Conditions: Parapneumonic Effusion Empyema, Pleural Coagulopathy
Keywords: VATS Decortication Surgical Pleural Decortication Fibrinolytic Therapy Pneumonia Thoracostomy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 10
Healthy volunteers: no

Brief summary:
This study aims to standardize the treatment of pleural space (parapneumonic) infections by comparing the difference in outcomes between 2 methods of treatment: early VATS (Video Assisted Thorascopic Surgery) decortication versus fibrinolytic therapy. During treatment, the patient's coagulopathy status will also be evaluated.

Detailed description:
The treatment of parapneumonic infections (infection in the pleural space) at the Denver Health Medical Center is not standardized, and timing for advanced interventions such as fibrinolytic therapy or surgical decortication remain unclear. The definitive treatment strategy in these patients may be sub-optimal, and lead to prolonged hospitalization and morbidity. This is concerning as the mortality rate of community acquired pneumonia triples in the presence of a parapneumonic process (5-15%) and can reach over 25% if it becomes bilateral(1). Prompt recognition of pleural space infections is essential for reducing morbidity and mortality. This is attributable to the progression of the disease from a simple fluid collection amenable to pleural space drainage, to necrotizing empyema requiring thoracotomy decortication and open drainage. The keys to management of parapneumonic effusions are early diagnosis, appropriate therapeutic intervention, and recognition of failure of conservative management. The investigators propose that a standardized pathway for identifying and treating parapneumonic effusions will be an important quality improvement. A key gap in the literature remains if patients with parapneumonic infections that cannot be drained with a chest tube should undergo a trial in intrapleural fibrinolytic therapy, or if they should go directly to video assisted thoracic surgery (VATS) for decortication of all infectious material.

Arms:
arm 1: Operative group that will undergo early VATS decortication of complicated parapneumonic effusion/empyema arm 2: Non-operative group that will undergo instillation of the drugs DNAse and tPA (tissue plasminogen activator) together i.e. 5mg DNAse and 10mg tPA twice a day for up to six doses, through chest tube as treatment of the patient's complicated parapneumonic effusion/empyema. Fibrinolytic therapy = DNAse + tPA; these medications are not mutually exclusive.

Interventions: intervention 1: VATS Decortication intervention 2: Fibrinolytic Therapy
Intervention descriptions: intervention 1: Surgical procedure to unroof all located collections of the pleural space through a chest wall incision intervention 2: Instillation of DNAse and tPA together through patient's chest tube already in placed to break down complex fluid collection in the pleural space. DNAse and tPA are are administered together only i.e. are not mutually exclusive.

Protocol document:
Prot_SAP_000.pdf: 
 
1 
w 
COMIRB Protocol 
 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
 
Protocol #: 17-0857 
Project Title: Early Intervention for Complicated Parapneumonic Effusion: Ran-
domized Controlled Trial for Fibrinolytic Therapy vs. VATs Decortica-
tion 
 
 
 
Principal Investigator: Pieracci 
Version Date: 
 
7/30/2019  
 
 
 
I. 
Hypotheses and Specific Aims 
Early VATS decortication in patients with complicated parapneumonic ef-
fusion unable to be drained by image thoracostomy tube reduces hospi-
talization time and is more cost effective than fibrinolytic therapy. 
 
Specific aims: 
1: Standardize a method for identifying patients with complicated parap-
neumonic effusions that require a secondary intervention to clear infec-
tion from pleural space 
 
2: Contrast outcomes in patients who undergo early VATS decortication 
vs. fibrinolytic therapy for complicated parapneumonic effusion 
 
3: Contrast the cost of early VATS decortication vs. fibrinolytic therapy for 
complicated parapneumonic effusion 
 
4: Contrast the complications associated with early VATS decortication 
vs. fibrinolytic therapy for complicated parapneumonic effusion 
 
5: Assess patient’s coagulation status while undergoing each intervention 
 
II. Background and Significance 
 
Introduction 
The treatment of parapneumonic infections (infection in the pleural space) at 
the Denver Health Medical Center is not standardized, and timing for advanced in-
terventions such as fibrinolytic therapy or surgical decortication remain unclear.  
The definitive treatment strategy in these patients may be sub-optimal, and lead to 
prolonged hospitalization and morbidity.  This is concerning as the mortality rate of 


 
2 
community acquired pneumonia triples in the presence of a parapneumonic process 
(5-15%) and can reach over 25% if it becomes bilateral(1).  Prompt recognition of 
pleural space infections is essential for reducing morbidity and mortality.  This is at-
tributable to the progression of the disease from a simple fluid collection amenable 
to pleural space drainage, to necrotizing empyema requiring thoracotomy decortica-
tion and open drainage. The keys to management of parapneumonic effusions are 
early diagnosis, appropriate therapeutic intervention, and recognition of failure of 
conservative management.  We propose that a standardized pathway for identifying 
and treating parapneumonic effusions will be an important quality improvement.  A 
key gap in the literature remains if patients with parapneumonic infections that can-
not be drained with a chest tube should undergo a trial in intrapleural fibrinolytic 
therapy, or if they should go directly to video assisted thoracic surgery (VATS) for 
decortication of all infectious material. 
 
