Preliminary Experience of Autologous Free Dermal Graft Combined With Free Myocutaneous Flap in the Treatment of Refractory Bronchopleural Fistula With Empyema

Background: To explore the effects of autologous free dermal graft combined with free myocutaneous �ap on bronchopleural �stula with empyema. Methods: Two patients with refractory empyema and bronchopleural �stula were treated with autologous free dermal graft combined with free myocutaneous �ap. The free dermal graft was harvested from the skin around the incision and the �stula was sutured intermittently. The lateral femoral myocutaneous �ap was selected as the free �ap. Using microsurgery techniques, the descending branch of the lateral femoral circum�ex artery and the thoracodorsal blood vessel were anastomosed intermittently to maintain the blood supply of the myocutaneous �ap. After surgery, the empyema, air leakage, and the survival of the myocutaneous �ap were observed. Results: No necrosis of the myocutaneous �ap was observed after surgery. There was no disease recurrence after follow-up for seven and six months, respectively. Re-examination of the chest computed tomography or magnetic resonance imaging indicated that the empyema residual cavity had disappeared. Conclusion: Autologous free dermal graft combined with free lateral femoral myocutaneous �ap transplantation is effective in the treatment of patients with bronchopleural �stula with refractory chronic empyema, with satisfactory clinical effects.


Background
Bronchopleural stula (BPF) refers to the stula formed between the alveoli, bronchi at various levels, and pleural cavity due to various reasons, usually occurring after lobectomy. Although BPF is relatively rare after lobectomy, the incidence is still reported to be 0.6% [1,2]. With the prolongation of the disease course, patients are prone to refractory hydropneumothorax, respiratory failure, chronic empyema, and even death [3]. Owing to the existence of chronic empyema cavity that cannot be easily eliminated, treatment of BPF is di cult, especially in patients with empyema, cartilage and other necrotic tissues, where local infections are di cult to be controlled. It continues to be a problem for clinicians to completely cure the refractory BPF with empyema [4,5]. Patients often have accompanying symptoms of systemic poisoning, such as cough, anemia, hypoproteinemia, and even hemoptysis, and require longterm drainage with a tube. Although there are various approaches to treat BPF with empyema, it remains a challenge to solve the disease fundamentally. During the treatment period, the choice of surgical methods and endoscopic intervention may positively in uence the treatment of individualized conditions. In any case, the goal is to control the infection, block the BPF, and effectively eliminate the empyema cavity.
Presently, in China, the treatment of BPF mostly focuses on non-surgical treatments, such as stula closure with the endoscopic bronchial stent and injection of the sclerosing agent. However, it is very di cult to completely cure the refractory BPF with empyema by conservative treatment. The repair of BPF using an autologous free dermal graft may still be in the nascent stage due to the lack of literature and related data. The objective of this study was to summarize and analyze two patients with refractory BPF and empyema who were treated with autologous free dermal draft combined with free myocutaneous ap, and to evaluate the safety and effectiveness of this surgery.

Methods
A retrospective analysis was performed on two patients with BPF and refractory empyema, who received surgery at the Cardiothoracic Surgery and Orthopedics Repair and Reconstruction Center of Tongde Hospital of Zhejiang Province. Autologous free dermal draft combined with free myocutaneous ap was used in the treatment of disease. The patient characteristics are presented in Tables 1 and 2.  Case-1 was a young woman of age 35 years. One and a half years ago, she was admitted to a local hospital for multiple bullae in both lungs and pneumothorax, and underwent bullectomy in the right upper lung at the same time. Two weeks after the operation, she began to develop cough, sputum, and fever, and her condition gradually worsened. Over time, purulent exudates appeared in her chest tube, which continued to leak air. However, to aggravate matters further, there was also a pneumothorax in the left lung, and both lungs continued leaking. The patient had a history of old pulmonary tuberculosis, which had subsequently been cured, and exhibited poor lung function without a history of hypertension, diabetes, or other diseases. Although the patient's condition was generally stable by adjusting antibiotics and maintaining smooth drainage, what made her uncomfortable was the drainage bottle that was always accompanied by turbidity and several bubbles, and the drainage tube xed in the chest cavity could not be pulled out in time, giving rise to irritating cough and low fever at irregular intervals. Computed tomography (CT) of the chest indicated hydropneumothorax in the right pleural cavity, simple pneumothorax in the left pleural cavity, and localized drainage tubes in both thoracic cavities (Fig. 1A).
