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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:

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.

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 Update on the Role of Intrapleural Fibrinolytic Therapy

INTRODUCTION However, some patients with a complicated

Pleural infections represent an important pleural effusion (CPE) may benefit from adjunct
group of disorders that is characterized by the approaches, such as intrapleural fibrinolytics,
invasion of pathogens into the pleural space to reduce the need for surgical interventions.4
and the potential for rapid progression to frank The present article provides review on the
empyema.1 Pleural effusion develops in about pathogenesis and interventional therapy of
36% to 57% of patients with pneumonia. Of pleural infections with an emphasis on the role of
these patients, about 10% develop empyema or intrapleural administration of fibrinolytic agents
complicated parapneumonic effusion, which has for the treatment of complicated parapneumonic
a 14% to 20% mortality rate. The classification effusions and empyema.
by Hamm and Light is particularly useful
because it correlates closely with the correct EPIDEMIOLOGY AND RISK FACTORS
approach to treatment of pleural infection. Complicated parapneumonic effusions and
The 4 stages are as follows: (1) pleuritis sicca, empyema are more common at both extremes
ie, pleural inflammation without effusion; (2) of age. At least two thirds of patients will have
exudative, ie, pleural effusion with normal an identifiable risk factor at presentation, which
pH; (3) fibropurulent, ie, pleural fluid with any may include immunosuppressive states (most
combination of pH less than 7.20, frank pus, frequently Human Imunodeficiency Virus
or bacteria by Gram stain or culture; and (4) infection, diabetes mellitus and malnutrition),
organizational, ie, organized fibrin membranes alcohol or intravenous drug abuse, bronchial
with pleural peels.2 aspiration, poor dental hygiene, gastro-
Previous epidemiologic studies have indicated oesophageal reflux, and chronic parenchymal lung
that empyema is increasing in prevalence, which disease. Microbial virulence and idiosyncrasies
underscores the importance of urgent diagnosis of the immune system are often also implicated,
and effective drainage to improve clinical principally in individuals with no apparent
outcomes. Unfortunately, limited evidence predisposition.3
exists to guide clinicians in selecting the ideal
drainage intervention for a specific patient
because of the broad variation that exists in PATHOPHYSIOLOGIC CLASSIFICATION AND
the intrapleural extent of infection, presence of
locules, comorbid features, respiratory status, and Pleural effusions develop when the balance
virulence of the underlying pathogen. Moreover, of pleural fluid formation and removal is altered.
many patients experience delays in both the Pleural effusions secondary to pneumonia
recognition of infected pleural fluid and the are termed parapneumonic effusions. Most
initiation of appropriate measures to drain the of these effusions remain sterile and resolve
pleural space.1Empyema and large or loculated with antibiotic therapy (termed uncomplicated
effusions need to be formally drained, as well parapneumonic effusions), but infections of the
as parapneumonic effusions with a pH <7.20, pleural space develop in a small ubset of patients
glucose <3.4 mmol/l (60 mg/dl) or positive and require drainage for full recovery (termed
microbial stain and/or culture.3 complicated parapneumonic effusions). Without
Several investigators have studied the effective drainage, complicated parapneumonic
efficacy and safety of intrapleural fibrinolytics in effusions progress to frank intrapleural pus,
the treatment of pleural effusion and empyema. which defines the presence of an empyema. This
These researchers report a 38–100% success progression may occur rapidly over a few days
rate (defined as improvement of symptoms, and necessitate surgical drainage (Figure 1).1
improvement of X-ray imaging, no need for Progression to empyema occurs in three
surgical intervention). One group stressed the phases. The exudative phase develops when
importance of accurate staging of empyema inflammatory fluid enters the pleural space across
when choosing to initiate intrapleural fibrinolytic vascular and visceral pleural membranes that
therapy. They found Computed Tomography have increased permeability due to pneumonia.
(CT) scan evidence of a pleural peel was Pleural fluid is nonviscous, free-flowing, and
predictive of failure with fibrinolytic therapy. readily drained by thoracentesis or chest tube.

