Fibrinolytic Therapy Versus Medical Thoracoscopy for Treatment of Severe Pleural Infection: A Randomized Clinical Trial
Phase: PHASE4
Conditions: Pleural Diseases
Sponsor: University of Florida

STUDY TITLE: Fibrinolytic Therapy versus Medical Thoracoscopy for Treatment of Pleural Infection: A 
Randomized Clinical Trial 
NCT03213834 
Date of document: 06-APR-2017 

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Protocol Document: Fibrinolytic Therapy versus Medical Thoracoscopy for Treatment of Pleural 
Infection: A Randomized Clinical Trial  
 
 
Study Team: 
 
Principal Investigator: Hiren Mehta, MD 
Sub Investigator: Michael Jantz, MD 
Sub Investigator: Tan Lucien Mohammed, M.D. 
Other research staff:  Erin Silverman, Ph.D. CCRC; Jesse West, RN 
 
 
Overall Objective: 
 
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.  
 
Introductory Statement and Background: 
 
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).1 It is associated with substantial 
morbidity and mortality as well as increased hospital costs despite advances in medical 
diagnostic and therapeutic strategies.2-4 The overall mortality of pleural infection approaches 
20% and it is above 30% in elderly patients over 65 years and immunocompromised patients.1,5-
8 
 

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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.9,10 
 
Rationale: 
 
The intrapleural therapy of combined tissue plasminogen activator (tPA) and human 
recombinant deoxyribonuclease (DNase) in the management of pleural infection has been 
shown to improve the chest radiographic appearance at day 7 in the Multi-center Intra-pleural 
Sepsis Trial (MIST2).9 However, this approach is expensive, with a substantial hospital stay 
(around 12 days), and had a no significant decrease in the rate of surgery referral as compared 
to placebo.9 
 
Although two randomized studies have shown that around 80% of patients with pleural infection 
can be successfully managed medically, early surgical intervention is still considered a first-line 
treatment for pleural infection in some regions around the world 9,10. This approach has been 
justified on the basis of improved clinical outcome and shorter hospital stays for patients 
managed in this way.11-15 
 
Video-assisted thoracoscopic surgery (VATS) has been suggested as a surgical invasive 
approach to clear potentially infected material from the pleural space. In one small randomized 
and another non-randomized prospective trial comparing VATS with intercostal drainage plus 
intrapleural streptokinase, VATS was associated with decreased hospital stays and overall 
costs.16,17 However, there are several limitations that need to be mentioned. First, these two 
trials were under-powered studies without appropriate sample size calculation. Second, VATS 
was compared to intrapleural streptokinase. The intrapleural activity of endogenous 
plasminogen activator inhibitor (PAI-1) in the pathogenesis of pleural infection is important since 
this mediator not only directly inhibits streptokinase but has also been shown to contribute to the 
severity of loculation and poor outcomes with intrapleural fibrinolytic therapy.18-20 Third, large 
case series have shown that VATS is usually performed on a younger and less comorbid 
population (i.e. highly selected patients), compared to the unselected population of patients 
(which are usually sicker, elderly and have multiple comorbidities) with pleural infection seen in 
the fibrinolytic studies.9,10, 11,21 Moreover, failure to respond to medical fibrinolytic therapy might 

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necessitate invasive surgical intervention, such as VATS, or even open thoracotomy, at a later 
stage of the pleural infection where adequate clearance of the dense septations and thickening 
within and around the pleural cavity is needed to reverse lung restriction and improve 
compliance. However, clinical outcomes are unpredictable, with some patients having no long-
term sequelae but others showing permanent impairment of lung function. 
 
Medical thoracoscopy (MT) is a minimally invasive procedure that can be used to treat pleural 
infection through improving clearance by mechanical adhesiolysis and targeted drain 
placement. MT can also be used in patients who are not fit for general anesthesia by using local 
anesthesia and sedation. MT has shown to be safe and effective in the treatment of pleural 
infection in observational studies.22-25 However, to date, there are no randomized controlled 
trials addressing the potential role of early MT versus fibrinolytic therapy in empyema and 
complicated pleural infection. 
 