Physiology of Pleural Space Fluid Shifts 
 
  
Appreciation of the pleural space physiology helps conceptually understand 
the progression of pleural space disease. This is an active region of fluid exchange 
due to the leaky pleural membrane and negative pressure of the pleural space(2). 
The fluid originates predominantly from the parietal capillaries because of hydro-
static pressure, augmented by the negative pressure of the pleural space. Less fluid 
is produced by the visceral pleura because the hydrostatic pressure is attenuated by 
pulmonary venous drainage. However, the visceral surface will add more pleural 
fluid with increased pulmonary interstitial pressure. A small volume of fluid is nor-
mal in the pleural space, but healthy individuals should have less than 4 mm of de-
pendent pleural fluid on decubitus ultrasound.(3) 
 Clearance of fluid from the pleural space is accomplished by lymphatics.  The 
visceral mesothelium of the pleural space is intricately connected to the lung paren-
chyma, whereas the parietal layer is more loosely connected to the thoracic struc-
tures separated by a variable fatty layer. The parietal pleura has specialized areas 
known as stoma, and an extensive lymphatic network exists below which is the pre-
dominant route of fluid resorption located at the dependent portion of the chest cav-
ity(4). Under normal conditions, it is estimated that each pleural cavity generates 
0.2 to 0.4 mL/kg per hour. The capacity for pleural fluid absorption is thought to ex-
ceed 500 mL of fluid from each cavity with an intact lymphatic system. Overall, the 
accumulation of pleural fluid is the result of a dynamic system of fluid production 
and absorption. Pathology of the pleural space tends to shift extra fluid into the re-
gion from increased oncotic drive due to increased particulate, increased permeabil-
ity of the pleural membrane, and decreased lymphatic clearance. 
 
 
 
 
 
 
 


 
3 
 
Evolution of Pleural Space Infection to Empyema 
 
Complicated parapneumonic effusions, and ultimately empyema, develop in 
three conceptual phases(5, 6). The early phase is a sterile effusion caused by paren-
chymal inflammation that activates mesothelial cells and enhances capillary perme-
ability, termed exudative (days 2–5). This is thought to be driven by proinflamma-
tory cytokines, including interleukin 8 and tumor necrosis factor-[alpha].(6) Ulti-
mately, the volume of fluid traversing into the pleural cavity exceeds the capacity to 
reabsorb the fluid and an effusion develops. The second phase is termed fibropuru-
lent, which is initiated by bacterial infection (days 5–10). At this point, the immune 
system is activated and the once hypocoagulable environment is changed dramati-
cally. 
 Bacterial and neutrophil activity acidify the fluid, consume glucose, increase 
protein content, and release lactate dehydrogenase (LDH) from cellular apoptosis 
and necrosis. The environment now becomes hypercoagulable because of the inte-
grated responses of the innate immune and coagulation systems.(7, 8) These find-
ings are directly relevant to the evolution of complicated effusions because the exu-
berant fibrin deposition is a concerted effort to control progressive infection. The fi-
nal state of a complicated effusion is referred to as the organization phase (days 10–
21). Fibroblasts migrate into the pleural space and create a dense fibrotic lining of 
the visceral and parietal surfaces. This phase is thought to be driven by regenerative 
cytokines, for example, transforming growth factor-[beta] and platelet-derived 
growth factor released primarily from activated mesothelial cells.(9) The net result 
is a progressive rind that encases the lung, reducing ventilatory capacity and se-
questering bacteria.  
 
 
Risk Factors and Bacteriology of Pleural Space Infection 
 
 
There are over a million patients hospitalized for pneumonia a year and 10% 
of these patients will develop a pleural space infection(10). Patients who present to 
the hospital with pneumonia have an increased risk for pleural space infection if 
they have a history of IV drug use and alcohol abuse(11), age less than 60(12), and 
male gender(13).  Nosocomial pneumonia have a higher rate of pleural space infec-
tion and have reported needs for operative intervention in up to a third of pa-
tients(14). The incidence of pleural infection in trauma patients with thoracic inju-
ries is around 3%.(15) Risk factors for developing a post-traumatic empyema in-
clude multiple rib fractures, thoracostomy tube placed in the emergency depart-
ment, and underlying pulmonary contusion.  Another risk factor is placement by 
non-surgical specialty (16). This has clinical significance as a retained post-trau-
matic hemothorax has the highest risk for empyema, with an infection rate of over 
25%(17).   
 
