n = 5), right pneumonectomy (n = 15), and lobectomy (n = 3). These same patients with LBPF had squamous cell carcinoma (n = 16), adenocarcinoma (n = 3), adenosquamous carcinoma (n = 2), and large cell carcinoma (n = 2). According to the TNM classification, 3 patients were in stage I, 7 in stage II, 10 in stage III, and 3 in stage IV.

When the overall patient condition permitted, reclosure was performed immediately, and was done in 6 patients (26.1%) just as reclosure in EBPF. These patients all have good results. The other 17 patients have chest tube drainage. Six of the 17 patients in poor general condition and with small fistulas less than 5 mm had their BPFs initially treated endoscopically using fibrin sealant, but in 4 patients, the fistula persisted. Three patients after lobectomy had chest tube drainage for about 2 months, and healed. The other 12 patients (52.1%) shifted from BPF to empyema, and had chest tube drainage until their death. The mortality rate associated with LBPF was 0%.

Early bronchopleural fistula
This study included 43 patients (0.65£¥) with early bronchopleural fistula, among all 6,239 patients, and consisted of 3 females and 40 males. These patients with EBPF had left pneumonectomy (n = 10), right pneumonectomy (n = 15), and lobectomy (n = 18). These same patients with EBPF had squamous cell carcinoma (n = 21), adenocarcinoma (n = 15), adenosquamous carcinoma (n = 3), or large cell carcinoma (n = 4). According to the TNM classification, 8 patients were in stage I, 12 in stage II, 20 in stage III, and 3 in stage IV.

When the overall patient condition permitted, reclosure was performed immediately in 35 patients (81.3%) after EBPF diagnosis. Ten patients (23.2%) who had postlobectomy and sleeve resection BPF required completion surgery. The bronchial stump was debrided, refashioned, reclosed by hand suture technique, and covered with a well-vascularized flap. Intercostal muscle (26 patients), pericardial fat pad (5 patients) and omental flap (4 patients) have been used with good results. When the overall patient condition did not permit, we only gave chest tube drainage, in 8 patients (18.6%). In 2 patients (9%) with poor overall condition, the initial treatment was endoscopic. But both the fistulas persisted. Compared with the mortality rate of LBPF (0%), the mortality rate of EBPF (11.6%) was significantly higher. Five patients died with EBPF. The main cause of death shifted from BPF to pneumonia, empyema, adult respiratory distress syndrome, sepsis, and respiratory insufficiency due to pneumonia.

Risk Factors
Univariate analysis
Seven preoperative variables and eight postoperative variables were considered for the univariate analysis. The results are provided in Table 1. Risk factors associated with higher risk of BPF development were radiotherapy after operation, pneumonia after operation, pneumonectomy, and age. Patients with pneumonectomy had a higher incidence of EBPF and LBPF than did patients with lobectomy (1.7% versus 0.3%, p < 0.05; and 1.4% versus 0.02%, p < 0.05, respectively).


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  		Table 1 Risk Factors for Bronchopleural Fistula on Univariate Analysis
 
Multivariate analysis
For LBPF, variables exhibiting a prevalence higher than 0.5% and a p value less than 0.25 in the univariate analysis were considered for entry in a multiple stepwise logistic regression analysis to achieve a prognostic model (sls = 0.1, sle = 0.1). Three independent variables remained in the final model as independent predictors of LBPF: radiotherapy, pneumonia after operation, and operative mode (Table 2). The {chi}2 was 2.3456 and significance was 0.8853 in the Hosmer-Lemeshow test.


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  		Table 2 Independent Risk Factors of Late Bronchopleural Fistula on Multivariate Analysis After Lung Cancer Surgery
 
For EBPF, variables exhibiting a prevalence higher than 0.5% and a p value less than 0.25 in the univariate analysis were considered for entry in a multiple stepwise logistic regression analysis to achieve a prognostic model (sls = 0.1, sle = 0.1). Three independent variables remained in the final model as independent predictors of EBPF: age, pneumonia after operation, and operative mode (Table 3). The {chi}2 was 3.2476 and significance was 0.5173 in the Hosmer-Lemeshow test.


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  		Table 3 Independent Risk Factors of Early Bronchopleural Fistula on Multivariate Analysis After Lung Cancer Surgery
 
Relationship Between LBPF and Mode of Pulmonary Resection
The average time of LBPF after pneumonectomy and lobectomy was significantly different. The average time of LBPF after left pneumonectomy was 57.80 ± 18.02 days; after right pneumonectomy, it was 97.67 ± 65.36 days; and after lobectomy, it was 238.33 ± 164.12 days. The average time of LBPF with other factors (different TNM stage in lung cancer patients, different tumor histology, and different sizes) was not different.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Footnotes
 Acknowledgments
 References
 
Several factors have been reported to be associated with the development of BPF, but few investigators have assessed the actual impact of such factors in a multivariate analysis [5, 6]. Some reports have suggested that pneumonectomy, residual tumor in the bronchial stump, preoperative radiation therapy, diabetes mellitus, and mechanical ventilation are the major factors associated with the development of BPF. In our data, both pneumonia and operative mode were included in the risk factors of early and late bronchopleural fistula.