Proposal: 
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. 
Methods and Procedures: 
Study Design 
 
This prospective randomized trial will be conducted at UF Health Shands Hospital in 
accordance with Good Clinical Practice Standards and under IRB supervision. A large number 
of patients with pleural infection are treated at our institution, with a multidisciplinary team 
comprised of experienced interventional pulmonologists, chest radiologists and thoracic 
surgeons. We plan to enroll a total of 60 patients with pleural infection that will be randomized 
utilizing a computerized system to either medical thoracoscopy (thoracoscopy group) or 
fibrinolytic therapy (fibrinolytic group). 
 
Patient Population 

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Subjects (> 18 years of age) with either CPPE or empyema will be screened for inclusion. 
Screening logs recording reasons for non-trial entry will be kept. 
 
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 27 (Figure 1) or 2) empyema. 
 
 
Figure 1. Throracic ultrasound showing complex pleural effusion along with septation 
(arrowhead) 
 
Prescreening / Study exclusion criteria are as follows:  
1) age <18 years; 
2) pregnancy  
3) inability to give informed written consent;  
4) previous thoracic surgery or thrombolytic therapy for pleural infection;  
5) medical thoracoscopy cannot be performed within 48 hours;  
Complex septated 

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6) inability to tolerate procedure due to hemodynamic instability or severe 
hypoxemia; 
7) inability to correct coagulopathy;  
8) presence of a homogeneously echogenic effusion on pleural US27 (Figure 2). 
 
Figure 2. Thoracic ultrasound showing homogeneously echogenic loculated effusion 
 
Patients who agree to participate in the trial will sign an informed consent. Next, all patients will 
undergo diagnostic thoracentesis as per standard of care. In addition to standard of care testing 
on pleural fluid, an additional 10 mLs of fluid will be collected to check for markers like 
interleukin-8 and vascular endothelial growth factor. All patients will receive intravenous 
antibiotics according to local hospital guidelines and local microbiology results. Intravenous 
antibiotics will be changed to oral consolidation therapy by the managing consultant in light of 
the clinical response. Antibiotic therapy will be continued for between 2 and 6 weeks, as 
required per standard of care. 
 
Following diagnostic thoracentesis and confirmation of pleural infection, participants will be 
randomly assigned to either receive thoracoscopy (treatment arm) or fibrinolytic therapy (control 
arm). (Figure 3) 
 
Pleural effusion will be defined as loculated if it (1) has a lobulated shape with a convex boarder 
or (2) it is compartmentalized or accumulated in a fissure or a non-dependent portion of the 
pleura. On chest ultrasound the pleural effusion will be defined as loculated if it has fibrin 
homogeneously 
echoegenic 

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strands or septa floating inside the anechoic/hypoechoic pleural effusion(s) along with the 
presence of defined multiple pockets in the pleural cavity. 28 
Pain scores and general physical status will be assessed using a participant-completed 100-mm 
visual analog scale (VAS) upon randomization, at 6 weeks (via phone call) and 12 weeks follow 
up. 
 
Study Protocol I- Thoracoscopy (Treatment Arm) 
 
Patients will undergo medical thoracoscopy (rigid or semi-rigid) within 48 hours of 
randomization. A single port (with a maximum of 2 ports) will be placed and thoracoscopy will be 
performed under monitoring as per standard protocols, with the patient in a lateral decubitus 
position. The pleura will be carefully inspected through the thoracoscope under direct 
visualization.  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. As per standard of care, a chest CT without contrast will be performed when 
chest tube drainage is < 75 mLs and if there was no evidence of significant pleural effusion 
(<200 ml), the catheter will be removed 29 The fluid volume will be calculated by measuring the 
maximum perpendicular distance between the surface and the chest wall right above the 
diaphragm with at maximum inspiration in the most dependent position.29 Any need for 
additional drainage or administration of fibrinolytic or surgery will be considered treatment 
failure.  
 
