SPECIAL ARTICLE
Update on the Role of Intrapleural Fibrinolytic Therapy
in the Management of Complicated Parapneumonic
Effusions and Empyema
Gurmeet Singh, Ceva W. Pitoyo, Anna Uyainah Z. Nasir, Cleopas M. Rumende,
Zulkifli Amin
Departement of Internal Medicine, Faculty of Medicine, University of Indonesia – Cipto Mangunkusumo Hospital.
Jl. Diponegoro no. 71, Jakarta Pusat 10430, Indonesia. Correspondence mail: divisipulmonologi@yahoo.co.id.
ABSTRAK
Efusi parapneumonia merupakan kumpulan cairan eksudatif di rongga pleura yang dihubungkan dengan
terjadinya infeksi paru. Efusi parapneumonia mewakili sekitar sepertiga dari seluruh efusi, dan sekitar 40%
pasien dengan pneumonia juga mengalami efusi. Pasien-pasien pneumonia yang mengalami efusi memiliki risiko
morbiditas dan mortalitas yang lebih tinggi. Sebagian penyebab dari mortalitas tinggi tersebut disebabkan oleh
karena kesalahan dalam tatalaksana efusi parapneumonia. Metabolisme bakterial dan leukosit dapat dengan
cepat merubah efusi parapneumonia eksudatif sederhana menjadi empiema purulen multi-lokulasi dengan pH
rendah dan kadar laktat dehidrogenase yang tinggi. Pendekatan optimal pada tatalaksana efusi parapneumonia
dan empiema pleura hingga saat ini masih kontroversial. Tatalaksana yang telah diterima terdiri dari antibiotik
sistemik dan drainase rongga pleura, yang dicapai oleh drainase chest tube medis atau dengan pembedahan.
Beberapa penelitian telah mempelajari efikasi dan keamanan fibrinolitik intrapleura untuk terapi efusi pleura
dan empiema. Instilasi agen fibrinolitik intrapleura dilakukan untuk melarutkan bekuan dan membran-membran
fibrinosa, mencegah sekuesterasi cairan, dan memperbaiki drainase. Deoksiribosa rekombinan dilaporkan
memperbaiki drainase pada pasien yang tidak memberikan respon baik dengan terapi fibrinolitik intrapleura.
Kata kunci: efusi parapneumonia, empiema, fibrinolitik intrapleura, deoksiribosa rekombinan.
ABSTRACT
A parapneumonic effusion is the collection of exudative fluid in the pleural space associated with a concurrent
pulmonary infection. Parapneumonic effusions account for approximately one-third of all effusions, and about
40% of patients with pneumonia develop a concomitant effusion. Patients with pneumonia who develop an effusion
have an increased risk of morbidity and mortality. Some of the excess mortality is due to mismanagement of the
parapneumonic effusion. Bacterial and white cell metabolism can rapidly turn a simple exudative parapneumonic
effusion into a multiloculated purulent empyema with low pH and high lactate dehydrogenase levels. The
optimal approach to treating parapneumonic effusions and pleural empyemas remains controversial. Accepted
management consists of systemic antibiotics and drainage of the pleural cavity, which is achieved by either
medical chest tube drainage or surgery. Several investigators have studied the efficacy and safety of intrapleural
fibrinolytics in the treatment of pleural effusion and empyema. Intrapleural instillation of fibrinolytic agents
is undertaken to dissolve fibrinous clots and membranes, to prevent fluid sequestration, and hence to improve
drainage. Recombinant deoxyribonuclease has been reported to improve drainage in a single patient who did
not respond to fibrinolytic therapy.
Key words: parapneumonic effusions, empyema, intrapleural fibrinolytics, recombinant deoxyribonuclease.
258 Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine
Vol 44 • Number 3 • July 2012
INTRODUCTION
Pleural infections represent an important
group of disorders that is characterized by the
invasion of pathogens into the pleural space
and the potential for rapid progression to frank
empyema.1 Pleural effusion develops in about
36% to 57% of patients with pneumonia. Of
these patients, about 10% develop empyema or
complicated parapneumonic effusion, which has
a 14% to 20% mortality rate. The classification
by Hamm and Light is particularly useful
because it correlates closely with the correct
approach to treatment of pleural infection.