A Gram stain and culture of the pleural fluid is often beneficial in directing 
management in pleural space infection, although 20% to 40% of the time, there is no 
reported identifiable pathogen.(12, 18, 19). However, the patient’s history is often 
helpful when directing empiric antibiosis while waiting for gram stains and cultures 
to finalize.   In empyema associated with community-acquired pneumonia, the most 


 
4 
common pathogen Streptococcus milleri (32%), whereas if hospital acquired, it was 
methicillin-resistant Staphylococcus aureus (28%). Patient characteristics, including 
diabetes, alcoholism, age older than 60 years, and trauma are associated with more 
anaerobic and resistant gram-positive organisms.(20) Hospital-acquired empyema 
is reported to have a fourfold greater risk of death compared with community ac-
quired.(12)  S. milleri is a commonly identified pathogen in patients who have un-
dergone surgical intervention of the chest or upper digestive tract and often require 
decortication.(21) Because of the differences in bacteriology of pleural space infec-
tions an adequate history of patients with parapneumonic processes (community vs. 
hospital acquired pneumonia, vs. chest space intervention) is essential for guiding 
early antibiosis.(22) Of note, although most antibiotics penetrate the pleura well, 
aminoglycosides may be inactivated at a lower ph.(23)  
 
 
Diagnosis of Pleural Space Infection  
 
Radiographic identification of an effusion in a patient with a systemic inflam-
matory response syndrome (SIRS) does not necessarily correlate with a pleural 
space infection.  Only 1 in 4 patients with an effusion associated with a CAP ulti-
mately require drainage of the pleural space.(1) The next step in management of an 
effusion is quantifying the volume of fluid.  The standard method to estimate the 
amount of pleural fluid has been the lateral decubitus chest x-ray(24). Recent com-
parative studies indicate that ultrasound is a more reliable method to quantitate a 
pleural effusion (24-26). As previously mentioned, an effusion measured up to 4 mm 
is considered normal.(3) Clinical studies by Light et al.(10) indicated that infections 
involving an effusion of less than 10 mm will resolve with antibiotics alone, and this 
has been supported by subsequent series.(27, 28).  Therefore patients with large ef-
fusions on upright films or CT images should proceed to drainage of the pleural 
space with a chest tube.  Patient with smaller effusions should have a bedside esti-
mate of the volume of fluid in their chest with ultrasound, and those with fluid levels 
less than 10 mm in height are likely to have resolution of their symptoms with anti-
biotic therapy alone.  
If the decision is made to perform a thoracentesis of the pleural space, the 
fluid removed should undergo evaluation for an active infection.  Gross purulence 
(empyema) at the time of thoracentesis is unusual but constitutes an indication for 
prompt video-assisted thoracoscopic surgery (VATS) decortication.(5) In all other 
circumstances, the pleural fluid should be submitted for laboratory analysis. The 
traditional technique to distinction an exudative versus transudative effusion is via 
Light’s criteria: protein greater than 0.5 serum, LDH greater than 0.6 serum, or LDH 
greater than two-thirds normal serum.(29) However, the most cost-effective means 
to analyze this is to measure the pH of the pleural fluid using a standard blood gas 
analyzer, available in most intensive care units. A pH less than 7.2 is the threshold, 
although less than 7.3 is considered high risk. (30-32) An exception is a Proteus in-
fection where the pH may exceed 7.4 because of ammonia production.(6) An alter-
native diagnostic criterion is a pleural fluid glucose less than 60 mg/dL when infec-
tion is suspected.(6) Because the evolution of an empyema may extend for days to 
weeks and the early phase is a sterile effusion, a repeat diagnostic thoracentesis 


 
5 
should be done in any patient with a persistent unexplained SIRS and unilateral 
pleural effusion.(5) 
 
Early Management of Pleural Space Infection  
 
 
Those patients with fluid tested in the chest space concerning for pleural in-
fection require empiric antibiotic treatment to cover suspected pathogens in addi-
tion to tube thoracostomy drainage.  The exception is in patients with gross puru-
lence aspirated from the pleural space that should under go prompt operative de-
cortication. The optimal size of the chest tube remains debated,(33, 34) but a 18F 
seems effective in removing this hypercoaguable fluid. This is a grade B recommen-
dation. These smaller chest tubes are associated with less chest wall pain than blunt 
dissection–inserted tubes, without compromise in clinical outcome. The position of 
the chest tube, however, is important.(34) The tube should be placed in the poste-
rior (dependent) pleural space and not within a pulmonary fissure. We have ob-
served that the typical “trauma” chest tube introduced through the fifth intercostal 
space (ICS), at the mid–axillary line, favors fissure placement. Consequently, we rec-
ommend ultrasonography-guided tube insertion via the sixth intercostal space. But 
this is based on our unpublished experience. A Gram stain and culture of the pleural 
fluid should be obtained at the time of tube thoracostomy to differentiate the organ-
ism, although as previously mentioned up to 40% if the time no pathogen may be 
found. More recent techniques such as countercurrent electrophoresis, latex aggluti-
nation, or bacterial DNA detection by polymerase chain reaction could in theory im-
prove pathogen identification, but are not currently standard of care in the clinical 
setting.(30)   
 
After tube placement vigilant follow up of chest tube output and changes in 
radiographic appearance are critical.  Pleural collections persisting for more than 24 
hours warrant prompt computed tomographic (CT) imaging for evaluation of the 
entire thoracic space.(9, 29).  Delay in diagnosis of an undrained simple fluid collec-
tion allows progression to a complex multilocular process and the final organization 
stage.(35) As Sahn and Light(28) stated in 1989, “the sun should never set on a 
parapneumonic effusion”; early diagnosis and treatment of complicated pleural in-
fection is essential for optimal outcomes. CT images are crucial for the next step in 
the management of pleural space infections that have not resolved with tube drain-
age as this dictates operative versus fibrinolytic therapy. 
 
