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A 37-year-old woman underwent bilateral lung transplantation for lymphangioleiomyomatosis. Dense pleural adhesions due to past pleurodesis for chylothorax were observed and dissected in both thoracic cavities. The patient developed chylothorax after transplant. Chylothorax in the right thoracic cavity was successfully treated by conventional pleurodesis; however, pleural effusion from the left thoracic cavity was not reduced. According to fluoroscopic images obtained by injecting a contrast medium through the chest tube, the remaining pleural space in the left thoracic cavity was small and localized in the lower region adjacent to the mediastinum. We opted to fill this space with fibrin glue; we injected fibrinogen and thrombin solution into the space through the chest tube. We performed fibrin glue treatment three times and pleural effusion was dramatically decreased. We removed the chest tube on day 107 post-transplant. No recurrent chylothorax has been recorded for 10 years after lung transplantation.
Lung transplantation is an effective therapeutic strategy for patients with end-stage lung disease, including lymphangioleiomyomatosis (LAM). LAM is a rare disease that predominantly affects women of reproductive age. Chylothorax is one of the most serious complications after lung transplantation in patients with LAM. It has been reported that chylothorax occurred in 6% to 9 % of patients who received transplants for LAM.1,2) It is often difficult to treat or control chylous effusion in LAM patients because of the typically large amount of effusion. Several treatments have been reported for chylothorax in LAM patients. Therapeutic thoracentesis, pleurodesis and dietary manipulation are initial treatment options for chylothorax after lung transplant. Surgical treatment options, such as pleuroperitoneal shunt and thoracic duct ligation, are also performed on patients with a large amount of pleural effusion.1,3) We report the case of a mid-thirties female who developed severe chylothorax after bilateral lung transplantation for LAM and was treated successfully by injection of fibrin glue into the thoracic cavity.
A female patient diagnosed with LAM was referred to Tohoku University Hospital for lung transplantation. She was diagnosed with LAM at late 20s of age and underwent bilateral pleurodesis with OK-432 (Picibanil, Chugai Pharmaceutical Co., Ltd. Tokyo, Japan) to control chylous pleural effusion. Because of the recurrence of chylothorax in the right thoracic cavity, a 2nd pleurodesis thorax with OK-432 was performed at a year after the 1st pleurodesis. Post-treatment, she had suffered from severe chyloptysis and shortness of breath and was hospitalized for the 4 years prior to lung transplantation. At mid-30s, 9 years after the onset of LAM, she underwent bilateral lung transplantation. The patient was 159 cm tall and weighed 45 kg. General anesthesia was induced and the chest was opened through a bilateral trans-sternal anterior thoracotomy. Dense pleural adhesions due to past pleurodesis were observed in both thoracic cavities. The adhesions were dissected carefully, and pulmonary artery, pulmonary vein and bronchus in each side were exposed. Pulmonary artery, vein and bronchus in each lung graft were anastomosed to each structure of the recipient. Cardiopulmonary bypass (CPB) was used during the dissection and anastomosis. Operating time was 15 h and 46 min, and CPB duration was 7 h and 10 min. Ischemic time was 10 h and 44 min for the right lung graft and 12 h and 23 min for the left lung graft. The amount of bleeding was 10620 ml.
Approximately 1000 ml/day of pleural effusion was observed in each side and continued for 7 days after lung transplant. On day 8 post-transplant, pleurodesis was performed in the right thoracic cavity by injecting 200 mg of minocycline into the pleural cavity. Additional pleurodesis was performed four more times: (1) with the same dose of minocycline; (2) with 40 mL of autologous blood; and (3–4) with 5KE each of OK-432 (Fig. 1A). The right chest tube was subsequently removed on day 41 post-lung transplant once the pleural effusion decreased to 180 ml/day (Fig. 1A). Chylothorax in the left thoracic cavity was treated by pleurodesis similarly as the right side (twice with 200 mg of minocycline, once with 40 mL of autologous blood and two times with 5KE of OK-432, Fig. 1B). In spite of these treatments, the amount of pleural effusion from the left thoracic cavity was not reduced (1430 ml/day on 48 day post-transplant, Fig. 1B). Thoracic duct scintigraphy on day 50 post-transplant showed diffuse accumulation of radiotracer in the left thoracic cavity (Figs. 2A and 2B2B); however, we could not define its leakage point. A pleuroperitoneal shunt (Denver Pleural Effusion Shunt, CareFusion Corporation, San Diego, CA, USA) was placed on day 57 post-transplant in order to transfer the left pleural fluid into the peritoneal cavity. However, the patient developed massive pleural effusion in the left thoracic cavity and ascites in the abdominal cavity within a few days, which caused severe abdominal bloating and nausea. We inserted a chest tube again on day 61 post-transplant and then removed the pleuroperitoneal shunt on day 63 post-transplant. Subsequently, two treatments of pleurodesis with minocycline plus OK-432, in addition to systemic administration of octreotide (a somatostatin analogue) in a fasting condition, and two treatments of pleurodesis with autologous blood were performed. However, all of these treatments proved to be ineffective (Fig. 1B). By injecting a contrast medium through the chest tube and obtaining fluoroscopic images, we confirmed that the remaining pleural space in the left thoracic cavity was small (approximately 80 ml) and localized in the lower region adjacent to the mediastinum (Figs. 2C–2F2F). We decided to fill this remaining space with fibrin glue, Beriplast P Combi-Set (CSL Behring, GmbH, Marburg, Germany), in order to prevent the production of pleural effusion. On day 94 post-transplant, we injected 15 ml of fibrinogen solution into the space through the chest tube and then flushed the tube with 25 ml of saline. Then, we injected 15 ml of thrombin solution and flushed the tube with 25 ml of saline. The amount of pleural effusion was low for 2 days after fibrin glue treatment, returning to over 1000 ml/day on day 3. Five days after the first fibrin glue injection, we performed the same treatment but with 20 ml each of fibrinogen and thrombin solution, and flushed the chest tube between solution applications with only 5 ml of saline in order to maintain a high concentration of fibrinogen and thrombin solution in the pleural space. Post-treatment, the pleural effusion dramatically decreased to less than 200 ml/day. We performed additional fibrin glue treatment using the same method, and removed the chest tube on day 107 post-transplant. The patient was discharged on day 132 post-transplant, and no recurrent chylothorax has been recorded for 10 years after fibrin glue treatment (Fig. 3).
