Controlled Trial of Intrapleural

Streptokinase in the Treatment of Pleural

Empyema and Complicated
Parapneumonic Effusions
Nyat Kooi Chin and Tow K. Lim

Chest 1997;111;275-279
DOI 10.1378/chest.111.2.275
The online version of this article, along with updated information and
services can be found online on the World Wide Web at:
http://chestjournal.chestpubs.org/content/111/2/275

CHEST is the official journal of the American College of Chest

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1997 by the American College of Chest Physicians
Controlled Trial of Intrapleural
Streptokinase in the Treatment of
Pleural Empyema and Complicated
Parapneumonic Effusions*
Nyat Kooi Chin, MBBS; and Tow K. Lim, MBBS

Objective: To compare the efficacy of adjunctive intrapleural streptokinase (SK) with simple
closed chest tube drainage (Drain) in the treatment of empyemas and complicated parapneumo¬
nic effusions.
Method: This was a controlled study of 52 patients (mean age, 57 years; 41 men) with pleura space
sepsis. Forty patients (77%) had empyema and 12 had complicated parapneumonic effusions.
Twenty-nine patients were treated with Drain only while 23 received, in addition, repeated daily
SK, 250,000 U in saline solution (mean, 5.3 days).
Results: The two groups of patients had comparable degrees of peripheral blood leukocytosis,
frequency of loculated effusions, pleural fluid pH, and lactate dehydrogenase levels. Infective
organisms were isolated in 54% of which 32% were anaerobic and 21% were polymicrobial
infections. The incidence of surgical decortication was 17% and mortality was 15%. A significantly
the SK treatment group (2.0 [1.5] L)
larger volume of pleural fluid was drained from patients inThere
than those in the Drain treatment group (1.0 [1.01] L). were no significant differences,
however, between the two treatment groups in terms of duration before defervescence, duration
of hospital stay, the need for surgical intervention, or mortality rates.
Conclusion: We conclude that thrombolytic therapy increased the volume of fluid drained from
pleural empyemas but did not markedly reduce morbidity and mortality.
(CHEST 1997; 111:275-79)

Key words: decortication; empyema; parapneumonic; pleural effusion; streptokinase; thoracoscopy

Abbreviations: Drain=simple tube drainage; LDH=lactate dehydrogenase; SK=streptokinase