Gurmeet Singh 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,
Figure 1. Serial chest radiographs and CT scan images imaging is performed to elucidate size and
demonstrating rapid progression of infected pleural fluid
to an empyema that required surgical drainage. A: a chest location of a possible pleural effusion. Upright
radiograph obtained at hospital admission demonstrates a Posteroanterior and Lateral Chest Films can
right pleural effusion and parenchymal density at the right lung demonstrate the general size of an effusion.
base. Therapy with antibiotics was begun, but thoracentesis
was not performed. The effusion became massive 3 days later Ideally, a Lateral Decubitus Chest Film will
(B) when a noncontrasted CT scan (C) demonstrated multiple be obtained to further determine if the fluid
locules that contained viscous pus during surgical drainage.
Without contrast, the CT scan could not clearly differentiate in
is loculated and better estimate the size of
some areas between loculated fluid and lung consolidation.1 the effusion. Other imaging including CT or
Ultrasound is even higher quality in helping to
determine the number of loculations and more
Unremitting inflammation deposits fibrin accurately quantify size of the effusion.9
that coats the visceral pleura and promotes If a pleural effusion is greater than 1.0 cm
the formation of locules that impede lung on lateral decubitus film when measured from
reexpansion during attempts at fluid drainage. the inner chest wall, then the effusion is thought
Pleural fluid becomes purulent and increasingly to be accessible to pleural fluid sampling with
viscous (Figure 2). thoracentesis. Pleural fluid sampling is typically
This fibrinopurulent phase may respond to performed if the etiology of the effusion is
therapy with antibiotics and chest tube drainage unclear or if the patient is not responding to
but often requires intervention to break down appropriate therapy. When a thoracentesis is
adhesions. If a fibropurulent effusion remains performed, the fluid is typically sent for Protein
undrained, fibroblasts eventually deposit fibrotic and LDH, historically known as Light’s Criteria
tissue that encases the lung in inelastic peels. to demonstrate transudative effusions from
At this organizing phase, resolution of the exudative effusions. Additional studies are
empyema requires surgical procedures to drain available for further information, including gram
pus, obliterate the empyema space, and reexpand stain and culture, pH, glucose, and cell count
the lung.1 Parapneumonic effusions represent with differential. These studies can further aid in
the most common cause of exudative effusions determining the cause of the effusion.9 A positive
and occur in 20 to 57% of hospitalized patients result from either the Gram stain or culture, or a
with pneumonia.6 Empyemas occur in 1 to 5% pH of <7.20 is associated with a worse outcome
of hospitalized patients with parapneumonic and indicates the need for drainage. If the pleural
effusions.7,8 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
The evaluation of a patient with a pleural
effusion begins with a detailed history and
thorough physical exam. Patients occasionally FLUID
There are several options available for the
management of the pleural fluid in patients
with parapneumonic effusion, range from non-
invasive 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
Figure 2. Fibrinopurulent Stage loculations in a parapneumonic In practical terms, however, the initial evaluation
effusion.5 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 Minimal, free-flowing effusion Culture and Gram stain

pH unknown No/No
parapneumonic) (<10 mm on lateral decubitus) results unknown

Small-to-moderate free-flowing
II (uncomplicated Negative culture and pH >7.20 or glucose
effusion (>10 mm and less Yes/No
parapneumonic) Gram stain >60 mg/dL
than one-half hemithorax)

Large, free-flowing effusion

(one-half hemithorax or
III (complicated Positive culture or pH <7.20 or glucose
greater); loculated effusion; Yes/Yes
parapneumonic) Gram stain <60 mg/dL
effusion with thickened parietal

IV (empyema) Pus Tests not indicated Yes/Yes

(1) Should the pleural space be drained? (2) How Society (BTS)11,12 and the ACCP guidelines10
should the pleural space be drained? (3) Should recommend fibrinolytic drugs as management
fibrinolytics be instilled? Table 1 is adapted options.
from the American College of Chest Physicians’ Numerous case series and controlled trials
(ACCP) consensus statement that categorizes have shown that intrapleural fibrinolysis is safe,
parapneumonic effusions according to the need increases drainage and improves radiological
for drainage.10 appearance. A randomized controlled study
It is important to realize that the pleural by Davies et al. 13 established that systemic
space anatomy (best visualized by means of fibrinolysis or bleeding complications did not
ultrasonography), pleural fluid appearance and occur with streptokinase, and that patients who
smell, as well as pleural pH are often the only were given intrapleural streptokinase drained
useful criteria for initial decision making, as all significantly more pleural fluid both during the
other laboratory tests need time for processing. days of treatment (n = 24; mean 391 vs. 124 ml,
Frank pus on aspiration, large effusions greater p<0.001) and overall. Patients who received
than half of one hemithorax, effusions with fibrinolytics also showed greater improvement
loculations, or fluid with a pH <7.20 all herald the on the chest radiograph at discharge. Bouros
need for immediate drainage. Further indications et al.14 demonstrated that urokinase was a safe
include a positive Gram stain, a positive microbial intrapleural fibrinolytic. The same group showed
culture and pleural fluid glucose of <3.4 mmol/l that streptokinase and urokinase were clinically
(60 mg/dl).3 and radiologically equally effective as intrapleural
fibrinolytics15, and that intrapleural urokinase
INTRAPLEURAL FIBRINOLYTICS decreased the duration of hospitalization, duration
When an infected pleural space progresses of pleural drainage and time to defervescence.
to the fibrinopurulent phase, fibrin creates Furthermore, Bouros et al.16 were able to show
intrapleural locules that impede chest tube that urokinase’s effect in empyema was through
drainage. Intrapleural instillation of fibrinolytic the lysis of pleural adhesions, rather than the
drugs offers a theoretical benefit for lysing volume effect of instilled urokinase and saline.
fibrin adhesions, promoting pleural drainage, The largest prospective double-blind
and avoiding surgery. Small studies have controlled study on the role of intrapleural
reported the beneficial effects of therapy with streptokinase for pleural infection was published
streptokinase, urokinase, and tissue plasminogen in 2005 (Multicenter Intrapleural Sepsis Trial -
activator(rtPA) for avoiding surgery, promoting MIST 1).17 In this study 454 patients with pleural
catheter drainage, and improving the radiographic pus, pleural sepsis with a pH <7.2 or bacterial
appearance of loculated effusions.1 Based on invasion of the pleural space were randomly
early reports of efficacy, the British Thoracic assigned to receive streptokinase or placebo. The

