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Intra-pleural fibrinolytic therapy versus conservative

management in the treatment of adult parapneumonic

effusions and empyema (Review)

Cameron RJ, Davies HRHR

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2009, Issue 3

http://www.thecochranelibrary.com

Intra-pleural fibrinolytic therapy versus conservative management in the treatment of adult parapneumonic effusions and empyema

(Review)

Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/

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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

9DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

12 AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Fibrinolytic versus placebo (loculation and empyema), Outcome 1 Treatment failure- death. 27

Analysis 1.2. Comparison 1 Fibrinolytic versus placebo (loculation and empyema), Outcome 2 Treatment failure- surgical

intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Analysis 1.3. Comparison 1 Fibrinolytic versus placebo (loculation and empyema), Outcome 3 Overall treatment failure. 29

Analysis 1.4. Comparison 1 Fibrinolytic versus placebo (loculation and empyema), Outcome 4 Significant treatment

complications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Analysis 2.1. Comparison 2 Fibrinolytic versus placebo (loculated effusions only), Outcome 1 Treatment failure- death. 31

Analysis 2.2. Comparison 2 Fibrinolytic versus placebo (loculated effusions only), Outcome 2 Treatment failure- surgical

intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Analysis 2.3. Comparison 2 Fibrinolytic versus placebo (loculated effusions only), Outcome 3 Overall treatment failure. 33

Analysis 3.1. Comparison 3 Streptokinase versus urokinase, Outcome 1 Treatment failure- death. . . . . . . . 34

Analysis 3.2. Comparison 3 Streptokinase versus urokinase, Outcome 2 Treatment failure- surgical intervention. . . 34

Analysis 3.3. Comparison 3 Streptokinase versus urokinase, Outcome 3 Overall treatment failure. . . . . . . . 35

Analysis 3.4. Comparison 3 Streptokinase versus urokinase, Outcome 4 Significant treatment side effects. . . . . 35

35ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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[Intervention Review]

Intra-pleural fibrinolytic therapy versus conservativemanagement in the treatment of adult parapneumoniceffusions and empyema

Robert J Cameron1, Huw Richard H R Davies2

1ICU, Northern SydneyCentral Coast AreaHealth Service, NSW, Australia, Gosford, Australia. 2c/o Division of Medicine, Repatriation

General Hospital, Daw Park, Australia

Contact address: Robert J Cameron, ICU, Northern Sydney Central Coast Area Health Service, NSW, Australia, PO Box 361, Gosford,NSW, 2250, Australia. [email protected].

Editorial group: Cochrane Airways Group.

Publication status and date: Edited (no change to conclusions), published in Issue 3, 2009.

Review content assessed as up-to-date: 3 January 2008.

Citation: Cameron RJ, Davies HRHR. Intra-pleural fibrinolytic therapy versus conservative management in the treatment of

adult parapneumonic effusions and empyema. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD002312. DOI:10.1002/14651858.CD002312.pub3.


A B S T R A C T

Background

Pleural effusions and empyema may complicate lower respiratory tract infections. Treatment of these collections of pus includes surgical

drainage and the use of intra-pleural fibrinolysis to break down fibrin bands that may cause loculation.

Objectives

To conduct a systematic review of the benefit of adding intrapleural fibrinolytic therapy to intercostal tube drainage in the treatment

of complicated para pneumonic effusions and empyema to reduce mortality or the need for subsequent surgical debridement of the

pleural space.

Search strategy

We searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. Trial authors were contacted for

further information and details regarding the possibility of unpublished trials was requested. The most recent search was conducted in

November 2006.

Selection criteria

All studies in the review were Randomised Controlled Trials in adult patients with post-pneumonic empyema or complicated para-

pneumonic effusions who had not had prior surgical intervention or trauma. The intervention was an intrapleural fibrinolytic agent

(streptokinase or urokinase) via an intercostal chest drain (ICD) versus control, or a comparison of the two agents.

Data collection and analysis

Two review authors independently extracted data . Study authors were contacted for further information.

1Intra-pleural fibrinolytic therapy versus conservative management in the treatment of adult parapneumonic effusions and empyema

(Review)

mailto:[email protected]:[email protected]

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Main results

Seven studies met the eligibility criteria of the review, recruiting 761 participants. The only consistent end points in all trials were

treatment failure, as gauged by the requirement for additional intervention including surgery or death. In studies where patients had

either loculation and empyema, there was no significant difference in the risk of death with fibrinolytics (RR 1.08; 95% CI 0.69 to

1.68). When treatment failure was considered as surgical intervention, fibrinolytics reduced the risk of this outcome (RR 0.63; 95%

CI 0.46 to 0.85), but there is discordance between earlier positive studies and the more recent negative study by Maskell.

Authors conclusions

Intrapleural fibrinolytic therapy confers significant benefit in reducing the requirement for surgical intervention for patients in the early

studies included in this review but not in the more recently published Maskell study. The reasons for this difference are uncertain.

Separate subgroup analysis of proven loculated/septated effusions from the available data in our meta-analysis suggests a potential overall

treatment benefit with fibrinolytics, but these results should be treated with caution as the data are incomplete and the benefit is not

significant in the subgroup of high quality trials (Cochrane Grade A). Intrapleural fibrinolytics have not been shown to significantly

increase adverse events, but the confidence interval is too wide to firmly exclude this possibility.

P L A I N L A N G U A G E S U M M A R Y

Intra-pleural fibrinolytic therapy versus conservative management in the treatment of adult parapneumonic effusions and

empyema

Infected purulent pleural effusions (empyema) with isolated collections (loculations) of fluid or pus (complicated parapneumonic

effusions) may develop with pneumonia. Drainage of this infected fluid via an intercostal catheter is important in healing. Evidence

from seven randomised controlled trials (RCTs) with 761 participants indicates that flushing the pleural space with a fibrinolytic agent

such as streptokinase or urokinase may help to break down the fibrinous bands or loculations that prevent total drainage of infected

pleural fluid and therefore may significantly increase the amount of pus drained. Meta-analysis of these RCTs indicates that intrapleuralfibrinolytic therapy confers a benefit in reducing the requirement for surgical intervention for patients in some studies but not in others

. The safety profile of intrapleural fibrinolytics remains uncertain.

B A C K G R O U N D

A parapneumonic effusion, resulting from pneumonia in up to

57% of cases (Sahn 1993), may constitute an incidental, non-sig-

nificant finding or become large and persistent. These effusions,

which may arise from a variety of infections, have been classifiedaccordingto their size,biochemical and microbiological properties

and the presence of fibrinous loculations - Lights criteria (Light1995; Light 1998). For the purposes of this review, a complicated

parapneumonic effusion may be defined as having pH < 7.2, lac-

tate dehydrogenase (LDH) > 1000 units, glucose < 40 mg/dl or 50% of cases in Bouros

1999 and 74% of patients in Maskell 2005 having at least one

other major co-morbidity. This may have an impact on treatment

failure, as seenin Maskell 2005which carries the highest mortality

rate. Chin 1997 (not included in meta-analysis) shows an overall

mortality of 7/52 (13.5%) and a high overall treatment failure rate

of 17/52 (33%) attributable to septicaemia in a study population

with 75% co-morbidity.

The intrapleural dose of fibrinolytics is empirical, without exper-imental foundation in the context of pleural disease. Daily strep-

tokinase 250,000 units and urokinase 100,000 units were em-

ployed in these studies. Frequency of dose is equally empirical,

generally being administered once daily, but given the effective

half-life of both fibrinolytics is less than half an hour ( Moulton

1995), it is possible that fibrin deposition may occur within the

24 hour period, and more frequent than daily administration may

therefore be appropriate. Higher doses of intrapleural fibrinolytics

have been used safely.