The 4 stages are as follows: (1) pleuritis sicca,
ie, pleural inflammation without effusion; (2)
exudative, ie, pleural effusion with normal
pH; (3) fibropurulent, ie, pleural fluid with any
combination of pH less than 7.20, frank pus,
or bacteria by Gram stain or culture; and (4)
organizational, ie, organized fibrin membranes
with pleural peels.2
Previous epidemiologic studies have indicated
that empyema is increasing in prevalence, which
underscores the importance of urgent diagnosis
and effective drainage to improve clinical
outcomes. Unfortunately, limited evidence
exists to guide clinicians in selecting the ideal
drainage intervention for a specific patient
because of the broad variation that exists in
the intrapleural extent of infection, presence of
locules, comorbid features, respiratory status, and
virulence of the underlying pathogen. Moreover,
many patients experience delays in both the
recognition of infected pleural fluid and the
initiation of appropriate measures to drain the
pleural space.1Empyema and large or loculated
effusions need to be formally drained, as well
as parapneumonic effusions with a pH <7.20,
glucose <3.4 mmol/l (60 mg/dl) or positive
microbial stain and/or culture.3
Several investigators have studied the
efficacy and safety of intrapleural fibrinolytics in
the treatment of pleural effusion and empyema.
These researchers report a 38–100% success
rate (defined as improvement of symptoms,
improvement of X-ray imaging, no need for
surgical intervention). One group stressed the
importance of accurate staging of empyema
when choosing to initiate intrapleural fibrinolytic
therapy. They found Computed Tomography
(CT) scan evidence of a pleural peel was
predictive of failure with fibrinolytic therapy.
Update on the Role of Intrapleural Fibrinolytic Therapy
However, some patients with a complicated
pleural effusion (CPE) may benefit from adjunct
approaches, such as intrapleural fibrinolytics,
to reduce the need for surgical interventions.4
The present article provides review on the
pathogenesis and interventional therapy of
pleural infections with an emphasis on the role of
intrapleural administration of fibrinolytic agents
for the treatment of complicated parapneumonic
effusions and empyema.
EPIDEMIOLOGY AND RISK FACTORS
Complicated parapneumonic effusions and
empyema are more common at both extremes
of age. At least two thirds of patients will have
an identifiable risk factor at presentation, which
may include immunosuppressive states (most
frequently Human Imunodeficiency Virus
infection, diabetes mellitus and malnutrition),
alcohol or intravenous drug abuse, bronchial
aspiration, poor dental hygiene, gastrooesophageal reflux, and chronic parenchymal lung
disease. Microbial virulence and idiosyncrasies
of the immune system are often also implicated,
principally in individuals with no apparent
predisposition.3
PATHOPHYSIOLOGIC CLASSIFICATION AND
CLINICAL STAGING OF PLEURAL FLUID
Pleural effusions develop when the balance
of pleural fluid formation and removal is altered.
Pleural effusions secondary to pneumonia
are termed parapneumonic effusions. Most
of these effusions remain sterile and resolve
with antibiotic therapy (termed uncomplicated
parapneumonic effusions), but infections of the
pleural space develop in a small ubset of patients
and require drainage for full recovery (termed
complicated parapneumonic effusions). Without
effective drainage, complicated parapneumonic
effusions progress to frank intrapleural pus,
which defines the presence of an empyema. This
progression may occur rapidly over a few days
and necessitate surgical drainage (Figure 1).1
Progression to empyema occurs in three
phases. The exudative phase develops when
inflammatory fluid enters the pleural space across
vascular and visceral pleural membranes that
have increased permeability due to pneumonia.
Pleural fluid is nonviscous, free-flowing, and
readily drained by thoracentesis or chest tube.
259
Gurmeet Singh
Figure 1. Serial chest radiographs and CT scan images
demonstrating rapid progression of infected pleural fluid
to an empyema that required surgical drainage. A: a chest
radiograph obtained at hospital admission demonstrates a
right pleural effusion and parenchymal density at the right lung
base. Therapy with antibiotics was begun, but thoracentesis
was not performed. The effusion became massive 3 days later
(B) when a noncontrasted CT scan (C) demonstrated multiple
locules that contained viscous pus during surgical drainage.
Without contrast, the CT scan could not clearly differentiate in
some areas between loculated fluid and lung consolidation.1
Unremitting inflammation deposits fibrin
that coats the visceral pleura and promotes
the formation of locules that impede lung
reexpansion during attempts at fluid drainage.
Pleural fluid becomes purulent and increasingly
viscous (Figure 2).
This fibrinopurulent phase may respond to
therapy with antibiotics and chest tube drainage
but often requires intervention to break down
adhesions. If a fibropurulent effusion remains
undrained, fibroblasts eventually deposit fibrotic
tissue that encases the lung in inelastic peels.