II-Fibrinolytic Therapy (Control Arm) 
 
A chest tube (14-French or less) 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. 
The dose of DNase (Pulmozyme, Genentech, USA) will be 5 mg and the dose of tPA (Actilyse, 
Genentech, USA) will be 10 mg, each in 50 ml of 0.9% NaCl. The tPA and DNase will not be 
mixed together in one syringe. 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. As per standard of care, a chest CT without contrast will 
be performed when chest tube drainage is < 75 mLs and if there was no evidence of significant 

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pleural effusion (<200 ml), the catheter will be removed 29. Any need for additional drainage or 
more doses of fibrinolytic from the existing drainage over and above the 6 doses mentioned or 
surgery will be considered treatment failure.  
 
Study Outcome 
Primary outcome measure: 
• 
Duration of hospital stay after intervention, as defined as thoracoscopy in the 
treatment arm and first dose of fibrinolytic in the control arm 
 
Secondary outcome measures: 
 
• 
Number of days with chest tube drainage 
• 
Total length of hospital stay 
• 
Failure rate of assigned treatment necessitating intervention defined as any of 
the following: 
1-Surgical intervention (VATS, open thoracotomy) in either arm 
2-Need of additional chest tube and/or fibrinolytic therapy in the medical thoracoscopy 
arm due to clinical non-responsiveness 
3-Need of additional chest tube in the fibrinolytic therapy arm due to clinical non-
responsiveness 
• 
Adverse events 
o 
Pleural bleeding defined as drop in serum hematocrit requiring blood 
transfusion or causing hemodynamic instability 
o 
Significant pain requiring escalation of analgesia  
• 
In-hospital and 30-day mortality 
• 
Change in pleural fluid volume on chest CT scan from randomization (day 0) to 
prior to chest tube removal measured by radiologist (Mohammed) blinded to treatment 
allocation using image J software. Volume of pleural effusion will be obtained by 
examination of radiographic images obtained during the standard-of-care CT 
examination. 
• 
Infectious biomarker (CRP) from randomization (day 0), at removal of chest tube 
and 12 weeks as per standard of care 
• 
Total costs of each treatment modality in each treatment site 

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Sample Size and Statistical Analysis 
The difference in length of post-intervention hospital stay of 2 days between the two treatment 
arms would be clinically important. 
 
This rationale was based on previous large VATS case series reported by Luh and colleagues30 
in which the mean postoperative stay was 7.2 d ± 3.2 d versus 11.8 d±9.4 d from randomization 
to fibrinolytic therapy until discharge in the MIST2 trial9 and 10 d ± 1.8 d from first intrapleural 
treatment dose until discharge reported by Piccolo and colleagues.31 
 
To demonstrate this difference with 5% significance and 80% power, a minimum of 30 patients 
will be needed in each study group. Baseline characteristics will be compared between the two 
groups using Chi square, t tests, and Mann-Whitney U tests as appropriate. All data will be 
analyzed according to the intention-to-treat principle. A p value of ≤ 0.05 will be considered 
statistically significant. 
 
Significance 
To our knowledge, there are no randomized clinical trials evaluating the efficacy of early medical 
thoracoscopy versus fibrinolytic therapy in patients with pleural infection. This study should 
clarify the role of early medical thoracoscopy in patients with complicated parapneumonic 
effusions or pleural empyema. Currently, many centers worldwide primarily treat patients with 
pleural infection by placing a chest tube with pleural fibrinolysis. In case of failure of such an 
approach, which means that several treatment days are lost, a more invasive procedure is 
needed. By this time, significant pleural septae have formed, and often a surgical VATS or 
thoracotomy under general anesthesia becomes necessary. Therefore, this pivotal study could 
lead to changes in the management of patients with pleural empyema/CPPE. 
Human Subjects Will Be Used 
The research team will explain the details about the study to the patient. This discussion will 
also serve to answer any questions that the subject may have. Potential risks will be minimized 
by providing adequate time and opportunity for the subjects to review and ask questions about 
the study prior to consenting to participate. The subject will have an option to opt out of the 

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study at any point of time without any obligations or loss of treatments through UF Health 
Shands Hospital or other treatment centers.  
All collected data will be de-identified and linked to the subject by a unique identifying number. 
The data will be secured by the research team and will not affect patient care in any manner. 
The investigators will not use or disclose the means of record identification for any other 
purpose. The protected health information (PHI) will not be reused or disclosed to any other 
person or entity except for other research for which the use of the PHI would be permitted under 
the Privacy Rule.  
After enrollment, a number will be assigned to the subject. This number will be used for all study 
documents to maintain the privacy of the subject. The subjects will have the phone numbers of 
the study team members for any questions or concerns that might arise throughout the study 
period. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent form, will be 
obtained before that subject is submitted to any study procedure. 
 