ID leural empyema
-*-
is a complication of
serious tions with bettersafety profiles.910 This has resulted
pneumonia associated with substantial morbid¬ in renewed interest in these agents as an adjunctive
ity and mortality.1-3 Treatment of pleural empy¬ treatment modality for empyema. A large number of
emas is based on early diagnosis and prompt reports have attested to the safety and efficacy of
evacuation of the pleural cavity.137 Failure to intrapleural thrombolysis in the treatment of tho¬
empty the infected pleural cavity may result in racic empyema.9-16 None of these studies, however,
deposition of fibrin with formation of multiple has directly compared pleural thrombolysis with
pleural loculations. This very often leads to de¬ simple tube thoracotomy in the treatment of patients
layed resolution, further pleural suppuration, and with pleural empyema. Since the management of
a prolonged hospital stay with the need for costly
empyema requires a multidisciplinary approach with
and risky surgical intervention.2-7 key contributions from interventional radiologists
The intrapleural administration of thrombolytic and thoracic surgeons whose skills and expertise may
agents has been used to treat empyema for more vary between different hospitals, studies comparing
than 40 years.8 It may prevent pleural fibrogenesis different treatment regimens should recruit patients
and facilitate drainage of pleural collections. This from the same institution.
approach did not receive wide acceptance until the We report a controlled study that compared in¬
recent introduction of newer thrombolytic formula-
trapleural streptokinase (SK) with simple tube drain¬
age (Drain) in the treatment of 52 patients with
*From the Department of Medicine, National University Hospi¬ complicated parapneumonic pleural effusions and
tal, Singapore.
Manuscript received August 9, 1996; accepted September 16. frank empyema.
CHEST 7111/2/ FEBRUARY, 1997 275
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1997 by the American College of Chest Physicians
 Table 1.Clinical and Demographic Information:* volume of pleural fluid drained on a daily and cumulative basis:
Mean (SD) (2) duration from the day of hospital admission to defervescence;
(3) duration of hospital stay; (4) need for surgical intervention:
SK Group Drain Group and (5) mortality.
No. 23 29 All results were expressed as mean (SD) values. Continuous
50 (19) 63 (14) variables were compared with paired and unpaired Student's t
Age, yr tests where appropriate while the x2 was used to test for
Sex ratio, M/F 18/5 23/6
differences between proportions.
Underlying disease, % 48 59
Blood TWBC, X106/L 18,200 (8,360) 16,210 (8,400)
*
Underlying disease: frequency of occurrence of diabetes mellitus
Results
and chronic lung diseases. TWBC=total WBC count. There were
no statistically significant differences between the two groups.
There were 52 patients (41 men and 11 women)
with a mean (SD) age of 57 (17) years, range
between 16 and 18 years. Most patients (75%) had
Materials and Methods some underlying disease, with diabetes in 41% and
chronic lung diseases in 31%. There were no signif¬
This was a 5-year (1990 to 1995), prospective study of 52 icant differences in age, sex ratio, frequency of
consecutive patients admitted to the hospital with community-
acquired empyema and complicated (high-risk) parapneumonic underlying disease, and degrees of peripheral blood
effusions.17 Empyema (40 patients) was defined according to one leukocytosis between patients on the SK and Drain
or more of the following criteria; (1) grossly purulent fluid; (2)
positive fluid culture; and (3) positive Gram stain for bacteria.1
treatment protocols (Table 1).
Complicated parapneumonic effusions (12 patients) were de¬ Forty patients (77%) had frank empyema and the
rest had complicated parapneumonic effusions.
fined according to Light1 viz (1) pH <7.00 or (2) lactate
dehydrogenase (LDH) level > 1,000 U/L. Patients with tubercu¬ Twenty-eight (54%) patients had positive pleural
lous, hospital-acquired, posttraumatic, and postoperative empy¬ fluid cultures, of which 32% were anaerobic and
emas were excluded. 21% were polymicrobial. The most common aerobic
Diagnostic thoracentesis with a 14-gauge venula was per¬ isolates were Klebsiella pneumoniae and Staphylo¬
formed for all patients on hospital admission. The pleural fluid coccus aureus while the most frequently isolated
samples were sent for biochemical analysis (sugar, protein, pH, anaerobe was Bacillus fragilis. There was no signifi¬
LDH); for differential cell counts; Gram stain; and aerobic,
anaerobic, and mycobacterial cultures. Closed tube thoracentesis cance difference between the two treatment groups
with a size 24 chest tube was performed at the bedside in patients in the frequency of gross empyema, bacterial iso¬
with large, dependent pleural collections. In patients with effu¬ lates, pleural fluid loculations, and biochemical ab¬
sions that were multiloculated and/or were in nondependent normalities (Table 2).
areas, 7 to 12F pigtail catheters were placed under ultrasound
guidance. All patients were seen at least daily to assess progress. The mean (SD) duration of tube drainage on the
The need for further imaging and drainage was decided on an Drain protocol was 12 (SD=8) days (n=29) with five
individual basis. CT examinations were made in all patients with patients requiring more than one tube insertion
suspected multiloculation and who failed to respond promptly. (Table 3). Four patients (14%) did not respond to
The two treatment protocols, Drain and tube drainage with the treatment and required surgical decortication.