The safety profile in these studies was generally good. The only

study to report significant side effects attributable to a fibrinolytic

(SK) was Maskell 2005 who reported a non-significant increase (P

= 0.08) in severe events in the streptokinase arm (14/208) versus6/222 in the control arm). Haemorrhage was found equally in

both arms, 7/208 versus 6/222.

A U T H O R S C O N C L U S I O N S

Implications for practice

Intrapleural fibrinolytic therapy has been shown in the trials in-

cluded in this review to confer significant benefit in reducing the

requirement for surgical intervention for patients in the early stud-

ies included in this review but not in the more recently published

Maskell study. The reasons for this difference are uncertain. Sepa-

rate subgroup analysis of proven loculated/septated effusions from

the available data in our meta-analysis suggests a potential overall

treatment benefit with fibrinolytics, but these results should be

treated with caution as the data are incomplete and the benefit is

notsignificant in meta-analysis of the subgroup of the high quality

trials (Cochrane Grade A). Intrapleural fibrinolytics have not been

shown to significantly increase adverse events, but the confidence

interval is too wide to firmly exclude this possibility.

Implications for research

A focus on patients with complicated parapneumonic effusions,

i.e. with loculations alone rather than the currently studied het-

erogenous group of empyema and complicated parapneumonic

effusions may clarify the niche in which fibrinolytics may play a

role. Other agents which more aggressively degrade fibrin, such as

deoxyribonuclease or TPA (both currently being trialled in Davies

2007) and possibly other proteolytic agents which can lyse more

organised intrapleural repair tissue could be considered for trial in

this group.

A C K N O W L E D G E M E N T S

Thanks to Dr. Peter Gibson for advice on preparation and Toby

Lasserson and Karen Blackall for long distance backup. We are

grateful to the authors ofBouros 1997; Davies 1997; Bouros 1999;

Tuncozgur 2001; Diacon 2004 and Misthos 2005 for assisting us

in obtaining further information about their studies.

R E F E R E N C E S

References to studies included in this review

Bouros 1997 {published data only} Bouros D, Schiza S, Patsourakis G, Chalkiadakis G,

Panagou P, Siafakas N. Intrapleural streptokinase versus

urokinase in the treatment of complicated parapneumonic

effusions. American Journal of Respiratory and Critical Care

Medicine1997;155(1):2915.

Bouros 1999 {published data only} Bouros D, Schiza S, Tzanakis N, Chalkiadakis G, Drositis

J, Siafakas N. Intrapleural urokinase versus normal saline

in the treatment of complicated parapneumonic effusions

and empyema. American Journal for Respiratory and CriticalCare Medicine1999;159(1):3742.

Bouros D, Schiza SE, Drositis J, Tzanakis N, Papalexatos S,

Mitrouska I, et al.Control study of intrapleural instillation

of urokinase in the treatment of multi-loculated pleural

effusion and empyema. American Journal of Respiratory and

Critical Care Medicine1998;157(3 Suppl):A65.

Schiza S, Bouros D, Maltezakis G, Drositis J, Tzanakis N,

Siafakas NM. Intrapleural urokinase vs normal saline in the

treatment of thoracic empyema: a randomized double blind

study. European Respiratory Journal1997;10(Suppl 25):

455s.

Davies 1997 {published and unpublished data} Davies RJO, Traill ZC, Gleeson FV. Randomised


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controlled trial of intrapleural streptokinase in community

acquired pleural infection. Thorax1997;52:41621.Diacon 2004 {published data only}

Diacon AH, Theron J, Schuurmans MM, Van de Wal BW,

Bolliger CT. Intrapleural streptokinase for empyema and

complicated parapneumonic effusions. American Journal of

Respiratory & Critical Care Medicine2004;170(1):4953.

Maskell 2005 {published data only}

Maskell NA, Davies CW, Nunn AJ, Hedley EL, Gleeson

FV, Miller R, et al.First Multicenter Intrapleural Sepsis

Trial (MIST1) Group. U.K. Controlled trial of intrapleural

streptokinase for pleural infection. New England Journal of

Medicine2005;352(9):86574.

Misthos 2005 {published data only}

Misthos P, Sepsas E, Konstantinou M, Athanassiadi K,

Skottis I, Lioulias A. Early use of intrapleural fibrinolytics

in the management of postpneumonic empyema. A

prospective study. European Journal of Cardio-Thoracic

Surgery2005;28(4):599603.

Tuncozgur 2001 {published and unpublished data}

Tuncozgur B, Ustunsoy H, Dikensoy O, Topal M, Sanli

M, Elbeyli L. Intrapleural urokinase in the management

of parapneumonic empyema: a randomised controlled

trial. International Journal of Clinical Practice2001;55(10):

65860.

References to studies excluded from this review

Bilaeroglu 1997 {published data only}

Bilaeroglu S, Cagirici U, Cakan A, Kumcuoglu Z, PerimK. Management of complicated parapneumonic pleural

effusions with image-guided drainage and intrapleural

urokinase or streptokinase: a controlled randomized trial.

European Respiratory Journal10;Suppl 25(325s).

Chin 1997 {published data only} Chin NK, Lim T. Controlled trial of intrapleural

streptokinase in the treatment of pleural empyema and

complicated parapneumonic effusions. Chest1997;111:

2759.

Chung 2003 {published data only}

Chung CL, Chen YC, Chang SC. Effect of repeated

thoracenteses on fluid characteristics, cytokines, and

fibrinolytic activity in malignant pleural effusion. Chest

2003;123(4):118895.Lim 1999 {published data only}

Lim TK, Chin NK. Empirical treatment with fibrinolysis

and early surgery reduces the duration of hospitalization in

pleural sepsis. European Respiratory Journal1999;13:5148.

Talib 2003 {published data only}

Talib SH, Verma GR, Arshad M, Tayade BO, Rafeeque

A. Utility of intrapleural streptokinase in management of

chronic empyemas. Journal of the Association of Physicians of

India 2003;51:4648.

Thomson 2002 {published data only} Thomson AH, Hull J, Kumar R, et al.A randomised trial

of intrapleural urokinase in the treatment of childhood

empyema. Thorax2002;57:3437.

References to ongoing studies

Davies 2007 {published data only}

Davies RJ. MIST2: Multi-centre intra-pleural sepsis trial

(to assess whether Dnase or Alteplase improve pleural fluid

drainage in pleural infection.). http://www.ctu.mrc.ac.uk/

studies/mist2.asp (accessed 4/10/2007).

Additional references

Aye 1991

Aye RW, Froese DP, Hill LD. Use of purified streptokinase

in empyema and hemothorax. American Journal of Surgery1991;161:5602.

Berger 1990

Berger HA, Morganroth ML. Immediate drainage Is not

required for all patients with complicated parapneumoniceffusions. Chest1990;97:7315.

Bergh 1977

Bergh NP, Ekroth R, Larsson S, Nagy P. Intrapleural

streptokinase in the management of haemothorax

and empyema. Scandinvaian Journal of Thoracic and

Cardiovascular Surgery1977;11:2658.

Cho 2000

Cho CH, Kwak SM, Park CS, Bae IY, Moon TH, Cho

JH, et al.The effects of urokinase instillation therapy via

percutaneous transthoracic catheter drainage in loculated

pleural effusion: a randomised prospective study. European

Respiratory Journal2000;16(Suppl 31):579s.

Davies 1998Davies CW, Lok S, Davies RJO. The systemic fibrinolytic

activity of intrapleural streptokinase. American Journal of

Respiratory and Critical Care Medicine1998;157:32830.