No Animals or Biohazardous Materials Will Be Used. 
Risks and Benefits 
If successful, this study may improve standard of care treatment for pleural infection by 
clarifying which of two standard-of-care procedures produces superior clinical outcomes 
including decreased length of stay and decreased need for adjuvant / subsequent treatments 
following initial treatment for pleural infection. 
Risk associated with thoracentesis: 
a. 
Pain during placement (minor and controlled with anesthesia) 
b. 
Bleeding. During insertion of the needle, a blood vessel in the skin or chest wall 
may be accidentally nicked. Bleeding is usually minor and stops on its own. Sometimes, 

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bleeding can cause a bruise on the chest wall. Rarely, bleeding can occur into or around 
the lung and may require a chest tube or surgery. 
 
Collapsed lung. When the needle is being placed, it may puncture the lung. This 
hole may seal quickly on its own. If the hole does not seal over, air can leak out and 
build up around the lung. This build-up of air can cause part or all of the lung on that side 
to collapse (pneumothorax). If this happens, the doctor can place a chest tube between 
the ribs into the chest to remove the air that is leaking from the lung  
 
Risks associated with sedation: 
a. Drowsiness, slurred speech, tremor, fatigue, and low blood pressure, increase 
carbon dioxide in your blood, slowing of the heart rate, anxiety, confusion, dizziness 
and shivering 
b. .Respiratory depression. Trained medical professionals with extensive 
experience and expertise will administer these medications and will be responsible 
for monitoring the participant during the course of the procedure. 
 
Risks associated with thoracoscopy: 
a. 
Chest pain (5%). The nerves between the ribs are bruised after the procedure, 
which can cause some persistent pain. 
b. 
Air leak from lung (1-5%). A small hole develops in the lung. This means the 
chest tube has to stay in longer.  
c. 
Bleeding (< 1%). Usually it is minor and settles quickly. Bleeding is more 
common if you have been taking blood thinning drugs. 
d. 
Heart problems (< 1%). A brief minor strain may be put on the heart. This can 
cause abnormal beating of the heart, fluid to accumulate in the lungs, a heart attack, or 
the heart may stop beating.  
e. 
Low oxygen levels (< 1%). Participants will be administered oxygen if needed.  
f. 
Death(< 1%) as a result of this procedure is  uncommon.  
 
Risks associated with chest tubes: 

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a. 
Pain during placement—Discomfort often occurs as the chest tube is inserted. 
Doctors try to lessen any pain or discomfort by giving a local numbing medicine. The 
discomfort usually decreases once the tube is in place. 
b. 
Bleeding (<5%)—During insertion of the tube, a blood vessel in the skin or chest 
wall may be accidentally nicked. Bleeding is usually minor and stops on its own. Rarely, 
bleeding can occur into or around the lung and may require surgery. Usually bleeding 
can just be watched with the chest tube in place. 
c. 
Infection (< 5%)—Bacteria can enter around the tube and cause an infection 
around the lung. The longer the chest tube stays in the chest, the greater the risk for 
infection. The risk of infection is decreased by special care in bandaging the skin at the 
point where the tube goes into the chest. 
 
Risks associated with fibrinolytic therapy: 
a. 
Pain (15%)-While the medications are in the pleural space, participants may feel 
some discomfort. Usually such pain can be relieved by analgesics. 
b. 
Bleeding (5%)-While medications are in the pleural space, participants may 
experience bleeding inside the pleural space. Usually, it resolves with stopping 
medications. Rarely, blood transfusion might be need or require surgery. 
 
Privacy risks: As with any study, there is a risk that personal health information, collected 
during the course of research, may be disclosed. The research team will to everything within 
their power to mitigate and minimize this risk. The data collected both written and electronic will 
be held securely in a locked cabinet and secure server behind the UF Health firewall 
respectively. Only the study individual will be contacted and the questionaries’ administered in 
the privacy of a secluded clinic room. The data collected will be restricted to only the minimum 
amount necessary to accomplish the aim of the study.  
 