 
Fibrinolysis Therapy for Treating Pleural Space Infections 
 
The rationale for obtaining a CT scan 24 hours after failure of appropriate 
tube drainage for a pleural infection is for recognition of a persistent pleural collec-
tion trapped via thin fibrin septa.  This fibrin deposition likely had an initial protec-
tive role. The prehistoric horseshoe crab uses a unique protease, Factor C, to initiate 
coagulation in the presence of endotoxin, trapping and killing pathogens(36). This 
has been extrapolated to animal models, in which it has been demonstrated that 
anti-fibrinolysis is protective in gram-negative infection(37).  However excessive fi-
brin deposition maybe pathologic and impaired fibrinolysis has recently been 


 
6 
described ventilated patients(38).  It has become increasingly apparent that the ma-
jority of patients with sepsis(39) or sustaining significant injury(40) have resistance 
to fibrinolytic activity and prone to developing organ failure from what is believed 
to be micro vascular fibrin deposition. This translates to the pleural space, where fi-
brin deposition is appreciated during inflammation and infection.(41) This early fi-
brin deposition may help contain the pathogen with impending progressive infec-
tion.  Pathologic fibrin deposition occurs when the body is unable to clear the patho-
gen and the speta become thickened, rendering chest tube drainage ineffective.  The 
proposed therapeutic option is to medically breakdown these fibrin depositions by 
up regulating the fibrinolytic system.  
The first report of fibrinolytic therapy in the pleural space was by Tillett and 
Sherry(42) in 1949. They infused purified hemolytic streptococcal concentrates, 
presumed to contain streptokinase and deoxyribonuclease (DNase). Although ap-
parently safe, there was no documented improvement in patient outcome during the 
ensuing 60 years. The first randomized trial, by Davies et al.(43) in 1997, demon-
strated radiographic improvement in 24 patients but no discernible clinical benefit. 
This was followed by a number of underpowered randomized studies in Europe, 
suggesting that urokinase demonstrated a therapeutic value.(44, 45) These conflict-
ing results led to the MIST I study(46) involving 52 hospitals in the United Kingdom 
with 412 randomized patients. The data indicated that 72 hours of streptokinase 
treatment resulted in no improvement in mortality, rate of surgery, or length of stay 
and was associated with an increased rate of serious adverse events. This study was 
criticized for including a heterogeneous mix of patients with different comorbidities 
and different stages of pleural disease.(47) A subsequent Cochrane review in 
2008(48) noted that there was a discordance between earlier studies and the MIST I 
data and concluded that fibrinolytics should be used selectively because there has 
not been a proven benefit in high-quality trials; however, the authors acknowledged 
that there may be certain subgroups of patients who benefit from this therapy. Clini-
cal studies in other arenas indicated that tissue plasminogen activator (tPA) was a 
more effective and safer agent than streptokinase or urokinase as a fibrinolytic 
agent.(49) Other studies suggested that the addition of DNase to streptokinase im-
proves evacuation of an empyema.(50, 51) Subsequently, MIST II, using tPA with or 
without DNase, has been completed.(52) Unfortunately, this study (n = 210; four 
study groups) was only powered sufficiently to evaluate radiographic changes.  But 
consistent with MIST I, tPA showed no benefit over any fibrinolytic treatment. The 
combination of tPA and DNase, however, was beneficial in both the primary end 
point (radiographic clearance) and secondary end points (need for thoracotomy, 
hospital length of stay). The authors responsibly conclude, “Our study shows that 
combination intrapleural t-PA and DNAse therapy improves the drainage of pleural 
fluid in patients with pleural infection… This combined treatment may therefore be 
useful in patients in whom standard medical management has failed and thoracic 
surgery is not a treatment option. However, appropriate trials are needed to accu-
rately define the treatment effects.” 
Thus, the debate continues regarding the role of fibrinolytics in the manage-
ment of pleural collections. Most intensivists have observed effective eradication of 
early empyema in some patients but agree that the appropriate population remains 


 
7 
ill defined. On the basis of the pathophysiology of empyema and the morbidity of 
thoracotomy for delayed intervention, most think that fibrinolytic treatment should 
be attempted for early empyema with simple collections separated by thin septa 
documented by CT scan if tube thoracotomy drainage fails. Image-guided direct in-
fusion of fibrinolytics into the collection is superior to delivery via the failed chest 
tube. The precise agent, dosage, and timing of infusion remain to be analyzed; the 
combination of tPA and DNase seems to be the most effective regimen at this 
time.(52) Large case series have emerged since the publication of MIST II.  Piccolo et 
al(53) reported a three-year experience using the MIST II protocol (5mg DNase and 
10mg tPA BID for up to six doses) in 10 different centers.  Inclusion criteria were pa-
tients with a pleural PH < 7.2 and clinical evidence of infection.  The majority of 
these patients were male (69%) had CAP (97%), middle aged (median 56 yrs.), and 
received 2 days of therapy.  Of the 107 patients included in the analysis 93% had 
successful fibrinolytic/DNAse to avoid surgery.  Of note 23% of patients had in-
creased pain associated with infusion and required additional analgesic medication, 
which should be taken into consideration when starting therapy.  A smaller case se-
ries from Mehta et al.(54) evaluating 55 patients using once a day therapy for 3 days 
had similarly positive results with 93% of patients not requiring surgical interven-
tion. They also appreciated that 15% of patients required additional analgesics dur-
ing treatments.  
 
