Modied Silicone Stent in the Treatment of Bronchopleural Fistula: Clinical Observation of 17 Cases

Objective: Bronchopleural stula is a rare but life-threatening event with limited therapeutic options. Aim of our study is to investigate the ecacy and safety of the modied silicone stent in patients with bronchopleural stula. Method: Between March 2016 and April 2020, we retrospectively collected 17 patients with bronchopleural stula and who underwent bronchoscopic placement of the modied silicone sten. The Y-shaped stent was tailored and sutured manually. The initial success, clinical success, the cured rate and complications were recorded. Results: Placement of the modied silicone stent was successful in 16 patients on rst attempt (initial success rate was 94.1%). The median follow-up time was 107(rang, 5-431) days. The amelioration of respiratory symptoms was reported in all patients. There were 14 patients with empyema, the daily drainage was signicantly decreased in 11 patients over time, and the purulent uid completely disappeared in six patients. The clinical success rate was 76.5%. There were seven stents was removed during follow-up, four (26.7%) removed for cured stula, two for the severe proliferation of granulation tissue and one for the dislocation of stent. No severe adverse events of stent migration and suture dehiscence happened. There were three cases were lost to follow-up and seven patients succumbed. The cause of death included progression of primary malignance, the uncontrolled infection, myocardial infarction and left heart failure. Conclusion: The modied silicone stent may be an effective and safe option for bronchopleural stula patients in whom the conventional therapy is inappropriate and contraindicated.


Introduction
Bronchopleural stula (BPF), the aberrant connection between the bronchial tree and the pleural cavity, is a dreaded complication of pulmonary resection. Despite the advancement in surgical technique [1,2], the BPF still occurred in 4.5-20% after pneumonectomy, and 0.5-15% after lobectomy [3,4]. It is associated with a high mortality which can up to 71%.
No consensus on treatment of the BPF has been established. Therapeutic options range from extensive surgical procedures to several bronchoscopic techniques. The surgical treatments includes different options as open window thoracostomy, thoracoplasty, and direct closure of the stula with aps of different origins [5]. However, the aggressive surgical options can be problematic for an already compromised patients. Moreover, recurrence rate of BPF after surgical repair is high [5]. In recent years, numerous bronchoscopic techniques have been used for closing the stula.
Among these endoscopic techniques, airway stents play important roles in the treatment of airway stula [6]. The silicone stent had been widely used in benign and malignance airway stenosis [7][8][9], but its use in airway stula was few reported. The relatively poor adaptability may be the limiting factor. However, the silicone stent has various merits that may contribute to the success of stula closure. In the past two decades, the use of modi ed silicone stent in BPF has been reported in some case reports or small series [10,11]. Hence, we attempt to conquer its de ciency by modifying the silicone stent and then use it in BPF patients. Based on the literatures and our clinical experience, we tried to explore the feasibility, e cacy and safety of modi ed silicone stent for BPF.

Patients and data review
In this retrospective study, we searched the medical records and collected all patients who had been treated for BPF by placing the modi ed silicone stent between March 2016 and April 2020 in our center.
The protocol has been approved by the Ethics committee of The Second A liated Hospital of Xiamen Medical College and all patients signed written informed consent before rigid bronchoscopy.
We searched the medical records manually and extracted the clinical information and bronchoscopic data. Initial success was de ned as successful insertion of the stent and immediate cessation of air leak from the residual cavity after stenting. Clinical success was de ned as the situations that included relief of symptoms, no air leak, no sign of persistent stula, and notably reduced volume of daily drainage were last for more than a month.

The bronchoscopic procedure and fabrication of silicone stent
The exible bronchoscopy was performed before stent placement to identify the site of stula ori ce and clear the secretion. For the stula which is not visualized by bronchoscopy, a balloon occlusion test or instillation of methylene blue was performed. The stula site and size were measured by multi-slice CT (three-dimensional reconstructions) and bronchoscopy. To further con rm the luminal diameter of the target bronchus, the sterilized straight stent segments with different outer diameters were used under rigid bronchoscopy to detect the optimal size of the stent. According to the measured results, the silicone stent (TRACHEBRONXANE™ DUMON®, Novatech, France) with appropriate diameter was chosen. Then the selected stent was modi ed manually on site to t individual airway. One of the lateral branches of the Y-shaped stent was randomly selected as the occluded branch. Basing on exible bronchoscopic ndings, the length of each branch was adjusted with scissors. The distal end of the occluded branch was sealed with nylon wires by continuous locking suture, in which the distance between the continuous sutures should be less than 2 mm (5-10 mm in common surgeries) to avoid leakage. Finally, the modi ed silicone stent consisted of the occluded branch, the main branch and the lateral branch ( Fig. 1-A). We tted a suitable stent ring by nesting or suturing to the selected stent in the case the size of stent was un t. (Fig. 1-B, C).
Thereafter, the modi ed stent was placed into the folding system. Under general anesthesia, the stent was implanted into the appropriate location through rigid bronchoscopy, and adjusted by using the surgical grasping forceps or foreign-body forceps. All patients were carefully and continuously monitored. Within one week after stenting, all patients underwent bronchoscopy and chest CT to identify the location of stent and airway patency.

other managements
In case of early BPF and BPF with empyema, urgent pleural drainage is required. The intercostal tube drainage with or without suction is used. All patients received antibiotic therapy adjusted according to bacterial culture reports. If the empyema was present, irrigation of the pleural empyema was needed. In addition, nebulization treatment is generally used to improve the retention of phlegm. If there was no air leak, no signs of persistent stula, the daily volume of drainage was less than 20 ml/h and disappearance of the purulent uid, the chest tube was removed.