Based on her clinical symptoms and the ndings of imaging, she was diagnosed to have BPF with empyema after right upper bulla resection and left spontaneous pneumothorax (compression about 30%). Therefore, the development of a detailed treatment plan was essential. The rst step was to replace the thin drainage tube on the left side of the patient with a 24F drainage tube to promote lung recruitment and then pull it out after there was no obvious air leak. In the second step, after ensuring that the left lung could function normally, we carefully examined the problem of the bronchopleural stula with empyema on the right side. After the patient was anesthetized, bronchoscopy was performed, which con rmed that the presence of a stula with a diameter of about 3 mm between the upper-right bronchus stump and the pleural cavity, and a covered bronchial stent (Boston Scienti c Corporation, Natick, Massachusetts) was placed under the endoscope. After the condition was clari ed, rib resection and thoracoplasty were performed simultaneously. After a part of the second rib was removed, the debridement, ushing, and removal of purulent pleural effusion and necrotic tissue were performed in the thoracic cavity. Two obvious alveolar pleural stulae were seen on the surface of the right upper lung in the tympanic lung, with a diameter of about 2-3 mm. Using pus culture, the pathogen was identi ed to be Mycobacterium spp. After timely adjustment of antibiotics and adequate drainage after surgery, the condition of the patient improved. No obvious pathogenic bacteria were detected again after pus culture. Subsequently, she received a second surgery. The third step was to incise the pedicled latissimus dorsi muscle ap of a size of about 14.0 cm × 8.0 cm and the serratus anterior myocutaneous ap of a size of about 10.0 cm × 6.0 cm. After the stula was sealed using medical glue, the myocutaneous ap was sutured and xed, and the abscess was completely packed after transposition.
Although the surgery went smoothly, the patient struggled with postoperative recovery. We discussed and agreed that the root cause was air leakage and infection. After the operation, the pedicled muscle ap also appeared to show partial atrophy, and the placed bronchial stent was coughed out of the body. The patient stayed for a long period in the hospital, during which she had undergone several debridement operations and bronchial stent closures with unsatisfactory effect. After multidisciplinary consultation, the free dermal draft combined with free myocutaneous ap was ultimately selected for the surgery. After anesthesia, the patient was placed in a semi-recumbent position. After su cient debridement, healthy skin around the incision was selected, and the subcutaneous and epidermal tissues were removed to make a dermal graft (Fig. 1B). The graft was inserted into the two stulas, and the exposed part was sutured and xed with surrounding tissues. There was no obvious air leakage after the lung bulged ( Fig.   1C). Later, the line connecting the right anterior superior iliac spine with the outer side of the patella was selected. Starting from the inside of the ap, the skin, subcutaneous tissue, and deep fascia were incised layer-by-layer to expose the muscle tissue. The rectus femoris and lateral femoral muscles were bluntly separated, and the descending branches of the lateral femoral muscle arteries and accompanying veins and nerves were separated. Ligation of the branches was distributed at the distal end of the muscle to completely free the muscle, its vascular pedicle, and nerve. The vascular pedicle was about 3 cm long.