Surgical Decortication 
 
There are no randomized control trials evaluating VATs vs. fibrinolytic ther-
apy in adults.  However in adolescents a small trial demonstrated equivalency in fi-
brinolytic therapy and VATS in clearing infection, but the surgical intervention 
group had 3 fewer days with a chest tube and 3 fewer hospital days(55).  This is im-
portant to take into the context of the patient’s physiologic status.  There is a need 
for a prospective randomized control trial to determine if VATS or fibrinolytic ther-
apy is the optimal treatment of patients with complicated parapneumonic effusions 
who are physically fit to undergo surgery. In addition there are also patents that 
should proceed to decortication and avoid attempts at fibrinolysis therapy. Multiloc-
ulated empyema with an established pleural peel evident on CT scanning should un-
dergo prompt VATS.(48) Although “medical” VATS using local anesthesia has been 
reported,(56) the standard procedure is lateral decubitus positioning with dual lung 
ventilation to facilitate comprehensive evaluation of the involved pleural cavity and 
systematic decortication. A key maneuver is to enter the pleural space without in-
juring the underlying lung because of extensive pleural adhesions. An initial incision 
in the upper thorax, where the empyema is least developed, is usually the safest 
strategy. In most cases, we have used the existing chest tube site to free the lung for 
placement of the initial port. With the thorascope in position and the lung at least 
partially deflated, additional working ports are added under direct vision. The sites 
for these ports are chosen to match the chest wall entrance of the chest tubes after 
VATS. 
 The objectives of VATS are to unroof all loculated collections, including those 
in the fissures, and to free the lung of the visceral pleural fibrous encasement. 


 
8 
Usually, the decortication is initiated in the upper lobe, where the process is more 
limited, and ultimately, the fibrous debris is removed as much as possible from the 
lung surface to enable re-expansion. Dissection must be done carefully on the medi-
astinal side to avoid injury to the phrenic nerve and pulmonary vasculature. Simi-
larly, clearing the diaphragm must be done cautiously to avoid perforation. In fact, 
the diaphragm does not need to be systematically debrided as long as the lower lobe 
is freed. After extensive decortication, the thorax is usually drained with three rela-
tively large chest tubes (28F) to facilitate removal of debris and blood associated 
with the procedure. The most inferior tube is usually an angled tube positioned in 
the posterior dependent recess of the chest. 
In the event of a dense fibrous peel that precludes clearance via VATS, a lim-
ited lateral muscle-sparing thoracotomy (“mini thoracotomy”) is performed to ac-
complish decortication. Transecting the posterior rib facilitates exposure of the fi-
brous cavity. Advanced empyemas often require scalpel incision to free the lung for 
re-expansion; inspection of the lung with periodic re-inflation should be done to 
avoid extensive pulmonary parenchymal air leaks. In the unusual case of a chronic 
empyema, a standard posterolateral thoracotomy is required. Often, the safest ap-
proach is to develop an extrapleural plane and directly enter the empyema cavity 
before any further thoracic dissection is done. After these extensive decortications, 
the thorax is drained with three relatively large chest tubes (28F), and the most in-
ferior tube is usually an angled tube positioned in the posterior dependent recess of 
the chest. Occasionally, these tubes are simply transected to provide external drain-
age for outpatient management of extended processes. 
Treatment of an advanced process caused by a necrotic infected lung with as-
sociated major air leaks in a severely immunocompromised patient warrants open 
thoracic drainage. The Eloesser flap, thoracic cavity marsupialization via segmental 
rib resection and suturing the skin to the underlying parietal surface, has been the 
standard for these complicated cases.(57) But recently, simple open drainage with 
suturing the skin margin to the chest wall, thoracostomy, and the application of a 
vacuum-assisted wound closure has been popularized.(58, 59) Ultimately, some of 
these wounds will heal by secondary intention, and the remaining can be closed 
with thoracomyoplasty.(60) 
 
Significance 
 
Infection of the pleural space is a morbid condition requiring prompt inter-
vention.  The keys to optimal care in these patients are 1) early identification 2) an-
tibiotics and 3) clearance of infection from the pleural space. When a chest tube has 
incompletely drained the pleural space within 24 hours CT imaging to better charac-
terize the pleural space is essential. The Western Trauma Association has published 
a critical decision algorithm for determining which patients should proceed to de-
cortication versus fibrinolytic therapy(61).  It is important to note that there have 
been no randomized trials in adults comparing early VATs to fibrinolytic therapy in 
patients who can tolerate surgery.  Future studies are warranted to address this gap 
in knowledge, as pediatric literature supports early decortication may be more cost 
effective and beneficial to the patient. Failure to appropriately treat pleural space 


 
9 
infection resulting in empyema results in highly morbid open operations requiring 
prolonged hospitalization and lengthy recovery.    
 