Follow-up
After stenting, the patients were followed-up without uniform schedule. The frequency depended upon each patient's general well-being and airway condition. Generally, the airway condition was checked by monthly bronchoscopy. The shrinkage of the thoracic cavity was followed by monthly chest CT. More frequent test was needed if the patient was symptomatic. The assessment indications included respiratory symptoms, air leakage, the volume of daily drainage, size of residual pleural cavity and the stent-related complications.
During the follow-up, the stent would be removed in the following situations:(1) the stula was healed (the closure of stula that was con rmed by instillation of methylene blue and the drainage tube was removed with disappearance of drainage uid); (2) the severe dislocation of the stent which is di cult to be adjusted by surgical grasping forceps or foreign-body forceps; (3) severe proliferation of granulation tissue that restricted the patients' breathing; (4) the placement of stent is intolerable for the patient.

Statistical analysis
SPSS version 18.0 (SPSS Inc., USA) was used for data analysis. Continuous characteristics conform to normal distribution were expressed as mean ± standard deviations (normality of distribution veri ed by the Kolmogorov-Smirnov test); otherwise, the median and range would be used. The change in variables over time was analyzed by Paired t test if followed normal distribution; if not, the nonparametric test was used. Categorical variables were presented as count (percentage).

Results
A total of seventeen BPF patients (15 men and 2 women) who received modi ed stent placement were included in our study. The mean age of these patients was 57.7 ± 8.1 (range, 47-72) years. Fifteen patients had lung cancer and two had tuberculosis. Eight patients received lobectomy and nine received pneumonectomy. Bronchial stumps were closed by mechanical stapler in eleven patients. The median time from lung resection to the diagnosis of BPF was 42 days (range, 5 days-37 months). The mean estimated diameter of stula was 9.1 ± 2.7 (range, 6-15 mm). Empyema happened in fourteen patients, and mean volume of daily drainage was 116 ± 64.2 (range, 20-270) ml. Characteristics of patients were shown in Table 1. The modi ed silicone stents were successfully placed into the culprit bronchus in all patients. Four patients received the modi ed stents that connected with stent rings. The information of the stent type and location of occluded branch were described in Table 2. The immediate cessation of air leak achieved in 16 patients (initial success rate was 94.1%). Only one patient failed to achieve initial success, in whom the occluded branch didn't t the airway well. The original stent was removed and fabricated by connecting a stent ring to the occluded branch. Then the new stent with "larger diameter" was reinserted.
After the second operation, the stula was closed and no gas spillovers was observed in the chest drainage tube. The bronchoscopic views of the stent placement were shown in Fig. 2 and Fig. 3. left inferior lobar bronchus. §: "Y" refers to the shape of stent, "a" and "b" refer to the outer diameters of the main branch and the two branches, respectively. The diameter is presented as millimeters.
The median follow-up time was 107(range 5-431days). The amelioration of respiratory symptoms was reported in all patients. The patients who had empyema (n = 14) received intercostal tube drainage and irrigation. One month after stenting, daily drainage was signi cantly reduced in eleven patients. The median volume of the daily drainage before and after stenting was 95 (range 20-260 ml) and 20 (range 0-70 ml), respectively (P = 0.001). The other three patients did not attend follow-up. The median volume at the end of the follow-up was further decreased to 7.5(range 0-20 ml) P < 0.001). Overall, the clinical success was achieved in thirteen (76.5%) patients. Among the four patients who cannot reached clinical success, one suffered recurrence of air leak for the enlarged stula fteen days after stenting and three lost to follow up within one month.
By the end of follow-up, the drainage tube was removed in eight patients. The residual cavity was observably shrunk over time in ten patients, and completely disappeared in six patients. The typical CT image was shown in Fig. 4. The stents were removed in seven patients. Four stents were removed when the stula was healed, two for the severe granulation proliferation and one for the dislocation of stent.
Stent placement was well tolerated in our study. No stent migration, airway rupture choking, laryngeal edema, and suture dehiscence took place during follow-up. Cough and postoperative retrosternal pain happened in almost all patients, but these symptoms were relieved under the assistance of antitussive agents and analgesic scheme. All patients had various degree of respiratory infection before stenting, the exacerbation of pulmonary infection was detected in two patients (11.8%). One case (patient 13) was controlled after adjusting the use of antibiotics while one cases suffered uncontrolled diffuse pneumonia (patient 4). Granulation proliferation was identi ed in all cases. This problem was successfully treated by bronchoscopic cryosurgery and argon plasma coagulation except for two patients. Mucus plugging was common after stenting, but it was mild and could be improved via using expectorant.
Three cases were lost to follow-up and eight succumbed during the follow-up. The cause of death included progression of primary malignance(n = 3), the uncontrolled infection(n = 1), myocardial infarction (n = 2) and left heart failure (n = 2).