Finally, the pedicle was cut according to the length required by the recipient area, and a myocutaneous ap of a size of about 20 cm × 12 cm, composed of skin, subcutaneous tissue, fascia, and lateral femoral muscle was obtained, with the descending branch of the lateral femoral artery as the pedicle. The size of the island was about 5 cm × 3 cm. After the myocutaneous ap was transplanted to the recipient area and the residual cavity was lled, the descending branch of the lateral femoral artery, vein, and nerve, and the thoracic dorsal artery, vein, and nerve were intermittently sutured under the microscope using a 9-0 prolene thread to ensure the blood supply of the tissue ap and muscle activity (Fig. 1D, E). Suture between dermal graft and myocutaneous ap was also performed to enhance the vascularization to dermal graft. After the operation, the ap was sutured to normal skin around the chest without tension (Fig. 1F), and the drainage tube and drainage skin were placed. The postoperative treatment consisted of postoperative anti-infection, anti-spasm, anti-coagulation, and other treatments. The color and temperature of the myocutaneous ap were closely monitored, and the transplanted myocutaneous ap was applied to keep it warm; thus, avoiding the compression of the anastomotic wound to ensure smooth blood ow [6]. The postoperative process went smoothly, and she was discharged from the hospital after complete recovery. The chest magnetic resonance imaging (MRI) indicated that the empyema cavity and BPF were successfully sutured after surgery (Fig. 1G). During the 6-month follow-up, there was no obvious recurrence of pleural stula and empyema. Case-2 Case-2 was a young man of age 21 years with a history of multiple bullae in the right lung with pneumothorax. Two and a half years ago, he was admitted to a local hospital and received surgical treatment. On the third day after the operation, purulent exudates appeared in the closed drainage tube of the chest cavity, accompanied by an unpleasant smell. His main symptoms were intermittent cough and low fever. Although his fever was relieved by antibiotics and active drainage, his cough continued, and several air bubbles over owed from the drainage bottle. The chest CT showed an abscess in the upper right chest, a gas-liquid plane in the chest cavity, a reduction in the thoracic volume, and a thickening of the pleura (Fig. 2A). Based on these observations, the patient was diagnosed to have the right BPF with empyema. After active pre-operative preparations, using the position of the original drainage tube as the appropriate incision plane, 2 mm BPF could be seen on the pleural surface near the top of the abscess cavity after removing the 3 rd , 4 th , and 5 th ribs along with part of the thickened pleura, and the volume of the abscess cavity was about 180 mL. Intraoperative debridement, ushing, and the removal of pus and necrotic tissue in the thoracic cavity were also performed. This patient had a lot of blood loss during the operation and was given a blood transfusion after the operation. During the next few weeks, anti-infection and nutritional support were the main treatment options to maintain a smooth ow. When the patient coughed actively, air leakage in the drainage bottle could be seen. The identi ed bacterium in the postoperative pus culture was Maltophilia stenotrophomonas, and antibiotics were adjusted in time for symptomatic treatment. When the patient's general condition was stable, we combined the rst patient's successful experience in repairing the stula with a dermal skin ap to evaluate whether the same approach was similarly effective. After careful pre-operative discussion and summary, considering the patient's larger abscess cavity, it was decided to directly treat the empyema with free dermal graft combined with free myocutaneous ap. The procedure was the same as that followed for the rst patient, and the postoperative recovery was unremarkable. After 1.8 months of hospitalization, he was discharged from the hospital, and the incision recovered well (Fig. 2B). Re-examination of chest MRI empyema showed no recurrence and disappearance of BPF (Fig. 2C). After six months of follow-up, he lived as a healthy person.

Results
Both patients underwent staged surgery according to the above-described procedure. Overall, the treatment was satisfactory. The rst patient was hospitalized for a relatively long time, which was attributed to the poor control of air leakage, in addition to the isolation and culture of mycobacteria (nontuberculous type) from the pus during the treatment process. The main component of the cell wall of these bacteria was mycolic acid, which may induce chronic infection in short-term and long-term prolonged and destructive tissue disease. Great attention has been paid to anti-infection and the choice of drainage methods. Based on the experience of case-1, the treatment cycle of case-2 was signi cantly shortened. Although Stenotrophomonas was isolated from the pus of this patient, their overall pathogenicity was not strong. Through active anti-infection and adequate drainage, a satisfactory effect of the treatment was achieved.