Gurmeet Singh Acta Med Indones-Indones J Intern Med

patients included were older than in most other fibrinolytic group, and streptokinase was found
studies (average age 60 years) and had a high to decrease the rate of surgical interventions and
prevalence of comorbidities. The MIST 1 study the length of hospital stay.
could not substantiate the role of streptokinase Some centers now use rtPA for fibrinolysis.
in pleural infections: There was no difference Walker et al.22 first reported the apparent benefits
in mortality, need for surgery, radiographic of rtPA in a patient with empyema. Subsequently,
outcome or length of hospitalization. The design Skeete et al.23 instilled rtPA through surgical chest
and execution of this study, however, were tubes into 42 patients with a variety of pleural
criticized.18-20 The lack of image-based selection conditions, of which 12 were empyemas. They
criteria meant that patients with pleural sepsis reported accelerated radiographic improvement
were included irrespective of presence, quantity and clinical benefit. Levinson and Pennington24
and quality of loculations. Questions were raised used fibrinolytic therapy for 30 patients with
about the reproducibility of clinical management largely multiloculated pleural infections; 20
decisions taken across 52 study centres, many patients received rtPA through small-bore,
of which lacked on-site surgical expertise and image-guided chest tubes. The mean length of
contributed only small numbers of patients. The hospital stay was 11 days, and no patient required
study permitted small-bore chest tubes, but did surgical drainage. Gervais et al.25 reported their
not report on pleural drainage volumes, which experience with rtPA instilled through image-
casts doubt on the efficacy of the drainage guided 8.5F to 16F catheters in 66 patients,
techniques used. Furthermore, owing to the of whom 53 had empyemas or complicated
decentralized and blinded design streptokinase/ parapneumonic effusions. In the study by Gervais
placebo was shipped to the study centres after et al.25 patients were selected for fibrinolysis if
randomization causing delays in the initiation of the initial pleural fluid drainage was incomplete.
treatment. The value of mortality as an endpoint The overall success rate was 86%, although the
was also questioned, as patients with serious outcomes were not specifically reported for the
concomitant illnesses that made survival beyond 53 patients with pleural infections. Based on
3 months unlikely were excluded from the study. CT imaging studies obtained before chest tube
The 3-month mortality after hospitalization insertion that demonstrated multiple locules, the
for pneumonia among middle-aged and older authors opined that rtPA successfully drained
patients is more closely associated with the fact effusions that would otherwise have required
that an episode of pneumonia often identifies surgery. The suggested dosages of the current
a fragile underlying health status than with the fibrinolytics in use are summarized in Table 2.3
severity of the acute episode of pneumonia
itself. Intrapleural streptokinase may therefore Table 2. Intrapleural fibrinolytics – Practical use3
not have been given a fair chance to improve Fibrinolytic Dose Instillation1 Duration
the short-term mortality.18 These deficiencies do
Daily for up to
not invalidate this large randomized trial, but 250,000 100–200 ml 7 days (until
concerns remain about the validity of its results IU saline drainage
<100 ml/day)
with regard to younger, more severely ill patients
and in different health care settings.3 Urokinase2
100,000 100 ml Daily for up to
IU saline 3 days
The most recent and second largest
prospective study was conducted by Misthos et tPA
10-25 100 ml Twice daily for
mg saline up to 3 days
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 Fibrinolytic drugs have negligible effects
thoracostomy and streptokinase instillation on decreasing the viscosity of empyema pus
(no placebo control). They found that tube in contrast to agents that depolymerize DNA,
thoracostomy was successful in 67.1% of cases, such as human recombinant deoxyribonuclease.
whereas the installation of streptokinase led The viscosity of pus is largely attributable
to a favourable outcome in 87.7% (p<0.05) to its deoxyribose nucleoprotein content. 26
and significantly shortened hospital stay. The Recombinant deoxyribonuclease has been
mortality rate was also significantly lower in the reported to improve drainage in a single

Vol 44 • Number 3 • July 2012 Update on the Role of Intrapleural Fibrinolytic Therapy

patient who did not respond to fibrinolytic and empyema, particularly in young, acutely ill
therapy. 27 Clinical trials on the efficacy of patients, poor surgical candidates and in centres
recombinant tPA and DNase are currently being with inadequate surgical facilities. Recombinant
performed. An interesting ex vivo observation deoxyribonuclease has been reported to improve
by Light et al.28 was that DNase combined with drainage in a single patient who did not respond
streptokinase (known as Varidase) was superior to fibrinolytic therapy.
to either streptokinase or urokinase at liquefying
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