 
 
III. Preliminary Studies/Progress Report:  
 
 We have previous completed a retrospective study at Denver Health evaluating 
Strep Milleri associated pleural infections(62). Over the 70-month period evaluated, 
39 patients had S Milleri infections of the pleural space; 26 (67%) patients under-
went operative intervention. The majority (72%) were men with a mean age of 46 
(range 22 to 63); the underlying etiology in those patients requiring operation was 
pneumonia (26 patients; 67%), trauma (9 patients; 23%), postoperative infection (2 
patients), foreign body ingestion (1 patient), and malignancy (1 patient). The aver-
age duration of chest tube drainage prior to operation was 4.4 days (95% confi-
dence interval [CI] 2.6 to 6.2) and antibiotic treatment was 6.0 days (95% CI 3.8 to 
8.2). Thirteen patients (50%) underwent video-assisted thoracoscopic surgery 
(VATS) and 13 patients required thoracotomy. VATS was performed more often 
when operative intervention occurred early (average hospital day 6.2) compared to 
initial thoracotomy or conversion from VATS to thoracotomy (average hospital day 
9.8). Hospital length of stay was less in the operative group (average 24 days; 95% 
CI 17 to 31) than in the non-operative group (34 days; 95% CI 19 to 49), discharge 
to home was greater in the operative group (77% vs. 16%), and mortality was less 
in operative group (0% vs. 23%). 
 
While this data was published before the routine use of antibiotics, it demonstrates 
key aspects of the current proposed study; 1) decreasing time to surgical consulta-
tion and chest tube placement 2) early operative intervention when indicated allow-
ing for minimally invasive surgery 3) decreased hospitalization time in patients 
when operative intervention is performed.  This study only included patients with 
Strep Milleri, which in regards to historic literature represents 1/3rd of all pleural 
space infections.   
 
IV. Research Methods 
 
A.  Outcome Measure(s):   
Primary: Length of stay (determined by when treating team deems medically fit for 
discharge, and excludes extended stay for social work related issues) 
 
Secondary: 
ICU free days 
 
 
        
Ventilator free days 
 
 
         
Days with chest tube in place after intervention 
 
 
        
Total cost - post intervention 
 
 
 
Pain scores 
 
 
 
Chest tube drainage post intervention 
 
 
 
Incentive spirometry volume post intervention for 5 days 
 
 
 
Days to wean off supplemental oxygen 


 
10 
 
 
 
Days to resolution of fever 
 
 
 
Days of antibiotic therapy after intervention 
 
 
 
Days to normalization of WBC 
 
 
 
Change in TEG variables after initiating intervention  
 
Covariates: Age, BMI, Diabetes, Duration of symptoms, Steroid use 
 
Adverse events: Air leak, bleeding requiring transfusion, need for additional 
chest tube, and need for secondary operation/intervention, mortality 
 
 
B. Description of Population to be Enrolled:   
Adults >18 admitted with pleural effusion diagnosed by chest x-ray or computed to-
mography, that undergo thoracentesis or chest tube drainage by any service.  
 
If the patient has a pleural fluid PH < 7.3, the patient will be screened for potential 
study enrollment.  If the patient does not have any exclusion criteria (listed below) 
the patient will be followed for study enrollment. If there is a persistent effusion 24 
hours after chest tube insertion, diagnosed by morning chest X ray, and no exclusion 
criteria identified, the patient may then undergo CT scan to characterize the effu-
sion. If CT scan is done and confirms a loculated fluid collection or if an additional 
CXR is grossly abnormal, despite chest tube drainage, these patients will then be ap-
proached for consent and randomized to either bedside fibrinolytic therapy through 
their chest tube versus operative VATS decortication. The patients that undergo 
VATS decortication, will subsequently be transferred to the surgery service for the 
remainder of their hospital stay.  
Exclusion:  
- Intrathoracic malignancy   
- Any existing malignancy causing malignant effusion  
- Prehospital pulmonary symptoms over 14 days prior to admission 
- Prior instrumentation of the chest during same admission  
- Malignant cells from initial pleural fluid sample 
- End stage liver disease  (Child’s B or greater) 
- Coagulopathy 
 
 
- Unable to tolerate surgical procedure 
 
 
- Frank purulent drainage (needs OR regardless) 
 
 
- Recent surgery of abdomen or thorax precluding the use of tPA 
 
 
- Pre-existing and permanent neurologic impairment 
 
C. Study Design and Research Methods  
 
This study is a proposed pragmatic prospective randomized open label clinical trial 
to treat patients with complicated parapneumonic effusion.  Complicated parapneu-
monic effusion is defined as fluid collection in the pleural space with a fluid pH<7.3.   
 