Davies 1999

Davies CW, Kearney SE, Gleeson FV, Davies RJ. Predictors

of outcome and long-term survival in patients with pleural

infection. American Journal of Respiratory and Critical Care

Medicine1999;160:16827.

Fraedrich 1982

Fraedrich G, Hofmann D, Effenhauser P, Jander R.

Instillation of fibinolytic enzymes in the management of

pleural empyema. Thoracic Caridvascular Surgery1982;30

(1):368.

Godley 1984Godley PJ, Randall CB. Major hemorrhage following

administration of intrapleural streptokinase. Chest1984;86:

4867.

Heffner 1995

Heffner JE, Brown LK, Barbieri C, DeLeo JM. Pleural fluid

chemical analysis in parapneumonic effusions.. American

Journal of Respiratory and Critical Care Medicine1995;151:

17008.

Henke 1992

Henke CA, Leatherman JW. Intrapleurally administered

streptokinase in the treatment of acute loculated lonpurulent

parapneumonic effusions. American Review of Respiratory

Disease1992;145:6804.


(Review)


8/3/2019 CD 002312

16/44

Hippocrates

Hippocrates. In: Lloyd GER editor(s). Hippocratic Writings(introduction by GER Lloyd). Penguin Classics, 1978.

Idell 1991

Idell S, Girard W, Koenig KB, McLarty J, Fair DS.

Abnormalities of pathways of fibrin turnover in the human

pleural space. American Review of Respiratory Disease1991;

144:18794.

Idell 2005

Idell S. Update on the use of fibrinolysins in pleural disease.

Clinical Pulmonary Medicine2005;12(3):18490.

Jadad 1996

Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds

DJ, Gavaghan DJ, et al.Assessing the quality of reports of

randomized clinical trials: is blinding necessary?. ControlledClinical Trials1996;17(1):112.

Jerjes-Sanchez 1996

Jerjes-Sanchez C, Ramirez-Rivera A, Elizalde J, Delgado R,

Cicero R. Intrapleural Fibrinolysis with Streptokinase as

an Adjunctive Treatment in Hemothorax and Empyema.

Chest 1996; Vol. 109:15149.

Kerr 1991

Kerr A, Vasudevan VP, Powell S, et al.Percutaneous catheter

drainage for acute empyema. New York State Journal of

Medicine1991;91:47.

Laisaar 2003

Laisaar T, Pullerits T. Effect of intrapleural streptokinase

administration on antistreptokinase antibody level in

patients with loculated pleural effusions. Chest2003;123

(4):4325.

Landreneau 1995

Landreneau RJ, Keenan RJ, Hazelrigg SR, Mack

M, Naunheim KS. Thoracoscopy for empyema and

hemothorax. Chest1995;109:1824.

LeMense 1995

LeMense PG, Strange C, Sahn SA. Empyema Thoracis.

Therapeutic management and outcome. Chest1995;107:

15327.

Lemmer 1985

Lemmer JH, Botham MJ, Orringer MB. Modern

management of adult thoracic empyema. Journal of Thoracic

and Cardiovascular Surgery1985;90:84955.

Light 1985

Light RW. Parapneumonic effusion and empyema. Clinical

Chest Medicine1985;6:5562.

Light 1995

Light RW. A new classification of parapneumonic effusions

and empyema. Chest1995;108:299301.

Light 1998

Light RW, Rodriguez RM. Parapneumonic effusions and

empyema. Clinical Chest Medicine1998;19(2):37382.

Light 2000

Light RW, Nguyen T, Mulligan ME, Sasse SA. The in vitro

efficacy of varidase versus streptokinase or urokinase for

liquefying thick purulent exudative material from loculated

empyema. Lung2000;178(1):138.

Moulton 1995

Moulton JS, Benkert RE, Weisiger K, Chambers JA.

Treatment of complicated pleural fluid collections with

image-guided drainage and intracavitary urokinase. Chest1995;108:12529.

Ogirala 1988

Ogirala RG, Williams MH. Streptokinase in a loculated

pleural effusion. Chest1988;94:8846.

Pothula 1994

Pothula V, Krellenstein DJ. Early aggressive surgical

management of parapneumonic empyemas. Chest1994;

105:8326.

Ridley 1991Ridley P, Bainbridge M. Thoracoscopic debridement and

pleural irrigation in the management of empyema thoracis.

American Thoracic Society1991;51:4614.

Roupie 1996

Roupie E, Bouabdallah K, Delclaux C, Brun-Buisson C,

Lemaire F, Vasile N, et al.Intrapleural administration of

streptokinase in complicated purulent pleural effusions-

a CT- guided strategy. Intensive Care Medicine1996;22:

13513.

Sahn 1993

Sahn SA. Management of complicated parapneumonic

effusions. American Review of Respiratory Disease1993;148:

8137.Silverman 1988

Silverman SG, Mueller PR, Saini S, et al.Thoracic empyema.

Management with image-guided catheter drainage.

Radiology1988;169:59.

Simpson 2003

Simpson G, Roomes D, Reeves B. Successful treatment

of empyema thoracis with human recombinant

deoxyribonuclease. Thorax2003;58(4):3656.

Skeete 2004

Skeete DA, Rutherford EJ, Schlidt SA, Abrams JE, Parker

LA, Rich PB. Intrapleural tissue plasminogen activator for

complicated pleural effusions. Journal of Trauma-Injury

Infection & Critical Care2004;57(6):117883.

Strange 1993

Strange C, Allen ML, Harley R, Lazarchick J, Sahn SA.

Intrapleural streptokinase in experimental empyema.

American Review of Respiratory Disease1993;147:9626.

Temes 1996

Temes RT, Fabrizio F, Kesller RM, Pett SB, Wernly J.

Intrapleural fibrinolytics in the management of empyema

thoracis. Chest1996;110(1):1026.

Thommi 2000

Thommi G, Shehan C, Bell A, Coughlin N, McLeay M.

Intrapleural instillation of TPA in the management of of

complicated pleural effusions. Chest2000;118(Suppl 4):

S164.


(Review)


8/3/2019 CD 002312

17/44

Tillett 1951

Tillett WS, Sherry S, Read CT. The use of streptokinase-streptodornase in the treatment of postpneumonic

empyema. Journal of Thoracic Surgery1951;21:27597.

Tokuda 2006

Tokuda Y, Matsushima D, Stein GH, Miyagi S. Intrapleural

fibrinolytic agents for empyema and complicated

parapneumonic effusions: A meta-analysis. Chest2006;129

(3):78390.

Wait 1997

Wait MA, Sharma S, Hohn J, Nogare AD. A randomised

trial of empyema therapy. Chest1997;111:54851.

Walker 2003

Walker CA, Shirki MB, Marva MT, Visconti J. Intrapleural

alteplase in a patient with complicated pleural effusion.Annals of Pharmacotherapy2003;37:3769.

Zhu 2006

Zhu Z, Guo Y, Drake W, Bilaceroglu S, Misra HL, Light

RW. Tissue plasminogen activator combined with human

recombinant deoxyribonuclease is effective therapy forempyema in a rabbit model. Chest2006;129(6):157783.

References to other published versions of this review

Cameron 1999

Cameron R, Davies H. Intra-pleural fibrinolytic therapy

for parapneumonic effusions and empyema. Cochrane

Database of Systematic Reviews 1999, Issue 4. [DOI: Art.

