Editorials
Ongoing Search for Effective Intrapleural Therapy
for Empyema
Is Streptokinase the Answer?
Empyema is one of the oldest and severest of diseases, and
drainage of pleural pus has always been regarded as the key to
its successful management (1). Hippocrates observed that “if an
empyema does not rupture, death will occur” (2). Incision and
drainage were strongly advocated by Osler who viewed empy-
ema as an abscess. Despite the effectiveness of surgical drainage
in evacuating pus, there is a long history of reservations on
subjecting patients to surgery. Dupuytren, Napoleon’s surgeon,
developed an empyema but chose to “die at the hands of God
than of surgeons” (2).
Today 65,000 patients in the U.S.A. and UK suffer from an
empyema or a complicated parapneumonic effusion each year,
with a mortality up to 20% and an estimated hospital cost of
$500 million (1, 3). Modern-day surgery (thoracoscopic surgery
or thoracotomy with decortication) remains the last resort for
empyema in many countries because of limited surgical re-
sources, risks of surgery, and philosophy of individual physicians.
There is thus an ongoing need for non-surgical adjunct therapies
to promote pus drainage.
Empyema is characterized by fibrinous septations which defy
complete evacuation of infected fluid by tube thoracostomy—
often resulting in ongoing sepsis despite parenteral antibiotics
(1). Local instillation of fibrinolytics to lyze adhesions and en-
hance drainage, although theoretically sound and widely prac-
ticed, has little evidence-based support. The study by Diacon
and coworkers (4), in this issue of the Journal (pp. 49–53), is an
important addition as the first randomized placebo-controlled trial
of intrapleural streptokinase in pleural infection that employed
pragmatic clinical outcomes (need of surgery or death) as primary
endpoints.
Clinicians’ enthusiasm for fibrinolytics in empyema stems
from two potentially deceptive observations. One, there have
been numerous uncontrolled observational reports, the method-
ological limitations of which are well known, advocating the use
of streptokinase. Two, clinicians and patients are often “reassured”
that “streptokinase is working” by the marked (up to 9-fold [5])
increase in pleural fluid drainage following fibrinolytic administra-
tion. However, drainage volume, the commonest principal end-
point in previous studies (5–7), is not an ideal clinical or research
outcome measure. Indeed, a non-randomized controlled study
showed that increased fluid output following streptokinase did
not translate into improved morbidity (8). In animal studies,
intrapleural streptokinase can induce pleural fluid accumulation
(9), casting further doubts on the validity of drainage volume
as an endpoint. In their study, Diacon and coworkers have taken
an important step forward by putting streptokinase to the “real
test”—against clinical outcomes.
Did the jury reach a verdict? In this study, 53 patients with
pleural infection were randomized to receive intrapleural strepto-
kinase or saline daily. The need for surgery was judged by clini-
Am J Respir Crit Care Med Vol 170. pp 1–9, 2004
Internet address: www.atsjournals.org
cians blinded to the treatment agents. The results were mixed,
and interpretions dependent on the reader’s bias. On one hand,
streptokinase provided no benefits over placebo in mortality (one
in each group) or in reducing the need for surgery at Day 3.
At Day 7, however, fewer patients in the streptokinase group
required surgery than the controls (9% versus 45%, p ⫽ 0.02)
(4). Are these results the “smoking gun” that supporters of
streptokinase have been waiting for? Careful analysis of the
data, with a healthy dose of skepticism, suggest no for two rea-
sons, both of which underscore important design issues of clinical
trials for empyema.
First, the significant difference at Day 7 was due to an unusu-
ally high failure rate in the control group (50%, versus 25–34%
in previous studies [6, 8]). The discrepancy probably arose from
the chosen criteria for referring patients for surgery. Surgery
and deaths are no doubt the most important outcome measures,
but the threshold for surgical drainage varies significantly among
clinicians. Diacon and coworkers referred patients for surgery
for either ongoing sepsis or a lack of satisfactory radiological
improvement beyond seven days (4). This contrasts with previ-
ous studies where patients referred for surgery satisfied both
criteria (6, 10). Many control patients who underwent surgery
in the study of Diacon and coworkers had no significant sepsis:
4 of those 10 patients had resolution of fever days before surgery;
none were reported to have persistently raised inflammatory
markers. The need of surgery for the lack of radiographic im-
provement, in the absence of sepsis, is arbitrary. Interestingly,
the authors showed that residual radiographic opacity in the
remaining patients resolved spontaneously without surgery with
no long-term sequelae (4). In future, establishing the optimal
timing and criteria for surgical referral is necessary for best
patient care and will allow standardization of clinical outcome
measures and comparison of results between trials.