Seven patients (30.4%) in the LBPF group and 7 patients (16.3%) in the EBPF group contracted pneumonia after the operation. Because the recovery of the bronchus stump is associated with the repairing ability of the mucosa [7, 8], if the bronchus stump was in chronic inflammation for a long time, its repairing ability of the bronchus mucosa was more limited.

Undoubtedly, the risk of BPF is higher after pneumonectomy than after lesser pulmonary resections [8]. Most authors, including us, have found a higher incidence of BPF after right pneumonectomy than after left pneumonectomy, probably because of the better protection provided by the mediastinal tissue for the left bronchial stump and the more devascularization produced around the right bronchial stump during lymph node resection.

There were a few similarities in the risk factors between late and early BPF, but they also differed in some cases. Early BPF is more like to develop sooner in the aged. According to Sakurai and associates [9], aged patients are not associated with BPF development. Our results regarding LBPF agreed with this observation.

The influence of neoadjuvant therapy is controversial [10]. Although previous reports have demonstrated a higher incidence of BPF in patients receiving radiotherapy [11], other investigators did not find such a relationship [12]. In our study, LBPF was associated with postoperation radiotherapy, not with age. This research also indicated that age and radiotherapy are different risk factors in the onset of EBPF and LBPF. The mortality rates were also different in EBPF and LBPF, indicating that we should use different treatments for EBPF and LBPF. Particularly, the fatality caused by EBPF should be fully understood. Earlier detection and earlier processing is important for EBPF.

In univariate analysis, the average times to LBPF after pneumonectomy and lobectomy were significantly different. The average time to LBPF, however, was independent of the dissimilarity of tumor type size and stage. Therefore, we should provide a different follow-up after pneumonectomy and lobectomy.

In conclusion, because BPF is a severe complication and is associated with high rates of mortality, reducing the potential risks for EBPF is of paramount importance. Some of the risk factors in EBPF and LBPF are similar, but others are different. We should analyze the different reasons for the occurrence of BPF, and adopt different preventive measures. Different follow-up should be provided for the different operations.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Footnotes
 Acknowledgments
References
 
A great number of people have gone to considerable lengths to help this work, among whom we would single out here the names of Professors Gening Jiang and Chang Chen. We thank Guangyu Chen for the illustration and statistical analyses. For all their kind help and hard work, we wish to express our heartfelt gratitude.


   Footnotes
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Footnotes
Acknowledgments
 References
 
* These authors contributed equally to the article. Back


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Footnotes
 Acknowledgments
 References
 

  1. Yu S, Huo J, Lin X, et al. Therapeutic efficacy of treating bronchopleuro cataneous fistulia by infusing tricholoroacetic acid via fiberoptic bronchoscope Zhongguo Neijing Zazhi 2001;7:36-38.
  2. Algar FJ, Alvarez A, Aranda JL, et al. Prediction of early bronchopleural fistula after pneumonectomy: a multivariate analysis Ann Thorac Surg 2001;72:1662-1667.[Abstract/Free Full Text]
  3. Varoli F, Roviaro G, Grignani F, Vergani C, Maciocca M, Rebuffat C. Endoscopic treatment of bronchopleural fistulae Ann Thorac Surg 1998;65:807-809.[Abstract/Free Full Text]
  4. Mountain CF. Revisions in the international system for staging lung cancer Chest 1997;111:1710-1717.[Abstract/Free Full Text]
  5. Al-Katlan K, Cattalani L, Goldsraw P. Bronchopleural fistula after pueumonectomy with a hand suture technique Ann Thorac Surg 1994;58:1433.[Abstract/Free Full Text]
  6. Mendel T, Jakubetz J, Steen M, Stuttmann R. Post-lobectomy bronchopleural fistula—a challenge for postoperative intensive care Anesthesiol Intensiv Med 2006;41:278-283.
  7. Suzuki M, Otsuji M, Baba M, et al. Bronchopleural fistulas after lung cancer surgery: multivariate analysis of risk factors J Cardiovasc Surg 2002;43:263-267.[Medline]
  8. Cameron D, John C, Douglas J, et al. Postpneumonectomy bronchopleural fistula after sutured bronchial closure: incidence, risk factors, and management J Thorac Cardiovasc Surg 1996;112:1367-1371.[Abstract/Free Full Text]
  9. Sakurai J, Hiraki T, Mukai T, et al. Intractable pneumothorax due to bronchopleural fistula after radiofrequency ablation of lung tumors J Vasc Interv Radiol 2007;18:141-145.[Medline]
  10. Dyszkiewicz W, Pawlak K, Gsiorowski L. Early post-pneumonectomy complications in the elderly Eur J Cardiothorac Surg 2000;17:246-250.[Abstract/Free Full Text]
  11. Hubaut JJ, Baron O, Habash Al, Despins PH, Duveau D, Michaud JL. Closure of the bronchial stump by manual suture and incidence of bronchopleural fistula in a series of 209 pneumonectomies for lung cancer Eur J Cardiothorac Surg 1999;16:418-423.[Abstract/Free Full Text]
  12. De Perrot M, Licker M, Robert J, Spiliopoulos A. Incidence, risk factors, and management of postpneumonectomy bronchopleural fistula Scand Cardiovasc J 1999;33:171-174.[Medline]



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