adjunctive intrapleural SK, were instituted in a sequential man¬ Two patients in this group stayed more than 60 days
ner with Drain utilized for the first 2.5 years and SK used
exclusively in the last 2.5 years of the study. The same team of in hospital. They developed complications (end-stage
chest physicians was responsible for patient care over the whole renal failure in one and postanoxic encephalopathy
study period with a consistent approach to the initial choice of in another) not related to the pleural sepsis that had
empiric antibiotics, the indications for further intervention (in¬ resolved after 12 and 15 days of tube drainage. If
cluding open or thoracoscopic surgical drainage and decortica¬
tion), and eventual discharge from hospital.
In the SK protocol, we administered 250,000 U of SK in 100
mL of saline solution into the pleural cavity on a daily basis. Each
dose of SK was left in the pleura for 4 h with the chest tube Table 2.Pleural Fluid Characteristics:* Mean (SD)
clamped following which the fluid was manually aspirated and
then released into an underwater seal for passive drainage. The SK Group Drain Group
total number of doses was determined by patient response.
Contraindications to the use of SK was known allergy or a history Empyema, % 74 79
of bleeding ulcer disease. Positive cultures, 48 59
The chest drains were removed when the daily drainage had Multiloculation, 9 22 7
fallen below 50 mL with clinical and radiologic resolution of the PH 7.2 (0.2) 6.96 (0.6)
pleural collection. Either thoracoscopic or open surgical drainage LDH, U/L 14,850 (10,000) 16,700 (18,000)
and decortication was performed only if there had been no *Empyema=percentage of patients with empyema as defined in the
response to either treatment protocols and the empyema had "Materials and Methods" section; positive cultures=percentage of
organized itself into a pleural peel visible on the CT. patients with positive bacterial isolates; multiloculation=percentage
We prospectively evaluated the effect of the two different of patients with two or more pleural locules. There were no
treatment protocols on the following clinical outcomes: (1) statistically significant differences between the two groups.
276 Clinical Investigations
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1997 by the American College of Chest Physicians
 Table 3.Clinical Outcomes:* Mean (SD) volume of fluid drained in the SK group was 1,982
SK Group Drain Group (1,500) mL. This was significantly higher than the
cumulative volume of pleural fluid in the Drain
Duration of hospitalization, d 22 (11) 21 (12)f group (1,007 [1,008] mL; p=0.007). Nine patients
Days before defervescence, d 10.6 (7) 7.7(5) had more than one chest tube inserted. One patient
Total volume of fluid drained, L 2.0 (1.5) 1.0(1.01)* who needed five tubes inserted into three locules
Days with chest tube 12 (5) 12 (8)
Surgical procedures, % 22 14 over a 2-week period made a complete recovery.
Mortality, %9 24 Five patients (22%) underwent thoracoscopic evac¬
Failure rate, % 30 34 uation and pleurodesis; all survived. Two patients in
*
Surgical procedures=percentage of patients who needed surgical the SK group died, one from myocardial infarction
drainage; failure rate=percentage of patients who either died or and the other from septicemia.
needed surgeiy. There were no significant differences in clinical
fTwo patients who had prolonged hospitalizations due to complica¬
tions unrelated to pleural sepsis were excluded. outcomes between the two groups (Table 3). The
*Only total volume of fluid drained was significantly different be¬ duration of hospital stay was 22 (11) days for the SK
tween the two groups (p=0.007). There were no significant differ¬
in all other outcome indexes.
group and 21 (12) for the Drain group (n=27,
ences
excluding the two patients described above who had
long stays hospital from complications not related
in
to pleural sepsis); the duration from the day of
these two patients were excluded, the mean (SD) hospital admission to defervescence was 10.6 (7)
duration of stay in hospital for this group was 21 (12) days for the SK protocol and 7.7 (5) days for the
Drain protocol. The percentage of patients who
days (n=27). One patient who stayed 21 days in
hospital developed a persistent fistula following chest eventually required surgical intervention was 22%
tube removal which resolved after 18 months of for the SK group and 14% for the Drain group, and
ambulatory care. Seven patients (24%) in this group there was also no significant difference in the mor¬
died, six from septicemia (one of these patients died tality, which was 9% in the SK group and 24% in the
following open drainage and decortication) and one Drain group. The overall failure rate (defined as
after an acute myocardial infarct. either surgical intervention or death) was 30% (7/23)
The patients on the SK protocol received between in the SK group and 34% (10/29) in the Drain group.
1 to 10 daily administrations of SK (mean [SD] 5.3
[2.7]). No adverse effect of SK was noted. Figure 1
shows the marked increase in pleural fluid drainage Discussion
after SK instillation. The mean (SD) total cumulative
Previous reports on the use of intrapleural throm¬
bolysis as an adjunctivethatmodality in the treatment of
5000 empyema suggested it may be highly effective
n = 23 with success rates ranging from
about 50 to
100%.816
P These include a multicenter report of 30 patients
from Mexico by Jerjes-Sanchez et al16 (SK was used)
4000 4- and a large series of 84 patients with multiloculated
effusions from Denver described by Moulton et al15
(urokinase was used). The overall success rate of
fr 3000 70% (SK group, n 23) in this study is comparable to
=