Second, the power of this study was limited. The advantage
of the streptokinase group at Day 7 (p ⫽ 0.026) was dependent
on a single patient and would become statistically insignificant
had one extra streptokinase patient required surgery (p ⫽ 0.06)
or one more control patient avoided surgery (p ⫽ 0.052), or
both (p ⫽ 0.11). The results thus require verification in larger
studies and cannot be regarded as definitive at present. Empyema
patients are heterogenous in their bacteriology, clinical presenta-
tions, and predisposing co-morbidities. Multicenter collaborations
are needed to provide sufficient power to draw reliable conclu-
sions. One example is the recently completed Multicentre In-
trapleural Sepsis Trial, which randomized 450 patients with pleural
infection from 72 British centers to receive twice-daily doses of
streptokinase or placebo for three days. Its results are awaited.
Withstanding these concerns, the positive results by Diacon
and coworkers provide hope and a platform for the ongoing
search of adjunct intrapleural therapy for empyema. Although
streptokinase lyzes adhesions, it is not bacteriocidal (8) and does
not reduce viscosity of pus (11). Pus is thick because of its high
DNA content from degranulated cells. It is plausible that a com-
bination of agents that reduce pus viscosity (e.g., DNase [11]) and
2 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 170 2004
those that break down loculations may be necessary to enhance
pus drainage. Manipulating the key molecules in the pleural fibro-
sis (e.g., transforming growth factor-␤ [12]) and fibrinolytic cas-
cades (e.g., urokinase plasminogen activator [13]) show a glimpse
of promise in providing targets for novel adjunct therapies.
Osler once stated, “empyema needs a surgeon and three in-
ches of cold steel, instead of a fool of a physician” (14). He under-
went rib resections for his own empyema. A century later, tube
thoracostomy and antibiotics form the first line treatment for
empyema (3), but surgical drainage stays a key armament if the
patient fails to respond (15). Despite widespread optimism, the
value of adjunctive intrapleural streptokinase remains unproven.
Conflict of Interest Statement : Y.C.G.L. receives royalties for a reference text on
pleural disease that he co-edited; he receives no payment as the co-editor of the
International Pleural Newsletter; Y.C.G.L. is an honorary respiratory consultant at the
Osler Chest Unit, Oxford, UK, where two of his colleagues (Drs R.J.O. Davies and F.V.
Gleeson) are members of the steering committee for the MIST trial on streptokinase,
but Y.C.G.L. was not involved in the study; Y.C.G.L. is a co-investigator of a multi-
center trial of deoxyribonuclease and fibrinolytics in empyema that is currently
under planning.
Y. C. Gary Lee
University College London
and Osler Chest Unit
Oxford, United Kingdom
References
1. Maskell NA, Davies RJO. Effusions from parapneumonic infection and
empyema. In: Light RW, Lee YCG, editors. Textbook of pleural dis-
eases. London: Arnold Press; 2003. p. 310–328.
2. Warren P. The surgical treatment of pulmonary and cardiac disease.
Available at: http://www.umanitoba.ca/faculties/medicine/history/notes/
surgery/ (Date accessed: May 18, 2004).
3. Davies CWH, Gleeson FV, Davies RJO. The British Thoracic Society
guidelines on the management of pleural infection. Thorax 2003;58:
ii18–ii28.
