Fibrinolytic Therapy Versus Medical Thoracoscopy

Study Overview
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Brief Summary
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The purpose of this prospective randomized clinical trial is to compare two currently accepted standard-of-care treatment strategies: medical thoracoscopy as compared to instillation of intrapleural tissue plasminogen activator (TPA) and human recombinant deoxyribonuclease (DNase) for the management of complicated pleural infections in adults as defined as complicated parapneumonic effusions or pleural empyema.

Detailed Description
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Pleural infection (empyema or complex parapneumonic effusion [CPPE]) represents one of the common clinical diagnoses encountered in clinical practice in the United States (US) and worldwide. The incidence of pleural infection continues to rise with an annual incidence of approximately 65,000 in the US and United Kingdom (UK). It is associated with substantial morbidity and mortality as well as increased hospital costs despite advances in medical diagnostic and therapeutic strategies. The overall mortality of pleural infection approaches 20% and it is above 30% in elderly patients over 65 years and immunocompromised patients. Treatment of CPPE or empyema requires antibiotics and drainage of the pleural cavity.3 However, in about 30% of cases, it is difficult to remove the fluid due to loculations, septations and increased viscosity of the pleural fluid, and around 20% will need surgical intervention to adequately treat the pleural infection. Specific Aim 1: To compare the efficacy of early medical thoracoscopy versus fibrinolytic therapy (tPA/DNase) in patients with complicated parapneumonic effusions or pleural empyema. CPPE is defined as non-purulent effusion in a patient with clinical evidence of infection such as fever and/or elevated blood leukocyte count and/or elevated CRP, with pleural fluid pH ≤ 7.2 (measured by blood-gas analyzer), or pleural fluid glucose < 60 mg/dl or pleural fluid LDH >1000 IU/L26. Empyema is defined as pus within the pleural space and/or presence of bacteria on pleural fluid Gram stain or culture. For patients to be considered for the trial they need to fulfill one of the following criteria: 1) CPPE along with evidence of septated pleural effusion on pleural ultrasonography and/or chest CT scan or 2) empyema.

Official Title
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Fibrinolytic Therapy Versus Medical Thoracoscopy for Treatment of Severe Pleural Infection: A Randomized Clinical Trial

Conditions
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Pleural Diseases

Intervention / Treatment
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* Procedure: Chest thoracoscopy
* Procedure: Chest fibrinolytic therapy
* Drug: tPA
* Drug: DNase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CPPE along with evidence of septated pleural effusion on pleural ultrasonography and/or chest CT scan empyema. Exclusion Criteria: age <18 years; Pregnancy inability to give informed written consent; previous thoracic surgery or thrombolytic therapy for pleural infection; medical thoracoscopy cannot be performed within 48 hours; inability to tolerate procedure due to hemodynamic instability or severe hypoxemia; inability to correct coagulopathy; presence of a homogeneously echogenic effusion on pleural US27 -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomly assigned to receive one of two standard-of-care treatments for severe pleural infection.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Thoracoscopy Arm<br>Consisting of chest thoracoscopy | Procedure: Chest thoracoscopy<br>* Thoracoscopy will be performed as per standard protocols, with patient lateral decubitus position. Ten mLs of fluid will be collected to check for biomarkers. Adhesiolysis will be attempted and pleural irrigation will be done. At the end of the procedure, a drain will be inserted and connected to an underwater seal with a negative pressure suction<br>|
| Active Comparator: Fibrinolytic Therapy Arm<br>Consisting of chest fibrinolytic therapy | Procedure: Chest fibrinolytic therapy<br>* A chest tube will be inserted under ultrasonography into the most dependent area of the pleural effusion or into the largest loculation in patients with multi-loculated effusions. A of DNase and tPA will be given. Concurrent tPA and DNase will be administered intrapleurally through the chest tube followed by saline flush. The tube will then be clamped for 120 minutes and after which it will be connected back to wall suction. The intrapleural therapy will be given twice daily for a maximum of 6 doses.<br>Drug: tPA<br>* tPA administered intrapleurally through the chest tube followed by saline flush. The intrapleural therapy will be given twice daily for a maximum of 6 doses.<br>* Other names: Actilyse;Drug: DNase<br>* DNase administered intrapleurally through the chest tube followed by saline flush. The intrapleural therapy will be given twice daily for a maximum of 6 doses.<br>* Other names: pulmozyme;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of hospital days for treatment of complicated parapneumonic effusions or pleural empyema. | Time between initiation of treatment and hospital discharge | 2 days - 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of chest tube | The number of days, during the hospital admission, where the patient demonstrated chest tube drainage | 2 days - 1 week | 
| Duration of entire hospital stay for complete treatment of pleural infection | Number of days patient registered as in-house for treatment of pleural infection | 2 days - 1 week | 
| Treatment Failure | Following intervention, if patient requires (1) surgical intervention (VATS, open thoracotomy), (2) an additional chest tube, or (3) a repeat procedure | 2 days - 1 week | 
| Frequency of adverse events | Number of recorded adverse events during hospital stay | 2 days - 1 week | 
| Mortality | In hospital and 30 day mortality measures | 30 days | 
| Change in pleural fluid volume | Change in pleural fluid volume on chest CT scan from randomization (day 0) to prior to chest tube removal measured by radiologist blinded to treatment allocation using image J software | 2 days - 1 week |