For the treatment of refractory BPF with empyema, we must focus on the control of infection and completion of the surgery under the condition of smooth drainage. We applied autologous free dermal graft repair combined with free myocutaneous ap tamponade and achieved the expected results. The myocutaneous ap was observed to be free of necrosis after the operation. After several months of follow-up, there was no recurrence of the original disease. During the re-examination, chest CT or MRI indicated that the original empyema cavity disappeared, the free myocutaneous ap was active, and the clinical effect was satisfactory.

Discussion
BPF is a serious complication after lung resection and leads to adverse effects, including intractable empyema and residual lung pneumonia with the progress of the disease. BPF itself adversely affects the quality of life and survival time of patients, which is also considered to be a challenge for thoracic surgeons. Presently, the etiology and mechanism of BPF with empyema remains poorly understood. Comprehensive analysis of multiple factors has indicated that the occurrence of BPF can be summarized as a major risk factor as well as a secondary risk factor [7,8]. These risk factors may include: a) the manual suture technique implemented by the clinician on the bronchial stump; b) excessive removal of the lymph nodes around the bronchial stump, causing the blood supply around the stump to be blocked; c) excessively long bronchial stump remaining after lung resection; d) the continued presence of tumor cells in the bronchial stump; e) long-term mechanical ventilation after major surgery; f) advanced age and poor nutritional status; g) exposure to high-dose chemotherapy or radiotherapy before or after surgery [9][10][11]. Recent studies have demonstrated that pneumonectomy bears a signi cantly higher risk of BPF than lobectomy. This may be attributed to the fact that there is an increased risk of avascular necrosis of the bronchial stump or accumulation of secretions, leading to bacterial overgrowth and colonization and poor nutritional status [12,13]. Clinical studies have reported that appropriate treatment is highly important for patients showing BPF with empyema. The timeliness of the treatment is mainly re ected in avoiding persistent infection of the pleural cavity as much as possible. The common assessment methods are chest CT and bronchoscopy. The patients transitioning from the acute phase to the chronic phase are often accompanied by chronic wasting with obvious symptoms of systemic poisoning and symptoms such as cough, anemia, hypoproteinemia, and hemoptysis.
Several BPF patients with empyema were admitted in our department, who were treated with a pedicled muscle ap or free myocutaneous ap. Regarding the choice of surgical methods, we have observed that abscesses of volume less than 100 mL could be treated with pedicled muscle aps, those of volume between 100 mL and 200 mL could be treated with pedicled muscle aps, free muscle skin, or a combination of the two treatments according to intra-operative conditions, and abscess of volume more than 200 mL could be treated with free myocutaneous ap. Generally speaking, the treatment options for patients with refractory BPF with empyema include conservative treatment, endoscopic treatment, and surgical treatment, of which the conservative treatment mainly involves adequate chest drainage and supportive treatment (Fig. 3). However, endoscopic treatment often involves bronchoscopy occlusion, which may be more practical for most patients. However, it is di cult to treat patients with BPF, such as bronchial dislocation, severe infection in the pleural cavity, and larger stulae, with poor e cacy of the treatment [14]. What should we do if we encounter this type of refractory BPF with empyema and a large abscess cavity? The data indicated that after full closed thoracic drainage of empyema, closure of the stula is a key factor for the success of the subsequent operation [12]. On the other hand, our treatment plans should also take the locations of stula and abscess cavity into consideration. If the visual eld exposure of stula is poor during the surgery, it may be di cult to be repaired by the free dermal graft. The two patients analyzed in this study both had upper lobe BPF. Based on the experiences in our center, patients with lower lobe defect had a relatively small abscess cavity, which could be treated with pedicled muscle ap alone. We have not found patients with large abscess cavity after lower lobectomy at present. Patients with lower lobe defect and large abscess cavity might be rare. Thus, although we believe the reliability of our treatment plan, evidence in patients with lower lobe defect and large abscess cavity is needed.