Analyzing Surfactant Metabolism in Humans
An Important First Step
Pulmonary surfactant is a complex mixture of lipids and specific
surfactant-associated proteins lining the epithelial surface of
lungs. Within the alveoli, its main function is to reduce surface
tension at the air–liquid interface and ensure alveolar stability
during respiratory motion (1). The clinical importance of surfac-
tant in maintaining lung homeostasis is evident from the signifi-
cant impact that exogenous surfactant administration has had
on preterm infant mortality, as well as the documented contribu-
tion of surfactant alterations to the respiratory failure associated
with the acute respiratory distress syndrome (ARDS) (2, 3). In
addition, pulmonary surfactant also functions as part of the in-
nate host defense system and contributes to the stability and
patency of the conducting airways (4, 5). These latter two func-
tions suggest that alterations of surfactant may contribute to the
pathophysiology of other diseases involving the mature lung
including bacterial pneumonia, bronchial asthma, and cystic fi-
brosis. Indeed, changes in surfactant composition have been
observed in bronchoalveolar lavage samples obtained from these
types of patients (6). Studies on animal models of lung injury,
including studies using radiolabeled surfactant precursors, have
shown that alterations in endogenous surfactant metabolism di-
rectly contribute to these observed changes. Unfortunately, even
though these studies have enhanced our knowledge about surfac-
4. Diacon AH, Theron J, Schuurmans MM, Van de Wal BW, Bolliger CT.
Intrapleural streptokinase for empyema and complicated parapneu-
monic effusions. Am J Respir Crit Care Med 2004;170:49–53.
5. Bouros D, Schiza S, Panagou P, Drositis J, Siafakas N. Role of streptoki-
nase in the treatment of acute loculated parapneumonic pleural effu-
sions and empyema. Thorax 1994;49:852–855.
6. Davies RJO, Traill ZC, Gleeson FV. Randomised controlled trial of
intrapleural streptokinase in community acquired pleural infection.
Thorax 1997;52:416–421.
7. Bouros D, Schiza S, Patsourakis G, Chalkiadakis G, Panagou P, Siafakas
NM. Intrapleural streptokinase versus urokinase in the treatment of
complicated parapneumonic effusions. Am J Respir Crit Care Med 1997;
155:291–295.
8. Chin NK, Lim TK. Controlled trial of intrapleural streptokinase in the
treatment of pleural empyema and complicated parapneumonic effu-
sions. Chest 1997;111:275–279.
9. Strange C, Allen ML, Harley R, Lazarchick J, Sahn SA. Intrapleural
streptokinase in experimental empyema. Am Rev Respir Dis 1993;147:
962–966.
10. Bouros D, Schiza S, Tzanakis N, Chalkiadakis G, Drositis J, Siafakas
NM. Intrapleural urokinase versus normal saline in the treatment of
complicated parapneumonic effusions and empyema. Am J Respir Crit
Care Med 1999;159:37–42.
11. Simpson G, Roomes D, Heron M. Effects of streptokinase and deoxyribo-
nuclease on viscosity of human surgical and empyema pus. Chest 2000;
117:1728–1733.
12. Sasse SA, Jadus MR, Kukes GD. Pleural fluid transforming growth factor-
beta1 correlates with pleural fibrosis in experimental empyema. Am
J Respir Crit Care Med 2003;168:700–705.
13. Idell S, Mazar A, Cines D, Kuo A, Parry G, Gawlak S, Juarez J, Koenig
K, Azghani A, Hadden W, et al. Single-chain urokinase alone or
complexed to its receptor in tetracycline-induced pleuritis in rabbits.
Am J Respir Crit Care Med 2002;166:920–926.
14. Bean RB. Sir William Osler: aphorisms from his bedside teachings and
writings. Available at: http://www.vh.org/adult/provider/history/osler/
5.html (Date accessed: May 18, 2004).
15. Wait MA, Sharma S, Hohn J, Dal Nogare A. A randomized trial of
empyema therapy. Chest 1997;111:1548–1551.
DOI: 10.1164/rccm.2404013
tant metabolism in health and disease, most animal models,
particularly for diseases such as asthma and cystic fibrosis are not
an accurate reflection of the human condition, thus the specific
surfactant alterations observed in such models have to be inter-
preted with caution. In addition, bronchoalveolar lavage samples
obtained from humans under different conditions only provide
a snapshot of the status of the surfactant system at one time,
so that accurate metabolic information cannot be elucidated.
Therefore, a more extensive evaluation of surfactant metabolism
in patients with these various respiratory conditions would repre-
sent an important advance. The study reported by Bernhard and
colleagues in this issue of the Journal (pp. 54–58) describes a
novel methodological approach to address this issue and is an
important first step in this direction (7).
Previous reports evaluating surfactant metabolism in humans
using stable isotope-labeled precursors involved preterm and/or
critically ill infants that were mechanically ventilated (7–10). The
current study is the first to evaluate surfactant metabolism in
spontaneously breathing adult subjects using the more specific,
deuterium-labeled precursor, choline, rather than labeled glu-
cose or fatty acid infusion. In addition to providing a more direct
assessment of de novo synthesis of the most abundant surfactant
lipid, phosphatidylcholine, the approach used by Bernhard and
colleagues involved a significantly shorter infusion time of pre-