 
 
 


 
11 
 
Standard of Care Procedure prior to study eligibility: 
Patients with parapneumonic effusions identified on chest x-ray or CT will be admit-
ted to the medicine service and started on the appropriate therapy.  The medi-
cine/pulmonary service will then perform a thoracentesis or place a chest tube in 
patients that there is a concern for an infectious process.  Pleural fluid sampling will 
undergo pH testing, and those patients with a low pleural pH (pH <7.3) will continue 
to be observed over the next 24 hours. Those patients who have persistent fluid col-
lections >24 hours from chest tube placement identified by a morning chest X ray, 
will undergo a CT scan of the chest to further characterize the pleural space. These 
eligible patients will be approached by a study team member for study consent to 
enroll and randomized into a treatment group (Fibrinolytic therapy vs. early VATS 
Decortication).   
 
Study Procedures: 
Eligible patients will be screened for study participation and after consenting will be 
randomized to early surgical decortication via VATs versus fibrinolytic therapy (FT) 
based off of the current MIST II protocol, currently utilized at Denver Health.  Should 
the patient be randomized into the FT group, initiation of fibrinolytic therapy will 
start within 24 hours of CT scan,. Conversely, if the patient is randomized into the 
surgery group, VATS decortication will occur as soon as the operating room is avail-
able.  The fibrinolytic therapy will be delivered by a member of the treatment team 
per current standard of care for 3 days.  Removal of chest tubes is dependent on the 
mutual agreement of both the surgical and pulmonary attending involved with the 
patients care.  Per standard clinical care, labs will be collected daily (determined by 
the medical team, but usually include complete blood count and basic metabolic 
panel). In addition to the standard of care labs, pleural fluid will be collected for 
study purposes and extra blood samples will be collected for thrombelastography 
(TEG) analysis. TEG assesses changes in clot strength in both plasma and pleural 
samples by measuring proteins related to coagulation with proteomic analysis.   
Thrombo Therapeutics, Inc. is not involved in this study. tPA-challenged TEG assay 
is used for research purposes only. The data from this test is not accessible for the 
clinical care providers and does not affect the patient care. We are using this assay 
to study the clot sensitivity and as a marker for massive blood transfusion. The re-
sults of tPA-challenged TEG assay will not be used for any clinical decision or re-
search subject assignment. At the moment there is no plan to submit tPA-challenged 
TEG data to the FDA.This study blood and pleural fluid will be drawn by the phlebot-
omy service or medical team member (nurse or physician to draw pleural fluid) and 
will be collected by a professional research assistant (PRA) trained in both running 
the TEG assay and in processing of blood for plasma analysis. Blood and pleural fluid 
samples will be 3.5ml each.  
 
Study blood will be drawn prior the intervention and then for 3 sequential days af-
ter (for a total of 4 draws).  This blood will be assayed by TEG with and without the 
t-PA challenge.  This modified TEG assay (t-PA challenge) is completed by taking 
500 microliters of patient blood out of the citrated tube and adding it to a pre made 


 
12 
glass container with lypohylized t-PA.  This blood is mixed with a defined concentra-
tion of t-PA is then added to a TEG cup for analysis.  This will quantify the patient’s 
systemic blood to fibrinolysis resistance.  In addition to the blood draws, pleural 
fluid will be drawn from the patient’s chest tube in the morning prior to the inter-
vention, and then after the intervention for 3 days (same days that blood samples 
are obtained, for a total of 4 pleural fluid samples).  Pleural fluid samples will only 
be drawn from chest tubes already in place.  In the event the chest tube is removed 
prior to 3 days post-intervention pleural fluid samples will be unattainable.  The 
pleural fluid would otherwise be discarded as human waste. We will also conduct a 
novel assay to determine if the pleural space content is fibrinolytic resistant.  This 
will be accomplished by an ex vivo diluting of the patient’s blood (from the collected 
citrated tube) by 25% with normal saline and conducting a t-PA challenge versus a 
25% dilution of the patient’s blood (from the collected citrated tube) with their 
pleural fluid.  The relative differences in the lysis at 30 minutes between these two 
assays will give a crude estimate of fibrinolytic inhibition.  Remaining blood after 
TEG analysis will be spun down to plasma and flash frozen for future measurements, 
such as elastase activity and a targeted cohort for proteins related to coagulation 
with proteomic analysis.  These results paired with proteomic analysis will enable 
correlations between fibrinolysis resistance and relative protein concentrations to 
identify potential mechanistic culprits driving fibrinolysis resistance. This study 
blood will be collected by PRA (drawn by the nurse and handed off to thePRA) 
trained in both running the TEG assay and in processing blood for plasma analysis.   
 