No.: CD002312]

Cameron 2004

Cameron R, Davies HR. Intra-pleural fibrinolytic therapy

versus conservative management in the treatment of

parapneumonic effusions and empyema. Cochrane Databaseof Systematic Reviews 2004, Issue 1. [DOI: Art. No.:

CD002312] Indicates the major publication for the study


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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Bouros 1997

Methods Double blind, two-armed, paral lel group randomised trial.

Participants 33 male, 17 female,age 15-92 years

Eligibility criteria: Parapneumonic effusion as defined by the following criteria: purulent fluid with

evidence of bacteria on gram stain or culture, pH 1000 IU/L, pleural

fluid glucose 70 ml via thoracostomy tube during the previous 24 hours

Exclusion criteria: Empyema as defined in Bouros 1999, florid sepsis, bronchopleural fistula, history

of previous thrombolysis with streptokinase (SK group only), known sensitivity to urokinase,

bleeding diathesis, and contraindication to thrombolytic therapy such as a history of haemorrhagic

stroke, intracranial neoplasm,cranial surgery or headtrauma within the previous 14 days, abdominal

or thoracic surgery within 10 days, or disease making survival

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Bouros 1997 (Continued)

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Yes Computer generated randomisation sequence

Allocation concealment? Unclear It is unclear from the data whether 2 patients

switched from SK to UK due to high fever were

excluded from the final analysis. Presumably the

trial allocation code must have been broken to

change treatment arms, but this is unclear

Blinding?

All outcomes

Yes The patient, treating physicians and outcome as-

sessors were all blinded

Bouros 1999

Methods Double-blind, placebo controlled, parallel group randomised controlled trial. There were no drop

outs

Participants 24 male, 7 female, age 21-78 years

Participants received antibiotics which were appropriate for the organisms cultured, or broad spec-

trum antibiotics to cover gram positive, gram negative and anaerobic organisms

Eligibility criteria: parapneumonic effusion as defined by the following criteria: purulent fluid with

evidence of bacteria on gram stain or culture, pH 1000 IU/L, pleural

fluid glucose

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Bouros 1999 (Continued)

1) Improvement in chest radiography (see Discussion)

2) Improvement in CT and/or chest ultrasound

3) Duration and total volume of pleural drainage

4) Subjective clinical improvement (score 1 for symptom improvement, 2 for no change and 3 for

deterioration.)

5) Time in days to defervescence

6) Time to leucocytes < 10 x 109/L

7) Evidence for coagulapathy at day 0, 3 and at discharge.

Withdrawal from the trial by continuing with fibrinolytic therapy or proceeding to surgery was

made by the attending physician on the basis of substantial (unspecified) residual pleural fluid

and persistent sepsis.

Treatment success was defined as pleural fluid drainage 1000 IU/L, pleural fluid/ blood glucose ratio < 0.25 with loculation/septation of pleural fluid on CT

Exclusion criteria: Previous treatment with streptokinase within the previous 2 years, bleeding

diathesis, and significant haemorrhage or stroke within the previous 6 months, or disease making

survival < 2 months unlikely

Participants all received antibiotics which were appropriate for the organisms cultured, or broad

spectrum antibiotics to cover gram positive, gram negative and anaerobic organisms

Interventions Daily intrapleural streptokinase 250,000 IU for 3 days versus normal saline

Intervention group: Intrapleural streptokinase 250 000 IU via a 14 French van Sonnenberg catheter

in 20 ml normal saline on three consecutive

Control group: 20 ml normal saline in the control group.


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Davies 1997 (Continued)

The drain was then clamped for 2 hours. Both groups received a background of 6 hourly 20 ml

normal saline flushes until the intercostal catheter was removed. The catheters were inserted into

the most dependent portion of the effusion or into the largest loculation. Continuous suction of -

20 cm water was applied

The intercostal catheter was removed after the 5th day and when the amount of fluid drained was

< 150 ml for two consecutive days. Further aspiration or catheter drainage was at the discretion of

the admitting physician

Follow up: three years.

Outcomes Days to defervescence, duration of hospital stay, duration of pleural drainage, plural fluid amount

over first 3 days treatment, improvement in chest radiograph, referral for surgery, death, overall

treatment failure, side effects of treatment. Haemorrhagic complications

Notes Parapneumonic effusion only

Risk of bias


Adequate sequence generation? Yes Computer generated randomisation sequence

Allocation concealment? Unclear Information not available

Blinding?All outcomes Yes Double-blind

Diacon 2004

Methods Double blind randomised controlled parallel group randomised trial. The results were analysed on

the intention-to-treat basis, with all patients who received at least one treatment in either arm being

entered into the final analysis of primary outcomes

Participants 33 male, 11 female, age 16 and older

All patients received broad spectrum antibiotic therapy, tailored to organisms grown thereafter

Eligibility criteria: Adult patients with a lung infection and concomitant pleural effusion were

included if they had an empyema or complicated para pneumonic effusion with pH less than 7.0

or pH less than 7.2 with evidence of fluid loculation on chest radiograph or ultrasoundExclusion criteria: less than 16 years of age, recent severe trauma, haemorrhage or stroke, bleeding

disorder or anticoagulation therapy, administration of streptokinase within 2 previous years, likely

survival of less than 6 months or with preceding thoracic drainage procedures

Interventions Streptokinase 250,000 IU once daily for up to 7 days or until net drainage less than 100 ml per day

A 24 or 28 French Argyle chest tube was inserted.

Intervention group: 100 ml normal saline with Streptokinase 250,000 IU

Control group: 100 ml of normal saline

The drain was clamped for 2 hours. The therapy was administered once daily for up to 7 days or

until net drainage was less than 100 ml per day


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Diacon 2004 (Continued)

Outcomes Death, the need for surgery and the response to treatment at day 3 and day 7 and at discharge with

all symptoms and signs improved or normalised,

patient temperature less than 37C for 24 hours, Chest radiograph with no or minimal pleural

pathology, drainage less than 100 ml per 24 hours or drain removed. Haemorrhagic complications

Notes Parapneumonic effusions and empyema.

Treatment success was defined as a study in point at Day 3 and Day 7 and at discharge.

This required the following.

(1) All symptoms and signs improved or normalised.

(2) Patient temperature less than 37C for 24 hours.

(3) Chest x-ray with no or minimal pleural pathology.(4) Drainage less than 100 ml per 24 hours or drain removed.

Criteria for referral to surgery were:

(1) Deteriorating patient with ongoing or progressive sepsis in combination with residual pleural

fluid.

(2) Lack of satisfactory or clinical radiological improvement beyond 7 days after chest drain inser-

tions

Referral for surgery required agreement of at least two physicians involved in the study

Risk of bias


Adequate sequence generation? Yes Computer generated sequence (stratified by blocks of 4).

Allocation concealment? Yes Only one author was aware of group assign-

ment throughout the trial and did not partici-

pate in clinical decision making. Randomisation

was concealed to all other participants through-

out the trial

Blinding?

All outcomes

Yes Double-blind

Maskell 2005

Methods Double blind randomised control led parallel group trial.