Discussion
The result of our study suggested that placement of the modi ed silicone stent under rigid bronchoscopy could be an effective and safe option for refractory BPF. This is the rst study with the largest sample size which explores the e cacy and safety of the modi ed silicone stent for BPF treatment.
The BPF is still a severe and even fatal complication. The good prognosis of BPF depends on early diagnosis and proper management. Early recognition is a challenging for BPF due to its insidious presentation [13]. At present, the main diagnostic techniques are CT and bronchoscopy. The chest CT is a common and useful technique that can detect peripheral BPF, optimize planning of management and facilitate the follow-up [14]. Bronchoscopy is able to evaluate and locate the stump simultaneously. In addition, bronchoscopic treatment is also a valuable treatment strategy for BPF [15].
The management of BPF is categorized into two strategies: supportive and de nitive treatments. The supportive strategy, such as drainage of thoracic cavity and ventilation, is the initial treatment to avoid aspiration pneumonia and treat presented empyema. The de nitive strategy is to close the stula, several techniques ranging from surgery to endoscopy can be carried out. Although some stulas may resolve spontaneously or with appropriate supportive management, the de nitive managements are required in vast majority of stulas [16]. Surgery remains the cornerstone, which included open window thoracostomy, completion pneumonectomy, thoracoplasty, suture closure with a vascularized pedicle of omentum or muscle. Although high success rate of surgical management of BPF has been reported, the risk of recurrence is also high [1]. Besides, most patients with BPF are too debilitated to receive second surgery. Compared to surgical management, the endoscopic closure has the advantages of lower cost, less invasive, and wider scope of application. Therefore, bronchoscopic interventions might consider to be the alternative to surgery in some condition [17]. Ravindra et al [18] subdivided the bronchoscopic management into two categories: the sealant and occlusive devices. The reported sealants mainly included: collagen matrix plugs [19], collagen screw plugs [20], different bio-glues [21,22], and synthetic hydrogel [23]. The utility of these materials was restricted to small BPFs (< 3 mm in size). The other strategy is occlusive devices, mainly included: stents and their modi cations, Amplatzar™ devices [24,25], endobronchial valves (EBVs) [26], and the endobronchial Watanabe spigot (EWS) [27]. However, many of these are expensive or not routinely available in developing countries. Therefore, the use of stent is relatively more prevalent and has been proven to be effective [8,[28][29][30]. It can occlude the segment(s) or lobar bronchus associated with BPF, which allows parenchymal rest and promotes distal healing.
Recently, the use of various type of stents for stula closure have been reported anecdotally. Most of these studies were comprised of small series with limited evidence, while Han et al. (15) reported the use of a new customized covered metallic stent in a large population (n = 148). Despite the high success rate, it is notable that the special stent was customized from the manufacturer. The time-consuming process limited its use in emergency situation. Besides, their study reported one manufacturing defect (a 1 mm hole in the stent bullet) and eight stent damage. It suggested that the rupture of membrane and the damage of metal components are common and adverse drawback for covered metallic stent. The silicone stent shows merits of durability and easy removability. Moreover, the smooth inner surface may facilitate the clearance of airway secretions and the Y-shape structure and studs outside the stent have been designed to prevent the stent from migration. The biggest weakness of silicone stent is the poor adaptability. However, the shortcoming can be overcome by modifying the stent manually. We modi ed the stent on site to obtain the individual stent without waiting.
There remain some disadvantages for the modi ed silicone stent. First, a stent acts as a foreign body, which would irritate proliferation of granulations and induce infection. Hence, it is suggested to be removed when the stula was cured. However, there is no consensus on the optimal time to remove the stent. Second, the displacement could be potentially life-threatening, although it happened rarely. Third, it must be deployed under rigid bronchoscopy, which require specialized equipment and well-trained team.
From the above, the successful management of BPF depend on multiple factors. It can be summarized as the appropriately selection of candidates, securely blocking the direct stulous tract, sustainable eliminating of all in ammatory effusion and precisely administration of appropriate antibiotics. No treatment or device has been shown to be superior to the others. The optimal treatment is the individualized management.
limitations of our study listed as follow: it was a retrospective study with small sample size, making it di cult to perform survival analysis. We cannot compare the different therapeutic options in bronchial stula treatment, since the BPF is a rare disease that always reported as solitary cases and the condition of candidates varies in different therapeutic options.

Conclusion
In conclusion, the modi ed silicone stent is effective and safe for the treatment of BPF, especially in those with large stula size and in whom surgery is inappropriate and contraindicated. Further prospective studies with large sample sizes are warranted.