that reported from elsewhere.8-16 None of these

previous studies, however, directly compared the
2000 4- clinical outcomes of adjunctive thrombolysis with
closed tube drainage alone. From the consistently
encouraging comments in the literature, we had
1000 anticipated a clear improvement in patient outcome
with the use of intrapleural SK. This was not the
case.
The administration of SK did increase the volume
of pleural fluid drained from our patients. In some
PreSK PostSK cases, this increase was dramatic (Fig 1). However,
Figure 1. The cumulative volumes of pleural fluid drained
this did not result in any significant improvement in
before (Pre SK) and after (Post SK) institution of intrapleural the key measures of clinical outcome such as dura¬
streptokinase. tion of hospital stay, the need for open surgical

CHEST / 111 / 2 / FEBRUARY, 1997 277

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1997 by the American College of Chest Physicians
 mortality (Table 3). Our results random¬
drainage,to orthose are very with prompt and complete clearance of the pleural
similar of another yet unpublished infection. Failure of the empyema to resolve, both
ized controlled trial discussed by Davies et al18 at the clinically and radiologically, within 48 to 72 h follow¬
American Thoracic Society meeting in May 1996. In ing the repeated use of intrapleural thrombolytic
23 patients (10 with frank empyema), they compared agents may be an indication for further intervention.
three daily doses of intrapleural SK with chest tube We suggest that it may be appropriate, at this stage,
drainage and found that while SKvolumes treatment drained to consider either early thoracoscopic debridement
more pleural fluid (cumulative of 2.5 L vs and evacuation or open surgical drainage in surgi¬
1.0 L, very similar to this study; see Table 3), it did cally fit patients with multiloculated empyemas.2122
While results of thoracoscopic management of em¬
not significantly affect duration of hospitalization and
success rates. Thus, two separate controlled studies pyemas have been encouraging, no controlled stud¬
have confirmed that pleural fibrinolysis improves ies have been reported (to our knowledge).2123"25
fluid drainage but not clinical outcome. The role of thoracoscopy in the management of
Strange and colleagues19,20 have shown, in a rabbit empyema is thus, unclear. Randomized trials are
model of pleural sepsis, that intrapleural thrombo¬ needed to compare chest tube drainage with fibrino¬
lytic agents caused two clinically significant effects. lytic agents vs either early thoracoscopic or open
They increased plasminogen-dependent fibrinolytic debridement and drainage.
This study has several limitations. It was not a
activity in the pleura and thus reduced the number
of pleural adhesions. They also, for yet unknown formal randomized controlled trial since the differ¬
reasons, increased the volume of pleural fluid inde¬ ent treatment regimens were not instituted in paral¬
drainage
pendentWeof think (from 4.8 [1.7] mL to 18.8 [5.1] lel but in series. The patients in the SK treatment
mL).19 that both these effects were
impor¬ group were younger and there were a larger number
tant in patients and accounted for the marked
our of patients with multiloculated empyemas than in the
difference in volume of fluid drainage between the Drain protocol. These differences were not statisti¬
two groups of patients. The effect of SK in increasing cally significant, however, and we think overall, the
pleural fluid production may not in itself be delete¬ two groups of patients had diseases of comparable
rious provided effective overall drainage is achieved severity. With regards to outcome, there were no
and patients show rapid clinical and radiologic im¬ marked differences between the two groups with
provement. It is possible, however, that SK treat¬ failure rates (defined as either death or surgical
ment could have been carried on for longer than intervention) of 30% and 34%) (Table 3). Further¬
appropriate in some patients. If the administration of more, the results of this study were very similar to
SK were to result, each time, in a large volume of those reported from the randomized controlled
"positive" fluid drained, this might delay decisions study by Davies et al.18from The higher mortality rate
regarding tube removal or the need for further (especially death rates septicemia which were
also not significantly greater than in the SK group) in
intervention. The average number of doses of SK
administered in this study (5.3 [2.7]) was comparable the group that did not receive SK may be related to
to most other series (4.9 in Moulton et al15 and 5.1 older age rather than less effective treatment. It is
[2] in Jerjes-Sanchez et al16). This suggests that we
were not unduly prolonging the SK regimen in our
possible that a randomized trial involving a larger
number of patients may be needed to demonstrate
patients comparison
in with current practice. Fur¬ the therapeutic impact of intrapleural fibrinolysis.
thermore, Davies et al,18 who used three doses of SK We conclude that, in the treatment of pleural
(over 3 days) for all patients, achieved very similar empyema, in comparison with simple closed-tube
patient outcomes. It is possible, however, as sug¬ drainage, ofthe adjunctive treatment with daily admin¬
gested by Moulton et al,15 that a better result might istration intrapleural significantly increased
SK
the volume of pleural fluid drainage, but did not
be achieved by administering two to three doses of
the thrombolytic agent within 24 h. This might markedly reduce mortality, morbidity, or the need
achieve a more intense fibrinolysis in the pleural for surgical intervention.
cavity over a shorter time and avoid any tendency to
delay. This approach will require more frequent References
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 Controlled Trial of Intrapleural Streptokinase in the Treatment of
Pleural Empyema and Complicated Parapneumonic Effusions
Nyat Kooi Chin and Tow K. Lim
Chest 1997;111; 275-279
DOI 10.1378/chest.111.2.275
This information is current as of September 8, 2010
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