Participants 299 male, 131 female aged 18 years or more

All patients received broad spectrum antibiotic therapy, subsequently tailored to microbiological

culture and sensitivity

Eligibility criteria: presence of pleural fluid which was macroscopically purulent, positive on culture

for bacterial infection, positive for bacteria on gram stain or pH < 7.2 in patients with clinical and

laboratory indicators of infection such as fever, raised white cell count and raised C reactive protein

Exclusion criteria: < 18 years,coincidental serious illness with survival at 3 months unlikely, previous

intrapleural fibrinolytic or surgical therapy, sensitivity to streptokinase, coincidental stroke or major

haemorrhage, major surgery within 5 days previous, previous pneumonectomy of same side as


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Maskell 2005 (Continued)

pleural infection, known pleural malignancy and females who were pregnant or lactating

Interventions Daily intrapleural streptokinase 250,000 IU every 12 hours for 6 doses versus placebo

Intervention group: 30 mls of normal saline delivered by an intercostal chest tube (medium size 12

French, interquartile range 12-20) installed every 12 hours for six doses, or streptokinase 250,000

IU in 30 mls of normal saline using the same regimen

Outcomes Primary outcome: treatment failure as defined by either patient death or requirement for surgical

drainage of infected pleural fluid within the first 3 months after randomisation. Referral for surgery

required substantial residual pleural fluid collection (quantity undefined) and the presence of per-

sistent infection on clinical or biochemical grounds

Secondary endpoints were death or the requirement for surgical drainage 12 months after ran-domisation, duration of hospital stay; and severity of residual abnormality on chest radiograph

expressed as a percent of base line chest radiograph findings on a categorical percentage scale with

comparison of the non affected hemithorax. Dynamic lung volumes were checked on admission

and at 3 months. Monitoring for complications of Streptokinase therapy included assessment of

bleeding risk at time of administration, and peri- operatively in those patients referred for empyema

drainage, and an assessment of anti-Streptokinase antibody response

Notes Parapneumonic effusions and empyema

Risk of bias


Adequate sequence generation? Yes At randomisation, the groups were balanced by

minimisation for the presence of frankly puru-

lent pleural fluid and the availability of of tho-

racic surgery in the recruiting centre

Allocation concealment? Yes Centrally prepared allocation schedule by tele-

phone from the study centre

Blinding?

All outcomes

Yes Both the patients and treating physicians were

blind to treatment group assignment

Misthos 2005

Methods Double blind randomised controlled parallel group trial. Method of randomisation was not ade-

quately concealed (odd or even last digit of hospital number)

Participants 96 men, 37 women, aged 19-77 years

Decision to continue with chest tube thoracostomy with or without fibrinolytic therapy, or to

proceed to surgery was made by an independent chest physician who was blinded to the mode of

treatment. All patients were assessed with CT or US scans or both for the presence of loculations.

All patients were managed with antibiotic treatment and thoracocentesis

Eligibility criteria: Primary bacterial post-pneumonic thoracic empyema, parapneumonic effusion

defined as purulent pleural fluid or positive effusion gram stain or culture for bacteria, or pH less


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Misthos 2005 (Continued)

than 7.2, glucose less than 40 mg per decilitre and LDH greater than 1000 IU/litre

Exclusion criteria: Participants who had a contraindication to surgery or with end stage underlying

disease or tuberculous empyema, bronchopleural fistula, the presence of a lung abscess, a known

sensitivity to Streptokinase or a contraindication to thrombolytic therapy were excluded

Interventions Daily intrapleural streptokinase 250,000 units for 3 days.

All patients had an Argyle intercostal drain size 28-32 French attached to suction at minus 20 cm

of water

Intervention group: Streptokinase 250,000 IU in 60 mls normal saline. The tube was clamped for

4 hours then re-opened. SK was given daily for three successive days and treatment result assessed

after 3 days. Drainage was left in place until daily output fluid was less than 50 mls and the

radiographic image remained unchanged. Absence of fluid at the posterior costophrenic angle atlateral chest radiograph or at CT scan was considered as adequate pleural fluid evacuation (author

communication)

The decision to proceed to surgery (VATS or open thoracotomy decortication) was indicated by

progressive or persistent sepsis and the presence of substantial residual pleural fluid. Criteria for

surgery included assessment of the amount of pleural fluid that could not drained with chest tube

thoracostomy because of trapped lung or chronicity and more specifically if the fluid filled the

posterior costophrenic angle and led to atelectasis of the posterior basal segments of the lower lobes

(author communication)

Outcomes Duration of symptoms and stay in thoracic ward and hospital, duration of pleural drainage, im-

provement in chest radiograph, referal for surgery, death, overall treatment failure, side effects of

treatment. Haemorrhagic complications

Notes Parapneumonic effusions only

Risk of bias


Adequate sequence generation? Unclear Pariticipants allocated to placebo or treatment

arms on the basis of their hospital admission

number

Allocation concealment? No Allocation concealment potentially threatened

by allocation procedure (hospital admissionnumber)

Blinding?

All outcomes

No The patient and treating physicians do not ap-

pear to have been blinded, but the results assess-

ment was blinded


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Tuncozgur 2001

Methods Double-blind, placebo controlled, parallel. There were no dropouts. The study methods and ran-

domisation procedure were well accounted for, (personal communication with author)

Participants 38 male,11 female, age 15-85 years

The participants all received antibiotics appropriate for the organisms cultured, or empirically

selected broad spectrum antibiotics

Exclusion criteria: Tuberculosis or hospital-acquired, post-traumatic or post-operative pneumonia

were excluded. Those older than 85 and younger than 15 were also excluded

Interventions Daily intrapleural urokinase 100,000 IU for 5 days

Outcomes 1) Rate of treatment failure as defined by death/referral for surgical decortication. The decision toproceed to surgery for decortication was made by the attending physician on the basis of substantial

residual pleural fluid and persistent sepsis.

2) Duration and total volume of pleural drainage. Treatment success was defined as pleural fluid

drainage < 50 ml clear yellow fluid in 24 hours after 5 days treatment (personal correspondence)

3) Duration of hospital stay.

4) Improvement in chest radiography and CT scan. Only stage 3 improvement, according to the

same criteria as Bouros 1997 (i.e. > 2/3 reduction in effusion size) was accepted as significant

radiological improvement.

5) Time in days to defervescence

6) Significant haemorrhagic side effects.

Notes Parapneumonic effusions only

Risk of bias


Adequate sequence generation? Yes Allocation was appropriately described by the au-

thor in private communication

Allocation concealment? Yes blinded opaque envelope allocation.

Blinding?

All outcomes

Yes The patient, treating physicians and outcome as-

sessors were all blinded

CT: computerised topography

IU: international units

LDH: lactate dehydrogenase

US: ultrasound

VATS: video-assisted thoracoscopic surgery


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Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Bilaeroglu 1997 Study results found in abstract form only. Too many missing details regarding all aspects of study to consider

inclusion

Chin 1997 Inadequate concealment of allocation excluded this study

This was sequential study in which the patients received either intrapleural saline or intrapleural streptokinase

250 000 IU. The patients were allocated to each of the treatment arms according to temporal sequence. There

was therefore inadequate concealment of allocation and the study was excluded. These two groups were the first

two of the three in the Lim 1999 study

Chung 2003 Non-randomised study.

Lim 1999 Inadequate concealment of allocation excluded this study. Three different treatments were compared in this trial.