At this organizing phase, resolution of the
empyema requires surgical procedures to drain
pus, obliterate the empyema space, and reexpand
the lung.1 Parapneumonic effusions represent
the most common cause of exudative effusions
and occur in 20 to 57% of hospitalized patients
with pneumonia.6 Empyemas occur in 1 to 5%
of hospitalized patients with parapneumonic
effusions.7,8
EVALUATION OF EFFUSION
The evaluation of a patient with a pleural
effusion begins with a detailed history and
thorough physical exam. Patients occasionally
Figure 2. Fibrinopurulent Stage loculations in a parapneumonic
effusion.5
260
Acta Med Indones-Indones J Intern Med
note symptoms such as dyspnea or cough, but
frequently are without symptoms. On physical
exam, the clinician may note localized decreased
breath sounds, dullness to percussion, or absent
tactile fremitus on pulmonary exam. Typically,
imaging is performed to elucidate size and
location of a possible pleural effusion. Upright
Posteroanterior and Lateral Chest Films can
demonstrate the general size of an effusion.
Ideally, a Lateral Decubitus Chest Film will
be obtained to further determine if the fluid
is loculated and better estimate the size of
the effusion. Other imaging including CT or
Ultrasound is even higher quality in helping to
determine the number of loculations and more
accurately quantify size of the effusion.9
If a pleural effusion is greater than 1.0 cm
on lateral decubitus film when measured from
the inner chest wall, then the effusion is thought
to be accessible to pleural fluid sampling with
thoracentesis. Pleural fluid sampling is typically
performed if the etiology of the effusion is
unclear or if the patient is not responding to
appropriate therapy. When a thoracentesis is
performed, the fluid is typically sent for Protein
and LDH, historically known as Light’s Criteria
to demonstrate transudative effusions from
exudative effusions. Additional studies are
available for further information, including gram
stain and culture, pH, glucose, and cell count
with differential. These studies can further aid in
determining the cause of the effusion.9 A positive
result from either the Gram stain or culture, or a
pH of <7.20 is associated with a worse outcome
and indicates the need for drainage. If the pleural
fluid pH is unavailable, the pleural fluid glucose
may serve as a surrogate. A glucose level >3.4
mmol/l (60 mg/dl) is associated with a better
prognosis.3
OPTIONS FOR MANAGEMENT OF PLEURAL
FLUID
There are several options available for the
management of the pleural fluid in patients
with parapneumonic effusion, range from noninvasive antibiotic therapy and observation, to
semi-invasive techniques such as therapeutic
aspiration, tube thoracostomy and intrapleural
fibrinolytics, to invasive interventions such as
thoracoscopy, thoracotomy or open drainage.6
In practical terms, however, the initial evaluation
should focus on three critical questions, namely:
Vol 44 • Number 3 • July 2012
Update on the Role of Intrapleural Fibrinolytic Therapy
Table 1. .ACCP system for staging pleural infections and recommending drainage10
Pleural fluid
Effusion stage
Pleural space features
Bacteriology
I (uncomplicated
parapneumonic)
Minimal, free-flowing effusion
(<10 mm on lateral decubitus)
Culture and Gram stain
results unknown
pH unknown
No/No
II (uncomplicated
parapneumonic)
Small-to-moderate free-flowing
effusion (>10 mm and less
than one-half hemithorax)
Negative culture and
Gram stain
pH >7.20 or glucose
>60 mg/dL
Yes/No
III (complicated
parapneumonic)
Large, free-flowing effusion
(one-half hemithorax or
greater); loculated effusion;
effusion with thickened parietal
pleura
Positive culture or
Gram stain
pH <7.20 or glucose
<60 mg/dL
Yes/Yes
Pus
Tests not indicated
Yes/Yes
IV (empyema)
(1) Should the pleural space be drained? (2) How
should the pleural space be drained? (3) Should
fibrinolytics be instilled? Table 1 is adapted
from the American College of Chest Physicians’
(ACCP) consensus statement that categorizes
parapneumonic effusions according to the need
for drainage.10
It is important to realize that the pleural
space anatomy (best visualized by means of
ultrasonography), pleural fluid appearance and
smell, as well as pleural pH are often the only
useful criteria for initial decision making, as all
other laboratory tests need time for processing.