 
13 
Data collection will be done prospectively by a member of the research team.  Data 
will be stored in a secure excel sheet accessible only to the study team members.   
Randomization 
 
  
 
Intervention 
VATS decortication 
Vs. 
tPA and DNASE per MISTII protocol 
 
 
 
D.   Description, Risks and Justification of Procedures and Data Collection 
Tools: 
 
The adverse events of the standard of care fibrinolytic therapy include pain, fever, 
bleeding, and failure to effectively clear infection from the pleural space requiring 


 
14 
surgery, which tend to be higher risk due to disease progression.  The VATS decorti-
cation is a slightly more invasive procedure, as it requires general anesthesia and 
single lung ventilation.  Complications from surgery include injury to lung causing 
an air leak, bleeding, pain, and need for conversion to an open operation. The VATS 
surgery uses small holes in the thoracic cavity that are similar in diameter to a chest 
tube.  This requires 1 or 2 additional holes in the chest cavity compared to the pa-
tients who already have one chest tube receiving fibrinolytic therapy.  The benefits 
of VATS over fibrinolytic therapy are reduction in chest tube time and overall reduc-
tion in hospitalization time.  In children VATS reduced the requirement of a chest 
tube by 3 days and associated with hospital discharge 3 days earlier with resolution 
of symptoms 3 days earlier.  This is logical as the chest is cleared of all infected ma-
terial with the VATS operation, while fibrinolysis is dependent on the medication 
breaking down all of the loculated fluid collections.  The second benefit may be a re-
duction in cost to the patient, and improvement in resource utilization of the hospi-
tal.  Three days of hospitalization out weighs the cost of the operating room.  All 
clinical outcomes will be monitored by a research team member who will be collect-
ing blood on a daily basis for 3 days post intervention and inputting data into a RED 
CAP data bank designed for the study.  As this study is associated with an operative 
arm a data safety monitoring board (DSMB) will be created to assess patient out-
comes after enrollment of 10 patients or once a year, even if enrollment has not in-
creased by 10.  This will not include an interim analysis on primary outcome, as this 
will decrease power and necessitate additional patients for enrollment.  We antici-
pate that roughly 2 patients per month will be eligible for enrollment in this study 
and would expect completion of the study within 18 months.   
 
 
 
E.   Potential Scientific Problems:   
 
This study is established as a pragmatic study as it is anticipated that some patients 
would prefer conservative fibrinolytic therapy to surgery.  We have adjusted for this 
in our power calculation (see below).  In addition the timing of availability of the op-
erating room staff is not predictable.  There may be a delay in taking the patient to 
the operating room.  The importance of performing this study is that it is perceived 
that fibrinolytic therapy should be the standard of care for treating these patients.   
However, pediatric literature supports that optimal care of these patients may be an 
early surgical intervention.  This is similar to an operative intervention for appendi-
citis.  While it is possible to treat patients with appendicitis with antibiotics and 
avoid surgery, it results in longer hospitalizations, in addition if medical treatment 
fails the appendical perforation can result in life threatening sepsis and require sur-
gery or additional procedures.  This parallels complicated parapneumonic infec-
tions, in which surgery can be avoided, but result in prolonged hospitalization and if 
fibrinolytic therapy fails, surgery becomes a riskier endeavor.   
 
F.   Data Analysis Plan:   
 


 
15 
Power analysis 
 
Using the pediatric literature assume effect size of reduction in 3 days of hos-
pitalization requirement with variability of 2.3 days with alpha of 0.05 and 1:1 
group allocation would require 12 patients per arm (24 total) to power the study to 
80%.  Anticipating up to 30% of patients may decline surgery we would seek to en-
roll 17 patients per arm.  Will conduct an analysis based on intention to treat (in-
cluded patients who declined surgery) in addition the treatment the patients re-
ceived. 
 
 
 
 
Statistical analysis will be performed using SPSS 22 software (Microsoft, Armonk, 
NY). Normally distributed data will be described as mean and standard deviation 
and non-normally distributed data were described as the median value with the 25th 
to 75th percentile values (IQR).  Outcomes will be contrasted between intervention 
arms with a T test (normal distribution) or Mann Whitney U test (non normal distri-
bution) for continuous variables or chi square analysis for dichotomous outcomes.  
Kaplan-Meier plot will be generated to identify the timing of chest tube removal 
from intervention, and time to hospital discharge from intervention.  
 
 
G.  Summarize Knowledge to be Gained:  
 
Complicated parapneumonic effusions are life-threatening infections 
that are progressive and if mistreated can result in prolonged hospitali-
zation and open thoracic surgery.  The optimal care of adult patients re-
mains controversial, and there may be a role for early operative inter-
vention versus conservative fibrinolytic therapy.  VATS is a minimally in-
vasive procedure that allows complete removal of all infected material 
from the chest cavity.  We believe that the benefit of a quicker recovery 
and definitive management of this disease process with VATS outweighs 


 
16 
the risk of undergoing surgery and may be superior to fibrinolytic ther-
apy is at risk of incompletely removing infected material.  This study is 
also a quality improvement project to standardize the identification of 
patients at risk of complicated parapneumonic processes to guide the 
medical service to early diagnosis and interventions the manage this 
process with guidance for when to initiate advance therapy in regard to 
fibrinolytic therapy versus operative intervention. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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