Simple chest tube drainage versus chest tube drainage and adjunctive intrapleural streptokinase versus chest tube

drainage

Repetition of study details from Chin 1997, as the first 2 groups were the same

Talib 2003 The study has patients with predominantly tuberculous effusions

Thomson 2002 Trial population fell outside the range of the review - median age: 3.3 years . Review inclusion criteria > 14 years

of age

Characteristics of ongoing studies [ordered by study ID]

Davies 2007

Trial name or title MIST2: Multi-centre Intra-pleural Sepsis Trial

Methods

Participants Adults

Interventions Intra-pleural Alteplase 10 mg bd + Intra-pleural DNase 5 mg bd; or

Intra-pleural Alteplase placebo bd + Intra-pleural DNase 5 mg bd; or

Intra-pleural Alteplase 10 mg bd + Intra-pleural DNase placebo bd; or

Intra-pleural Alteplase placebo bd + Intra-pleural DNase placebo bd

All given twice daily for 3 days

Outcomes primary endpoint is radiographic improvement in pleural collection

Starting date 2006

Contact information


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Davies 2007 (Continued)

Notes Trial already underway


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D A T A A N D A N A L Y S E S

Comparison 1. Fibrinolytic versus placebo (loculation and empyema)

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Treatment failure- death 6 702 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.69, 1.68]

1.1 Cochrane Grade A studies 5 575 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.72, 1.79]

1.2 Cochrane Grade C Studies 1 127 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.01, 5.00]

2 Treatment failure- surgical

intervention

6 702 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.46, 0.85]


2.2 Cochrane C Grade studies 1 127 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.17, 0.81]

3 Overall treatment failure 6 702 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.56, 0.90]


3.2 Cochrane Grade C studies 1 127 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.16, 0.74]

4 Significant treatment

complications



4.2 Cochrane Grade C studies 1 127 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

Comparison 2. Fibrinolytic versus placebo (loculated effusions only)


studies

No. of


1 Treatment failure- death 3 207 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.01, 5.00]

1.1 Cochrane Grade A studies 2 80 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

1.2 Cochrane C Grade studies 1 127 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.01, 5.00]


intervention








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Comparison 3. Streptokinase versus urokinase


studies

No. of


1 Treatment failure- death 1 48 Risk Ratio (M-H, Fixed, 95% CI) Not estimable


intervention



4 Significant treatment side effects 1 50 Risk Ratio (M-H, Fixed, 95% CI) 5.0 [0.25, 99.16]

Analysis 1.1. Comparison 1 Fibrinolytic versus placebo (loculation and empyema), Outcome 1 Treatment

failure- death.

Review: Intra-pleural fibrinolytic therapy versus conservative management in the treatment of adult parapneumonic effusions and empyema

Comparison: 1 Fibrinolytic versus placebo (loculation and empyema)

Outcome: 1 Treatment failure- death

Study or subgroup Fibrinolytic Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Cochrane Grade A studies

Bouros 1999 0/15 0/16 0.0 [ 0.0, 0.0 ]

Davies 1997 0/12 0/12 0.0 [ 0.0, 0.0 ]

Diacon 2004 1/22 1/22 1.00 [ 0.07, 15.00 ]

Maskell 2005 32/206 30/221 1.14 [ 0.72, 1.81 ]

Tuncozgur 2001 0/24 0/25 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 279 296 1.14 [ 0.72, 1.79 ]

Total events: 33 (Fibrinolytic), 31 (Control)

Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.92); I2 =0.0%

Test for overall effect: Z = 0.56 (P = 0.57)

2 Cochrane Grade C StudiesMisthos 2005 0/57 2/70 0.24 [ 0.01, 5.00 ]

Subtotal (95% CI) 57 70 0.24 [ 0.01, 5.00 ]


Heterogeneity: not applicable


Total (95% CI) 336 366 1.08 [ 0.69, 1.68 ]




0.01 0.1 1 10 100

Favours treatment Favours control


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Analysis 1.2. Comparison 1 Fibrinolytic versus placebo (loculation and empyema), Outcome 2 Treatment

failure- surgical intervention.



Outcome: 2 Treatment failure- surgical intervention

Study or subgroup Fibrinolytic Control Risk Ratio Weight Risk Ratio



Bouros 1999 2/15 6/16 6.8 % 0.36 [ 0.08, 1.50 ]

Davies 1997 0/12 3/12 4.1 % 0.14 [ 0.01, 2.50 ]

Diacon 2004 3/22 10/22 11.7 % 0.30 [ 0.10, 0.94 ]

Maskell 2005 32/206 32/221 36.1 % 1.07 [ 0.68, 1.69 ]

Tuncozgur 2001 7/24 15/25 17.2 % 0.49 [ 0.24, 0.98 ]

Subtotal (95% CI) 279 296 75.9 % 0.71 [ 0.50, 0.99 ]


Heterogeneity: Chi2 = 8.60, df = 4 (P = 0.07); I2 =53%


2 Cochrane C Grade studies

Misthos 2005 7/57 23/70 24.1 % 0.37 [ 0.17, 0.81 ]

Subtotal (95% CI) 57 70 24.1 % 0.37 [ 0.17, 0.81 ]




Total (95% CI) 336 366 100.0 % 0.63 [ 0.46, 0.85 ]




0.01 0.1 1 10 100



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Analysis 1.3. Comparison 1 Fibrinolytic versus placebo (loculation and empyema), Outcome 3 Overall

treatment failure.Review: Intra-pleural fibrinolytic therapy versus conservative management in the treatment of adult parapneumonic effusions and empyema


Outcome: 3 Overall treatment failure




Bouros 1999 2/15 12/16 9.4 % 0.18 [ 0.05, 0.67 ]

Davies 1997 0/12 3/12 2.8 % 0.14 [ 0.01, 2.50 ]

Diacon 2004 4/22 11/22 8.9 % 0.36 [ 0.14, 0.97 ]

Maskell 2005 64/206 62/221 48.6 % 1.11 [ 0.83, 1.48 ]

Tuncozgur 2001 7/24 15/25 11.9 % 0.49 [ 0.24, 0.98 ]

Subtotal (95% CI) 279 296 81.8 % 0.79 [ 0.62, 1.02 ]




2 Cochrane Grade C studies

Misthos 2005 7/57 25/70 18.2 % 0.34 [ 0.16, 0.74 ]

Subtotal (95% CI) 57 70 18.2 % 0.34 [ 0.16, 0.74 ]




Total (95% CI) 336 366 100.0 % 0.71 [ 0.56, 0.90 ]




0.05 0.2 1 5 20



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Analysis 1.4. Comparison 1 Fibrinolytic versus placebo (loculation and empyema), Outcome 4 Significant

treatment complications.



Outcome: 4 Significant treatment complications




Bouros 1999 0/15 0/16 0.0 [ 0.0, 0.0 ]

Davies 1997 0/12 0/12 0.0 [ 0.0, 0.0 ]

Diacon 2004 0/22 0/22 0.0 [ 0.0, 0.0 ]

Maskell 2005 14/206 7/221 2.15 [ 0.88, 5.21 ]

Tuncozgur 2001 0/24 0/25 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 279 296 2.15 [ 0.88, 5.21 ]





Misthos 2005 0/57 0/70 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 57 70 0.0 [ 0.0, 0.0 ]



Test for overall effect: Z = 0.0 (P < 0.00001)

Total (95% CI) 336 366 2.15 [ 0.88, 5.21 ]




0.1 0.2 0.5 1 2 5 10



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Analysis 2.1. Comparison 2 Fibrinolytic versus placebo (loculated effusions only), Outcome 1 Treatment

failure- death.Review: Intra-pleural fibrinolytic therapy versus conservative management in the treatment of adult parapneumonic effusions and empyema

Comparison: 2 Fibrinolytic versus placebo (loculated effusions only)





Bouros 1999 0/15 0/16 0.0 [ 0.0, 0.0 ]

Tuncozgur 2001 0/24 0/25 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 39 41 0.0 [ 0.0, 0.0 ]Total events: 0 (Fibrinolytic), 0 (Control)

Heterogeneity: Chi2 = 0.0, df = 0 (P

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Analysis 2.2. Comparison 2 Fibrinolytic versus placebo (loculated effusions only), Outcome 2 Treatment

failure- surgical intervention.