Frank pus on aspiration, large effusions greater
than half of one hemithorax, effusions with
loculations, or fluid with a pH <7.20 all herald the
need for immediate drainage. Further indications
include a positive Gram stain, a positive microbial
culture and pleural fluid glucose of <3.4 mmol/l
(60 mg/dl).3
INTRAPLEURAL FIBRINOLYTICS
When an infected pleural space progresses
to the fibrinopurulent phase, fibrin creates
intrapleural locules that impede chest tube
drainage. Intrapleural instillation of fibrinolytic
drugs offers a theoretical benefit for lysing
fibrin adhesions, promoting pleural drainage,
and avoiding surgery. Small studies have
reported the beneficial effects of therapy with
streptokinase, urokinase, and tissue plasminogen
activator(rtPA) for avoiding surgery, promoting
catheter drainage, and improving the radiographic
appearance of loculated effusions.1 Based on
early reports of efficacy, the British Thoracic
Chemistry
Thoracentesis/
drainage
Society (BTS)11,12 and the ACCP guidelines10
recommend fibrinolytic drugs as management
options.
Numerous case series and controlled trials
have shown that intrapleural fibrinolysis is safe,
increases drainage and improves radiological
appearance. A randomized controlled study
by Davies et al. 13 established that systemic
fibrinolysis or bleeding complications did not
occur with streptokinase, and that patients who
were given intrapleural streptokinase drained
significantly more pleural fluid both during the
days of treatment (n = 24; mean 391 vs. 124 ml,
p<0.001) and overall. Patients who received
fibrinolytics also showed greater improvement
on the chest radiograph at discharge. Bouros
et al.14 demonstrated that urokinase was a safe
intrapleural fibrinolytic. The same group showed
that streptokinase and urokinase were clinically
and radiologically equally effective as intrapleural
fibrinolytics15, and that intrapleural urokinase
decreased the duration of hospitalization, duration
of pleural drainage and time to defervescence.
Furthermore, Bouros et al.16 were able to show
that urokinase’s effect in empyema was through
the lysis of pleural adhesions, rather than the
volume effect of instilled urokinase and saline.
The largest prospective double-blind
controlled study on the role of intrapleural
streptokinase for pleural infection was published
in 2005 (Multicenter Intrapleural Sepsis Trial MIST 1).17 In this study 454 patients with pleural
pus, pleural sepsis with a pH <7.2 or bacterial
invasion of the pleural space were randomly
assigned to receive streptokinase or placebo. The
261
Gurmeet Singh
patients included were older than in most other
studies (average age 60 years) and had a high
prevalence of comorbidities. The MIST 1 study
could not substantiate the role of streptokinase
in pleural infections: There was no difference
in mortality, need for surgery, radiographic
outcome or length of hospitalization. The design
and execution of this study, however, were
criticized.18-20 The lack of image-based selection
criteria meant that patients with pleural sepsis
were included irrespective of presence, quantity
and quality of loculations. Questions were raised
about the reproducibility of clinical management
decisions taken across 52 study centres, many
of which lacked on-site surgical expertise and
contributed only small numbers of patients. The
study permitted small-bore chest tubes, but did
not report on pleural drainage volumes, which
casts doubt on the efficacy of the drainage
techniques used. Furthermore, owing to the
decentralized and blinded design streptokinase/
placebo was shipped to the study centres after
randomization causing delays in the initiation of
treatment. The value of mortality as an endpoint
was also questioned, as patients with serious
concomitant illnesses that made survival beyond
3 months unlikely were excluded from the study.
The 3-month mortality after hospitalization
for pneumonia among middle-aged and older
patients is more closely associated with the fact
that an episode of pneumonia often identifies
a fragile underlying health status than with the
severity of the acute episode of pneumonia
itself. Intrapleural streptokinase may therefore
not have been given a fair chance to improve
the short-term mortality.18 These deficiencies do
not invalidate this large randomized trial, but
concerns remain about the validity of its results
with regard to younger, more severely ill patients
and in different health care settings.3
The most recent and second largest
prospective study was conducted by Misthos et
al.21 In their study, patients were randomized to
a group managed solely with tube thoracostomy
or a group treated with a combination of tube
thoracostomy and streptokinase instillation
(no placebo control). They found that tube
thoracostomy was successful in 67.1% of cases,
whereas the installation of streptokinase led
to a favourable outcome in 87.7% (p<0.05)
and significantly shortened hospital stay. The
mortality rate was also significantly lower in the
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Acta Med Indones-Indones J Intern Med
fibrinolytic group, and streptokinase was found
to decrease the rate of surgical interventions and
the length of hospital stay.