Risks associated with psychological stress: Participants may feel embarrassed or 
uncomfortable responded to questions. Participants will be informed that they may refuse to 
answer any of the questions and may take a break at any time during the study. Participants are 
also free to withdraw from the study at any time. 

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Conflict of Interest 
All research personnel associated with this protocol report no actual or perceived conflicts of 
interest. 

13 
 
 
Trial Entry / Prescreening 
1. Patients with pleural infection  
2. Fulfills inclusion criteria and does not meet exclusion criteria 
3. Written informed consent is obtained 
Randomization  
Thoracentesis  
Medical Thoracoscopy 
Fibrinolytic therapy (TPA/Dnase)  
Follow- up (Post Intervention)  
Inpatient/ Outpatient assessment for data collection as standard of care 
•
General physical status and pain scale scores at 6 and 12 weeks (telephone 
assessment or clinic visit)  
•
Death  
Figure 3. Proposed Study Protocol  
Screening  

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References 
1- 
Light RW, Girard WM, Jenkinson SG, et al. Parapneumonic effusions. Am J Med 
1980; 69: 507–512 
2- 
Grijalva CG, Zhu Y, Nuorti JP, et al. Emergence of parapneumonic empyema in 
the USA. Thorax 2011;66:663-8 
3- 
Davies HE, Davies RJO, Davies CWH; the BTS Pleural Disease Guideline 
Group. Management of pleural infection in adults: British Thoracic Society pleural disease 
guideline 2010. Thorax 2010;65 (suppl 2):ii41–ii53 
4- 
Søgaard M, Nielsen RB, Nørgaard M, et al. Incidence, length of stay, and 
prognosis of hospitalized patients with pleural empyema: a 15-year Danish nationwide 
cohort study. Chest 2014; 145:189-92 
5- 
Davies HE, Davies RJ, Davies CW, and the BTS Pleural Disease Guideline 
Group. Management of pleural infection in adults: British Thoracic Society Pleural 
Disease Guideline 2010. Thorax 2010; 65 (suppl 2): ii41–53 
6- 
Ferguson AD, Prescott RJ, Selkon JB, et al. The clinical course and 
management of thoracic empyema. QJM 1996; 89: 285–289 
7- 
Davies CW, Kearney SE, Gleeson FV, et al. Predictors of outcome and long-term 
survival in patients with pleural infection. Am J Respir Crit Care Med 1999; 160: 1682–
1687 
8- 
Alemán C, Alegre J, Monasterio J, et al. Association between inflammatory 
mediators and the fibrinolysis system in infectious pleural effusions. Clin Sci 2003; 105: 
601–607 
9- 
Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, Peckham D, 
Davies CW, Ali N, Kinnear W, et al. Intrapleural use of tissue plasminogen activator and 
DNase in pleural infection. N Engl J Med 2011; 365:518–526 
 
10- 
Maskell NA, Davies CW, Nunn AJ, Hedley EL, Gleeson FV, Miller R, Gabe R, 
Rees GL, Peto TE, Woodhead MA, et al.; First Multicenter Intrapleural Sepsis Trial 
(MIST1) Group. U.K. controlled trial of intrapleural streptokinase for pleural infection. N 
Engl J Med 2005; 352:865–874 
11- 
Marks DJ, Fisk MD, Koo CY, et al. Thoracic empyema: a 12-year study from a 
UK tertiary cardiothoracic referral centre. PLoS One 2012; 7: e30074 