Generally, free dermal drafts are mainly used to repair skin and mucous membrane defects caused by burns and wounds but are relatively rarely utilized in the repair of BPF, as evident from the availability of only a few clinical reports. Autologous free dermal grafts (de-epidermized) have their unique advantages, including good exibility and contractility, strong anti-infective ability, and abundance of surrounding capillaries. After the repair of the stula, the air leakage was signi cantly reduced, and the curative effect exceeded expectations. After completing the repair of the stula, we again selected free myocutaneous aps to ll the abscess cavity. With a recent increase in the number of cases receiving tissue aps to treat empyema, its therapeutic effect has also been unanimously recognized by thoracic surgeons. It retains the shape of the thorax and does not signi cantly affect the respiratory and circulatory function. Furthermore, the free myocutaneous ap does not require skin grafting due to chest wall skin defects.
After the operation, the color of the ap can be observed in time to evaluate the blood supply.
Currently, the chronic empyema has been frequently treated with pedicled muscle aps, while the free myocutaneous aps have rarely been used, which may be due to the operation involving microscopic vascular anastomosis, surgical di culty, and greater trauma. Pedicled muscle aps are not applicable if the patient suffers from refractory BPF with empyema and if part of the muscle group has been severed due to previous thoracotomy or when the abscess cavity is large [15]. The free myocutaneous ap can reach almost any position in the chest cavity and can ll the contaminated cavity. In some cases, free myocutaneous aps can also be combined with pedicled muscle aps, pedicled pericardium slices, or pedicled omentum to treat complex empyema [16,17]. During the operation, we applied microsurgery techniques to use the descending branch of the lateral femoral circum ex artery of the free myocutaneous ap transplanted into the abscess cavity as the donor vessel to align with the recipient's blood vessel, and the recipient's blood can generally be from the thoracic and dorsal arteries and veins. Thoracic dorsal arteries and veins are destroyed, and intercostal vessels, intramammary vessels, and transverse cervical vessels can be selected [4]. During the operation, it is necessary to prevent the tension of the vascular pedicle and the edge of the myocutaneous ap after anastomosis, which may affect the blood supply and activity of the free myocutaneous ap.

Conclusions
In summary, the autologous free dermal graft combined with free myocutaneous aps was an effective surgical treatment for some patients with refractory BPF with empyema. Perhaps, the number of cases in which we have applied this method to treat complicated empyema is low, and even the position of some patients with pleural stula is not suitable for repair or is irreparable, but we had only selected the suitable cases, and the patients had recovered well in the short and mid-term. Thus, it is necessary to further clinically test this procedure on a larger patient population.  Figure 1 Clinical images of patient-1 A. The chest computed tomography at admission showed left pneumothorax and right hydropneumothorax with drainage tubes placed in the thoracic cavity on both sides. B. The incised skin tissue was made into a suitable dermal graft. C. The two stulae located at the stump of the right upper lung bronchus were completely repaired with free dermal graft, without obvious air leakage (black arrow). D. Free thoracodorsal arteries, veins and nerves, and lateral femoral myocutaneous ap and its vascular pedicles and nerves (black arrow). E. Anastomosis of blood vessels and nerves during the surgery (black and white arrows). F. After surgery, the myocutaneous ap was sutured to normal skin around the chest without tension. G. The chest magnetic resonance imaging indicated that the empyema cavity and bronchopleural stula were successfully blocked (red arrow).

Figure 2
Clinical images of patient-2 A. The chest computed tomography at admission showed right hydropneumothorax with drainage tube placed in the right thoracic cavity. B. The myocutaneous ap was active, and the incision healed well after surgery. C. The chest magnetic resonance imaging indicated that the empyema cavity and bronchopleural stula were successfully blocked (red arrow).

Figure 3
The staging operation owchart was used to design treatment plans according to the different conditions of the patients.