Intrapleural Fibrinolysis in Post-tubercular Loculated Pleural Effusions at a Tertiary-Care Respiratory Center : An Uncontrolled Blinded Before-After Intervention Study

Copyright © 2018 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http:// creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1. Background Loculated pleural effusions usually occur as a result of adhesions and sequelae of complicated tuberculosis, parapneumonic effusion, empyema, haemothorax and malignant effusions.1,2 The loculations result due to delay in initiating treatment, inappropriate use of antibiotics and long standing pleural effusion. Delayed hypersensitivity responses to Mycobacterium tuberculosis is implicated in the causation of pleural effusion in tuberculosis.3-5 The presence of septae lead to formation of loculi resulting in poor drainage despite appropriately positioned patent intercostal tube, thereby increasing the susceptibility to device-associated secondary infections by emerging multidrug resistant organisms acquired in the hospital environment.6-9 The consequential fibrosis of pleural cavity leads to pleural thickening and compromised pulmonary function, posing a therapeutic challenge for life. Early and effective drainage of pleural effusion reduces Abstract

residual pleural thickening and helps in faster recovery of pulmonary function in patients with loculated pleural effusions. 10Fibrinous locules in infected pleural cavity become a major hindrance for effective drainage of pleural effusion.Ultrasound guided catheter insertion and drainage is considered safe and effective procedure in pleural effusion, however the success rate is low when the effusion is loculated and septate. 11,12Video assisted thoracic surgery (VATS) in loculated effusions is undoubtedly a better option, however it is both inaccessible and expensive option for vast majority of the population in resource limited facilities/communities.Open surgical modalities are more invasive and may be inaccessible or unaffordable by patients in developing countries. 13Various agents used as fibrinolytics like streptokinase, urokinase and tissue Plasminogen Activator can be used intra-pleurally. 14,15lthough there are existing controversies in the choice of fibrinolytic drug, 33 000 kDa low-molecular-weight urokinase is preferred over streptokinase due to rapid plasma half-life and ability to directly activate plasminogen to form plasmin. 16,17 In developing country set up, where tuberculosis is widely prevalent, it is essential to identify appropriate, effective and economical treatment modality for loculated pleural effusion so as to reduce the burden of its sequelae.

Objective
A pre-post intervention study to determine the effectiveness of intra-pleural fibrinolytic therapy (IPFT) using urokinase in patients with loculated pleural effusions was conducted at a tertiary-care respiratory centre after approval and written informed consent.

Methods
The present study was conducted as an uncontrolled, blinded, before-after intervention study in a 600-bedded Indian tertiary-care respiratory centre after approval by Institutional Ethics Committee and written informed consent of all patients.All 51 patients with persistent pleural fluid and poor chest-tube drainage despite an appropriately positioned and patent drain; multiple loculi or fibrin strands in pleura as depicted by ultrasonography or CT scan chest were included in the study.Patients who were less than 18 years of age, or having haemothorax, haemorrhagic pleural effusion, known sensitivity to urokinase, or any contraindications to thrombolytic therapy like haemorrhagic stroke, intracranial neoplasm, cranial surgery or head trauma within 14 days, major thoracic or abdominal surgery within ten days, and PT INR greater than 2 were excluded from the study.
On clinical suspicion of pleural effusion, chest radiography was done followed by ultrasonography for confirmation and quantification of fluid.Presence of loculations and marking of chest wall for site of insertion of chest drain was done with ultrasonographic assistance.Chest tube or pigtail thoracostomy catheter was inserted using strict aseptic precautions and fluid drained daily was noted.Patients with persistent fluid and poor tube drainage despite an ultrasonography-confirmed appropriately positioned and patent drain or multiple loculi or fibrin strands, depicted by ultrasonography or CT scan of chest, were included in the study for IPFT.Three doses of 100 000 IU of low molecular weight urokinase in 100 ml isotonic 0.9% sodium chloride solution were instilled in the chest tube at eight hours interval.Tube was clamped for 2 hours after instillation of each dose.Clinical response along with daily and cumulative drainage of pleural fluid was noted.X-ray and ultrasonography of chest was done after 48 hours after the instillation of last dose of urokinase.Patients with insignificant drainage and insignificant reduction in amount of fluid less than 50% radiologically were subjected to a repeat cycle of 3 doses.Chest tube was removed when both daily drainage of clear pleural fluid was less than 50 mL and ultrasonography chest showed presence of less than 50 mL of fluid in pleural cavity.Expansion of the lung was assessed radiologically by chest x-ray taken before and after the administration of urokinase.The reduction in the amount of pleural fluid by ultrasonography after IPFT was calculated.Spirometry was done after 48 hours of removal of chest tube.Pre and post-IPFT clinical and radiological response by removal of fluid, ultrasound, chest radiography and forced vital capacity were compared.The respiratory physician, sonologist, radiologist and spirometrist were blinded at all steps of the intervention study.
Data was entered and analyzed in IBM SPSS version 21.0.Means and proportions were calculated for continuous and categorical variables.Kolmogorov-Smirnov test was used for Normality test.A p value of less than 0.05 was considered statistically significant.