15 
 
12- 
Suchar AM, Zureikat AH, Glynn L, Statter MB, Lee J, Liu DC. Ready for the 
frontline: is early thoracoscopic decortication the new standard of care for advanced 
pneumonia with empyema? Am Surg 2006; 72: 688–92 
13- 
Solaini L, Prusciano F, Bagioni P. Video-assisted thoracic surgery in the 
treatment of pleural empyema. Surg Endosc 2007; 21: 280–84. 
14- 
Chung JH, Lee SH, Kim KT, Jung JS, Son HS, Sun K. Optimal timing of 
thoracoscopic drainage and decortication for empyema. Ann Thorac Surg 2014; 97: 224–
29 
15- 
Schweigert M, Solymosi N, Dubecz A, et al. Surgical management of pleural 
empyema in the very elderly. Ann R Coll Surg Engl 2012; 94: 331–35 
16- 
Wait MA, Sharma S, Hohn J, Dal Nogare A. A randomized trial of empyema 
therapy. Chest 1997; 111: 1548–51 
17- 
Lim TK, Chin NK. Empirical treatment with fibrinolysis and early surgery reduces 
the duration of hospitalization in pleural sepsis. Eur Respir J 1999; 13: 514–18 
18- 
Komissarov AA, Florova G, Azghani A, Karandashova S, Kurdowska AK, Idell S. 
Active α-macroglobulin is a reservoir for urokinase after fibrinolytic therapy in rabbits with 
tetracycline induced pleural injury and in human pleural fluids. Am J Physiol Lung Cell 
Mol Physiol 2013; 305: L682–92 
19- 
Karandashova S, Florova G, Azghani AO, et al. Intrapleural adenoviral delivery of 
human plasminogen activator inhibitor-1 exacerbates tetracycline-induced pleural injury in 
rabbits. Am J Respir Cell Mol Biol 2013; 48: 44–52 
20- 
Florova G, Azghani A, Karandashova S, et al. Targeting of plasminogen activator 
inhibitor 1 improves fibrinolytic therapy for tetracycline-induced pleural injury in rabbits 
Am J Respir Cell Mol Biol 2015; 52: 429–37 
21- 
Farjah F, Symons RG, Krishnadasan B, Wood DE, Flum DR. Management of 
pleural space infections: a population-based analysis. J Thorac Cardiovasc Surg. 2007; 
133: 346–51 
22- 
Brutsche MH, Tassi GF, Györik S, et al. Treatment of sonographically stratified 
multiloculated thoracic empyema by medical thoracoscopy. Chest 2005; 128: 3303–09 
23- 
Ravaglia C, Gurioli C, Tomassetti S, et al. Is medical thoracoscopy efficient in the 
management of multiloculated and organized thoracic empyema? Respiration 2012; 84: 
219–24 
24- 
Soler M, Wyser C, Bolliger CT, et al. Treatment of early parapneumonic 
empyema by “medical” thoracoscopy. Schweiz Med Wschr 1997; 127: 1748–1753 

16 
 
25- 
Tacconi F, Pompeo E, Fabbi E, Mineo TC. Awake video-assisted pleural 
decortication for empyema thoracis. Eur J Cardiothorac Surg 2010; 37: 594–601 
26- 
Heffner JE, Brown LK, Barbieri C, et al. Pleural fluid chemical analysis in 
parapneumonic effusions. A meta-analysis. Am J Respir Crit Care Med. 
1995;151(6):1700. 
27- 
Chen KY, Liaw YS, Wang HC, Luh KT, Yang PC. Sonographic septation: 
a useful prognostic indicator of acute thoracic empyema. J Ultrasound Med. 2000 
Dec;19(12):837-43 
28- 
Arenas-Jiménez J, Alonso-Charterina S, Sánchez-Payá J, Fernández-Latorre F, 
Gil-Sánchez S, Lloret-Llorens M. Evaluation of CT findings for diagnosis of pleural 
effusions. Eur Radiol. 2000;10(4):681-90 
29- 
Eibenberger KL, Dock WI, Ammann ME, Dorffner R, Hormann MF, Grabenwoger 
F. Quantification of pleural effusions: sonography versus radiography. Radiology 1994; 
191:681–684 
30- 
Luh SP, Chou MC, Wang LS, Chen JY, Tsai TP Video-assisted thoracoscopic 
surgery in the treatment of complicated parapneumonic effusions or empyemas: outcome 
of 234 patients. Chest. 2005 Apr;127(4):1427-32 
31- 
Piccolo F, Pitman N, Bhatnagar R, et al. Intrapleural tissue plasminogen activator 
and deoxyribonuclease for pleural infection. An effective and safe alternative to surgery. 
Ann Am Thorac Soc 2014; 11:1419-25