Bouros 1999 2/15 6/16 14.1 % 0.36 [ 0.08, 1.50 ]

Tuncozgur 2001 7/24 15/25 35.7 % 0.49 [ 0.24, 0.98 ]

Subtotal (95% CI) 39 41 49.8 % 0.45 [ 0.24, 0.85 ]Total events: 9 (Fibrinolytic), 21 (Control)




Misthos 2005 7/57 23/70 50.2 % 0.37 [ 0.17, 0.81 ]

Subtotal (95% CI) 57 70 50.2 % 0.37 [ 0.17, 0.81 ]




Total (95% CI) 96 111 100.0 % 0.41 [ 0.25, 0.67 ]




0.1 0.2 0.5 1 2 5 10



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Analysis 2.3. Comparison 2 Fibrinolytic versus placebo (loculated effusions only), Outcome 3 Overall

treatment failure.Review: Intra-pleural fibrinolytic therapy versus conservative management in the treatment of adult parapneumonic effusions and empyema






Bouros 1999 2/15 12/16 13.1 % 0.18 [ 0.05, 0.67 ]

Maskell 2005 43/154 41/164 44.9 % 1.12 [ 0.77, 1.61 ]

Tuncozgur 2001 7/24 15/25 16.6 % 0.49 [ 0.24, 0.98 ]

Subtotal (95% CI) 193 205 74.6 % 0.81 [ 0.60, 1.10 ]





Misthos 2005 7/57 25/70 25.4 % 0.34 [ 0.16, 0.74 ]

Subtotal (95% CI) 57 70 25.4 % 0.34 [ 0.16, 0.74 ]




Total (95% CI) 250 275 100.0 % 0.69 [ 0.52, 0.92 ]

Total events: 59 (Fibrinolytic), 93 (Control)Heterogeneity: Chi2 = 14.81, df = 3 (P = 0.002); I2 =80%


0.1 0.2 0.5 1 2 5 10



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Analysis 3.1. Comparison 3 Streptokinase versus urokinase, Outcome 1 Treatment failure- death.


Comparison: 3 Streptokinase versus urokinase


Study or subgroup Streptokinase Urokinase Risk Ratio Risk Ratio


Bouros 1997 0/23 0/25 0.0 [ 0.0, 0.0 ]

Total (95% CI) 23 25 0.0 [ 0.0, 0.0 ]

Total events: 0 (Streptokinase), 0 (Urokinase)


Test for overall effect: Z = 0.0 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10

Favours sk Favours uk

Analysis 3.2. Comparison 3 Streptokinase versus urokinase, Outcome 2 Treatment failure- surgical

intervention.




Study or subgroup Streptokinase Urokinase Risk Ratio Weight Risk Ratio


Bouros 1997 2/23 2/25 100.0 % 1.09 [ 0.17, 7.10 ]

Total (95% CI) 23 25 100.0 % 1.09 [ 0.17, 7.10 ]




0.1 0.2 0.5 1 2 5 10



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Analysis 3.3. Comparison 3 Streptokinase versus urokinase, Outcome 3 Overall treatment failure.






Bouros 1997 2/23 2/25 100.0 % 1.09 [ 0.17, 7.10 ]

Total (95% CI) 23 25 100.0 % 1.09 [ 0.17, 7.10 ]




0.1 0.2 0.5 1 2 5 10


Analysis 3.4. Comparison 3 Streptokinase versus urokinase, Outcome 4 Significant treatment side effects.



Outcome: 4 Significant treatment side effects



Bouros 1997 2/25 0/25 100.0 % 5.00 [ 0.25, 99.16 ]

Total (95% CI) 25 25 100.0 % 5.00 [ 0.25, 99.16 ]




0.1 0.2 0.5 1 2 5 10



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A D D I T I O N A L T A B L E S

Table 1. Search Strategies

CENTRAL search MEDLINE search EMBASE search

1. PLEURAL EFFUSION

2. EMPYEMA PLEURAL

3. empyema*

4. (parapneumonic near effusion*)

5. (pleural near effusion*)

6. parapneumonic*

7. (#1 or #2 or #3 or #4 or #5 or #6)

8. FIBRINOLYTIC AGENTS

9. (antithrombotic* or thrombolytic* or

antithrombic* or fibrinolytic*)

10. alprostadil or anistreplase or enoxaparin

or ancrodor aspirin or batroxobin or brino-

lase or heparin or hirudin or nadroparin or

plasmin or plasminogen or protein c or

streptokinase or tedelparinor ticlopidine or

tissue plasminogen activator

11. STREPTOKINASE

12. (avelizin or awelysin or celiase or dis-

treptase or kabikinase or kabivitrum or

streptase or streptodecase or apsac)

13. URINARY PLASMINOGEN ACTI-

VATOR

14. (urokinase or plasminogen activator*

or u-plasminogen activator* or abboki-

nase or renokinase or u-pa)

15. (#8 or #9 or #10 or #11 or #12 or #13

or #14)

16. (#7 and #15)

1.Pleural Effusion

2. Empyema, Pleural/

3. empyema$.mp.

4. (parapneumonic adj5 effusion$).mp.

5. (pleural adj5 effusion$).mp.

6. parapneumonic$.mp.

7. 1 or 2 or 3 or 4 or 5 or 6

8. exp Fibrinolytic Agents/

9. (antithrombotic or thrombolytic or an-

tithrombic or fibrinolytic).mp.

10. (Alprostadil or Anistreplase or Enoxa-

parin or Ancrod or Aspirin or Batroxobin

or Brinolase or Heparin or Hirudin or

Nadroparin or Plasmin or Plasminogen or

Protein C or Streptokinase or Tedelparin or

Ticlopidine or Tissue Plasminogen Activa-

tor).mp.

11. exp Streptokinase/

12. (avelizin or awelysin or celiase or

distreptase or Kabikinase or kabivitrum

or Streptase or streptodecase or apsac or

anisoylated plasminogen-streptokinase ac-

tivator complex or brl-26921).mp.

13. exp Urinary Plasminogen Activator/

14. (Urokinase or plasminogen activator$

or u-plasminogen activator$ or Abbokinase

or renokinase or u-pa).mp.

15. 8 or 9 or 10 or 11 or 12 or 13 or 14

16. 7 and 15

(This search was combined with the Air-

ways Group MEDLINE RCT search strat-

gey)

1. Pleural Effusion/

2. Empyema, Pleural/

3. empyema$.mp.

4. (parapneumonic adj5 effusion$).mp.

5. (pleural adj5 effusion$).mp.

6. parapneumonic$.mp.

7. 1 or 2 or 3 or 4 or 5 or 6

8. exp Fibrinolytic Agents/

9. (antithrombotic or thrombolytic or an-

tithrombic or fibrinolytic).mp.

10. (Alprostadil or Anistreplase or Enoxa-

parin or Ancrod or Aspirin or Batroxobin

or Brinolase or Heparin or Hirudin or

Nadroparin or Plasmin or Plasminogen or

Protein C or Streptokinase or Tedelparin or

Ticlopidine or Tissue Plasminogen Activa-

tor).mp.

11. exp Streptokinase/

12. (avelizin or awelysin or celiase or

distreptase or Kabikinase or kabivitrum

or Streptase or streptodecase or apsac or

anisoylated plasminogen-streptokinase ac-

tivator complex or brl-26921).mp.

13. exp Urinary Plasminogen Activator/

14. (Urokinase or plasminogen activator$

or u-plasminogen activator$or Abbokinase

or renokinase or u-pa).mp.