Results
Out of 51 patients, majority of the study participants (41.2%) were in the age group of 30-50 years, with an overall predominance of males (90.2%).Among all the study participants tuberculosis was the most common etiology (80.0%) leading to loculated pleural effusion followed by three cases of pneumonia with parapneumonic effusion and seven cases of malignant pleural effusion.Right-sided pleural effusion was more common (58.8%) than left-sided (35.3%).Three patients had bilateral pleural effusion and out of them two were more than 50 years of age (Table 1).All seven patients with malignant pleural effusion were more than 40 years of age including three females.There were four smokers.Five patients had primary carcinoma lung, one carcinoma breast with metastasis and another underwent diagnostic thoracoscopy to establish the diagnosis of malignant pleural effusion.
82.4% study participants required at least 2 cycles of IPFT before noticeable resolution in post-IPFT chest radiograph was observed in 80.4%.New onset undesired effects associated with IPFT included chest pain (13.7%) and fever (9.8%), however a vast majority of 76.4% of them did not report any.No bleeding was seen in any patient.Undesired effects did not require cessation of IPFT.No patients required more than three cycles of urokinase (Table 2).
Statistically significant differences in mean intra-pleural fluid present before and after IPFT from 184.51 ± 81.1 mL to 67.84 ± 52.1 mL was seen.Significant improvement in lung function post-IPFT was seen (Table 3).
The use of IPFT in malignant pleural effusion resulted in improvement of symptoms and helped prepare the patient for chemical pleurodesis which was attempted before ICD removal.

Discussion
Treatment of loculated pleural effusion was always challenging, considering the controversies existing in the modalities of treatment and sequelae.The present study evaluated the effectiveness of urokinase as intra-pleural fibrinolytic agent in treatment of patients with loculated pleural effusion.These patients represent those individuals who usually do not respond to traditional modes of treatment for tubercular/parapneumonic/malignant pleural effusion.6][17][18][19] Pleural fluid present despite a radiologically confirmed correctly positioned intercostal drainage tube represents multiple locules in pleural cavity or tube obstruction due to increased viscosity of fluid.][20][21] IPFT with urokinase in loculated pleural effusion resulted in statistically significant reduction in the residual amount of fluid as noted by other researchers. 18][24] There is a dearth of studies on the use of urokinase for IPFT from developing countries despite its proven efficacy in the management of loculated pleural effusion from developed world.The present study establishes the effectiveness of urokinase as IPFT for loculated pleural effusion in a developing country set up.It prevents surgical decortication in large number of patients, an intervention associated with significant morbidity.IPFT has minimal and tolerable undesired effects and prevents sequelae such as pleural thickening and consequent compromise of respiratory function.It is easy to administer in a hospital set up and can be monitored by bedside ultrasonography.Morphological (hemorrhagic, serosanguinous, serous), cytological, biochemical (glucose and lactate dehydrogenase) and special (Interferon gamma and adenosine deaminase for tuberculosis) examination of aspirated pleural fluid may be required to differentiate various exudative pleural effusions.IPFT can also be administered in patients who have been subjected to What Is Already Known?Tuberculous, parapneumonic and traumatic loculated pleural effusions pose a therapeutic challenge due to the resultant pleural thickening and compromised lung function for life.

What This Study Adds?
IPFT with urokinase is an effective treatment modality in patients with post-tubercular loculated pleural effusions.IPFT has minimal and tolerable side effects and prevents sequelae such as pleural thickening and the consequent compromise of respiratory function.
Research Highlights flushing with isotonic saline, placement of more catheters in loculi after ultrasound localization, thoracoscopic debridement and thoracotomy along with decortications, as IPFT does not require pre-conditioning. 25he possible limitations of the study include lack of control group of patients which was a consideration of the ethical issues.The intervention demonstrated improvement in pleural fluid drainage and lung function irrespective of the cause of effusion.The outcomes of the present study should be generalised with caution as the study population was not representative in terms of age and sex distribution.Being a single institutional experience of IPFT, infrastructural, logistic and procedural limitations need to be accounted for. 26

Conclusion
IPFT with urokinase is an effective treatment modality in patients with post-tubercular loculated pleural effusions, preventing surgical decortications which is associated with significant morbidity.IPFT has minimal and tolerable undesired effects and prevents sequelae such as pleural thickening and consequent compromise of respiratory function.