Chylothorax is a major complication that can develop after lung transplantation for LAM.1,2) In these cases, long-term drainage is necessary due to the large amount of pleural effusion and it can be an obstacle to physical and pulmonary rehabilitation after transplant. Dietary manipulation, such as a low-fat medium-chain triglyceride diet and complete cessation of oral intake, can be an initial treatment for postoperative chylothorax. Cerfolio et al. reported that 13 out of 47 patients with postoperative chylothorax were successfully treated by dietary manipulation; however, the remaining 34 patients (72.3%) required further treatment.4) They also demonstrated that the median daily chest drainage for the first 7 postoperative days was 511 ml in patients who were successfully treated by dietary manipulation.4) Pleurodesis is another option to treat chylothorax. Pleurodesis can be performed using multiple chemicals or autologous blood and can reduce pleural effusion in a variety of diseases, including chylothorax after lung transplantation. Indeed, chylothorax in the right thoracic cavity was successfully controlled by pleurodesis in the present case. On the other hand, a large amount of pleural effusion, such as the >1500 ml/day observed from the left thoracic cavity in the present case, is often difficult to be managed by pleurodesis.
The placement of a pleuroperitoneal shunt is an effective option for refractory chlyothorax,5–7) despite reported complications such as infection, shunt failure and pneumoperitoneum.8,9) However, we could not control chylothorax by using a pleuroperitoneal shunt in the present case. The most likely cause is that the amount of pleural effusion produced in the left cavity was more than the amount that the peritoneal cavity could absorb due to small body size. Shimmyo et al. reported a case of chylothorax and chylopericardium managed with chylous pleural effusion of 1500 to 3000 ml/day using a pleuroperitoneal shunt.6) Khiatani et al. demonstrated that a chylothorax case with daily pleural effusion, ranging from 500 ml to 3500 ml, was successfully treated by pleuroperitoneal shunt.7) In both cases, the authors reported male cases; these patients may have had a larger body type and therefore could have absorbed more pleural effusion when compared to our case.
Thoracic duct ligation is also a surgical treatment option for chylothorax after lung transplantation for LAM.1,3) In considering thoracic duct ligation, we performed thoracic duct scintigraphy to locate the injury site of the thoracic duct in the present case. However, our results showed diffuse accumulation of radiotracer in the left thoracic cavity and we did not identify its leakage site from the thoracic duct. It was thought that injuries were present in the main thoracic duct as well as in accessory ducts. Thus, it would be difficult to treat chylothorax by thoracic duct ligation in this case.
Mutations in the tuberous sclerosis complex genes cause the activation of mammalian target of rapamycin kinase (mTOR) and result in the growth, increasing motility and survival of LAM cells.10) Treatment by sirolimus, a mTOR inhibitor, has been shown to be associated with a reduction in the size of chylous effusions in patients with LAM.11) In addition, oral administration of sirolimus was also reported as a treatment option for chylothorax after transplant.12) Ohara et al. reported a successful case using sirolimus treatment for chylous pleural effusion after bilateral living donor lung transplantation for LAM. They began oral administration of sirolimus on day 66 after transplant and removed bilateral chest tubes 35 days after the initiation of the treatment.12) Sirolimus administration may have been a therapeutic option in the present case. It has been reported that sirolimus causes wound dehiscence and airway complications if it is used immediately post-transplant.13,14) Therefore, the timing of sirolimus administration should be carefully decided prior to application.
Fibrin glue is widely used to stop bleeding and alveolar air leakage in thoracic surgeries. Whereas conventional pleurodesis with chemicals or autologous blood failed to decrease the pleural effusion in the left pleural cavity of the present case, the injection of fibrin glue into the left thoracic cavity successfully controlled the chylous pleural effusion and the chest tube was removed 13 days after the first injection. One reason why pleural effusion was controlled quickly is that, unlike pleurodesis with chemicals, the injection of fibrin glue into the thoracic cavity does not cause inflammatory responses such as fever and pain in patients; therefore, we were able to repeat the injections within a short time span. Autologous blood injection also does not induce so severe inflammatory responses and it may have reinforced the following fibrin glue treatment in the present case. An important factor for successful treatment is the injection of fibrin glue of high concentration into the pleural space at the second and third fibrin glue treatment application. This was easily achieved in the present case because the remaining pleural space was small and localized in the lower region adjacent to the mediastinum in the thoracic cavity due to prior pleurodesis. In addition, measuring volume of the space by injecting a contrast medium through the chest tube and obtaining fluoroscopic images, or possibly by CT volumetry, is also important in order to inject high concentration of fibrin glue in an appropriate amount of injection.
In summary, we report a patient with refractory chylothorax after lung transplantation for LAM who was successfully treated by injection of fibrin glue into the thoracic cavity. This treatment causes no fever and pain and can be repeated in a relatively shorter time, compared to pleurodesis with chemicals. Maintaining a high concentration of fibrin glue is a key to successful control of chylous effusion in this treatment.
The authors of this manuscript have no conflicts of interest to disclose as described by the Annals of Thoracic and Cardiovascular Surgery.