15. 8 or 9 or 10 or 11 or 12 or 13 or 14

16. 7 and 15

(This search was combined with the Air-

ways Group EMBASE RCT search strat-

gey)


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Table 2. Design and Jadad scores

Study ID Design Allocation grade Jadad score (0-5)

Bouros 1997 Double-blind parallel group. Com-

puter generated randomisation se-

quence. There were no dropouts

from the trial. The patient, treat-

ing physicians and outcome asses-

sors were all blinded. It is unclear

from the data whether 2 patients

switched fromSK toUK due to high

fever were excluded from the finalanalysis. Presumably the trial alloca-

tion code must have been broken to

change treatment arms, but this is

unclear

A 5

Bouros 1999 Double-blinded parallel group trial.

Computer generated randomisation

sequence. There were no dropouts

from the trial. The patient, treat-

ingphysicians andoutcome assessors

were all blinded

A 5

Davies 1997 Double-blind parallel group trial.Computer generated randomisation

sequence. There were no dropouts

from the trial

A 5

Diacon 2004 Double blind

parallel group trial. Computer gen-

erated sequence (stratified by blocks

of 4). Only one author was aware

of group assignment throughout the

trial and did not participate in clini-

cal decision making. Randomisation

was concealed to all other partici-

pants throughout the trial

A 5

Maskell 2005 Multi-centre double blind parallel

group trial. Centrally prepared allo-

cation schedule by telephone from

the study centre. Both the patients

and treating physicians were blind

to treatment group assignment. At

randomisation, the groups were bal-

anced by minimisation for the pres-

ence of frankly purulent pleural fluid

and the availability of of thoracic

surgery in the recruiting centre

A 5


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Table 2. Design and Jadad scores (Continued)

Misthos 2005 Parallel group trial. Pariticipants al-

located to placebo or treatment arms

on the basis of their hospital ad-

mission number.Allocation conceal-

ment may have been compromised

by this. The patient and treating

physicians do not appear to have

been blinded, but the results assess-

ment was blinded

C 2

Tuncozgur 2001 Double-blind parallel group trial.

Allocation was appropriately de-

scribed by the author in private

communication,with a randomised,

blinded opaque envelope allocation.

There were no dropouts from the

trial. The patient, treating physi-

cians and outcome assessors were all

blinded

A 5

Table 3. Study results

Study ID Findings

Bouros 1997 There were no significant differences between the patients in the two treatment groups in terms of baseline demo-

graphics, pleural fluid biochemical and microbiological analyses. A microbiological diagnosis was obtained in 19/

50 patients. There was appropriate randomisation into urokinase and streptokinase groups. The statistical analysis

did not differentiate between complicated parapneumonic effusions and empyema. Underlying predisposing fac-

tors were found in 10/25 patients in the SK group and 14/25 patients in the UK group. There were no dropouts

during the study.

Improvement in clinical parameters was noted in all but 2 of each group. Details of these parameters and duration

of hospital stay were not provided.

The final numbers in the SK group were reduced as a result of therapeutic complications. Two patients were

changed from SK to UK after spiking a pyrexia >39 degrees C, which was deemed to be a result of the SKinstillation. The number of patients in each group on an intention-to-treat basis was 25 each, but the actual

numbers at the end of the trial would be 23 in SK and 27 in the UK group. It appears from the section on

radiographic improvement that the final analysis reflected the intention-to-treat population. This approach will

be used for this analysis.

The number of pleural instillations required to effect adequate clinical and radiological response was equal in both

groups at 6 +/- 2.2 for SK and 5.9 +/- 2.1 for UK. The mean volume of pleural fluid drained in the 24 hours after

instillation was comparable with 380 +/- 99 ml in the SK group and 421 +/- 110 in the UK group. The mean

total fluid volume drained was 1596 +/- 68 ml vs 1510 +/- 55 ml; this was not statistically significant. The mean

length of stay was not different between treatment groups.


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Table 3. Study results (Continued)

The degree of improvement in chest radiograph was equivalent in both groups with score 3 (excellent) in 17/25

SK patients vs 19/25 in the UK patients; score 2 in 5/25 SK vs 4/25 UK and score 1 (minimal) in 3/25 SK vs 2/

25 UK. Mean overall improvement was 2.5 +/- 0.7 vs 2.7 +/- 0.8 was not significant.

Two patients from each group underwent a surgical drainage procedure, which constituted treatment failure. One

patient in the UK group died of underlying malignancy, which the authors felt was unrelated to the fibrinolytic

therapy, with a clear pleural cavity on autopsy. For the purposes of this review therefore, this will not be considered

a treatment failure.

Cost analysis in US dollars showed a lower drug cost of SK vs UK $180 +/- 47 vs $320 +/- 123 but the authors

did not factor this into the overall estimated cost of treatment in hospital

Bouros 1999 There were no significant differences between the 31 patients in terms of baseline demographics, pleural fluid

biochemical and microbiological analyses between the urokinase and control groups. A microbiological diagnosis

was obtained in 12/31 patients. There were more complicated parapneumonic effusion (21) than empyemata

(10) with appropriate randomisation of each into intervention and control groups. The statistical analysis did

not differentiate between these 2 diagnoses. Underlying morbidity was found. There were no dropouts during

the study. Treatment failure, for the purposes of this analysis was judged either by the requirement for surgery

or the withdrawal from a treatment arm to administer alternative therapy due to clinical or radiological failure

to progress. 2/15 (13.5%) UK patients vs 12/16 (75%) control patients were felt to have inadequate pleural

drainage. For the purposes of this review, the analysis goes no further. All 12 failed control patients received

UK, with 6 achieving adequate pleural drainage, and 6 proceeding to surgery. The 2 failed UK patients also

underwent a surgical drainage procedure. One patient in the UK group had abnormalities in clotting parameters

that resolved after drainage and did not necessitate alteration in therapy. There were no other significant treatment

side effects in either group. All treatment modalities were well tolerated, with no side effects. Improvement inclinical parameters significantly favoured the UK group with mean time to defervescence 6 +/- 4 vs 12 +/- 5 days

(p

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large standard deviations in these results indicate a broad range of results. The changes in pleural fluid volume

were gauged by the reduction of the largest linear dimension of the fluid collection on chest radiograph. This

significantly favoured the SK group at 6.0 +/- 2.7 cm vs 3.4 +/- 2.7 cm; with a difference of 2.6 cm; 95% CI

0.3 to 4.9 cm. At discharge, 10/12 of the SK group showed >75% improvement from the original size compared

to 4/9 in the control group. Three patients were not strictly eligible for assessment in the control group as they

underwent surgery, giving >75% improvement in 4/9. The authors suggest however that these patients would

not have improved to that extent (hence the requirement for surgery) and therefore technically only 4/12 patients

in the control group showed 75% reductions in pleural fluid volume. This significantly favours the SK group

(p

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Tuncozgur 2001 All 49 patients completed the trial, with no dropouts. 24 received urokinase and 25 normal saline control. The

patient demographics in both groups were not statistically different, with a young mean age of 33-34 years (SD

14-16) and p

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C O N T R I B U T I O N S O F A U T H O R S

RC: protocol initiation and development. Selection of studies for inclusion. Study assessment, data extraction and data entry. Interpre-

tation and discussion.

HD: protocol development. Study assessment. Interpretation and discussion.

D E C L A R A T I O N S O F I N T E R E S T

There were no potential conflicts of interest.

I N D E X T E R M SMedical Subject Headings (MeSH)

Empyema, Pleural [drug therapy]; Fibrinolytic Agents [administration & dosage]; Pleural Effusion [drug therapy]; Pneumonia

[complications]; Randomized Controlled Trials as Topic; Streptokinase [administration & dosage]; Thrombolytic Therapy [methods];

Urokinase-Type Plasminogen Activator [administration & dosage]

MeSH check words

Adult; Humans

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