Some centers now use rtPA for fibrinolysis.
Walker et al.22 first reported the apparent benefits
of rtPA in a patient with empyema. Subsequently,
Skeete et al.23 instilled rtPA through surgical chest
tubes into 42 patients with a variety of pleural
conditions, of which 12 were empyemas. They
reported accelerated radiographic improvement
and clinical benefit. Levinson and Pennington24
used fibrinolytic therapy for 30 patients with
largely multiloculated pleural infections; 20
patients received rtPA through small-bore,
image-guided chest tubes. The mean length of
hospital stay was 11 days, and no patient required
surgical drainage. Gervais et al.25 reported their
experience with rtPA instilled through imageguided 8.5F to 16F catheters in 66 patients,
of whom 53 had empyemas or complicated
parapneumonic effusions. In the study by Gervais
et al.25 patients were selected for fibrinolysis if
the initial pleural fluid drainage was incomplete.
The overall success rate was 86%, although the
outcomes were not specifically reported for the
53 patients with pleural infections. Based on
CT imaging studies obtained before chest tube
insertion that demonstrated multiple locules, the
authors opined that rtPA successfully drained
effusions that would otherwise have required
surgery. The suggested dosages of the current
fibrinolytics in use are summarized in Table 2.3
Table 2. Intrapleural fibrinolytics – Practical use3
Fibrinolytic
Dose
Instillation1
Duration
Streptokinase
250,000
IU
100–200 ml
saline
Daily for up to
7 days (until
drainage
<100 ml/day)
Urokinase2
100,000
IU
100 ml
saline
Daily for up to
3 days
10-25
mg
100 ml
saline
Twice daily for
up to 3 days
tPA
Fibrinolytic drugs have negligible effects
on decreasing the viscosity of empyema pus
in contrast to agents that depolymerize DNA,
such as human recombinant deoxyribonuclease.
The viscosity of pus is largely attributable
to its deoxyribose nucleoprotein content. 26
Recombinant deoxyribonuclease has been
reported to improve drainage in a single
Vol 44 • Number 3 • July 2012
patient who did not respond to fibrinolytic
therapy. 27 Clinical trials on the efficacy of
recombinant tPA and DNase are currently being
performed. An interesting ex vivo observation
by Light et al.28 was that DNase combined with
streptokinase (known as Varidase) was superior
to either streptokinase or urokinase at liquefying
empyemic pleural material obtained from rabbits.
When thick empyemic material from rabbits is
incubated with either streptokinase or urokinase,
there is no significant liquefaction of the fluid.
In contrast, when the fluid is incubated with
Varidase, the fluid becomes completely liquefied
over 4 h. Although Varidase is presently not
available in the United States, recombinant
human DNase (Pulmozyme;Genentech, San
Francisco, CA) is available. It was postulated that
the streptodornase (DNase) was necessary for the
liquefaction of the deoxyribose nucleoproteins,
which make up a sizable proportion of the solid
sediment of purulent exudates. Simpson and
coworkers have recently demonstrated that
recombinant DNase by itself is very effective at
reducing the viscosity of human empyema fluid.29
At the present time, there is another multicenter
trial underway in the United Kingdom in which
patients with complicated parapneumonic
effusions are randomized to saline, 10 mg tPA,
1 mg recombinant DNase, or the combination
of tPA and DNase twice a day. Until the results
of this trial are available, the use of intrapleural
fibrinolytics should be reserved for patients in
centers without access to video-assisted thoracic
surgery and for patients who are not surgical
candidates.6
CONCLUSION
Modern principles of managing pleural
space infections emphasize the importance
of the early detection of effusions in patients
with pneumonia, and the prompt drainage of
complicated parapneumonic effusions and
empyemas. Delays in effective drainage increase
morbidity and mortality. It is recommended that
a stepwise approach be taken with patients with
parapneumonic effusions. The treatment options
are therapeutic thoracentesis, tube thoracostomy,
tube thoracostomy with intrapleural fibrinolytics,
thoracoscopy, and thoracotomy. The use of
fibrinolytics remains controversial, although
evidence suggests a role for the early use in
complicated, loculated parapneumonic effusions
Update on the Role of Intrapleural Fibrinolytic Therapy
and empyema, particularly in young, acutely ill
patients, poor surgical candidates and in centres
with inadequate surgical facilities. Recombinant
deoxyribonuclease has been reported to improve
drainage in a single patient who did not respond
to fibrinolytic therapy.
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