Thorax 1994;49:856-859

Intrapleural streptokinase in the management

of empyema

R F H Taylor, M B Rubens, M C Pearson, N C Barnes

The London ChestHospital, BonnerRoad, London E2 9JX,UKR F H TaylorM B RubensM C PearsonN C Barnes

Reprint requests to:Dr N C Barnes.Received 8 March 1994Retumed to authors5 April 1994Revised version received25 April 1994Accepted for publication28 April 1994

AbstractBackground - Significant morbidity andmortality result from the ineffective eva-

cuation of empyema. Failure of con-

ventional first line treatment with closedintercostal tube drainage and antibiotictherapymay result in fibrin deposition andloculated empyema. Enzymatic de-bridement using intrapleural instillationof streptokinase is a non-invasive thera-peutic option which may obviate the needfor surgical intervention.Methods - Eleven adults with multi-loculated post-pneumonic empyemas whohad failed to respond satisfactorily tointercostal tube drainage and antibiotictherapy were treated with intrapleuralstreptokinase between November 1992 andJanuary 1994. A small catheter was in-serted under ultrasound guidance into a

loculation within the pleural space. Ali-quots of 250 000 units of streptokinase in100 ml normal saline were instilled into thepleural cavity and the tube clamped forfour hours. Response was assessed by clin-ical outcome, measurement of drain out-put after unclamping, and subsequentpleural ultrasound, chest radiography, or

both.Results - Streptokinase enhanced drain-age in all patients. Complete resolutionof the empyema with re-expansion of theunderlying lung was effected in eight pa-

tients, all of whom remain well. Furtherresolution of minimal pleural thickeningwas shown on subsequent chest radio-

graphs. Two patients with considerablythickened visceral pleura following em-

pyema drainage underwent successful de-cortication. The other, with myocarditisand a pyopneumothorax, underwent sur-

gery for non-resolution of the pneumo-

thorax but died perioperatively fromcardiac failure. The number of strepto-

kinase instillations per patient rangedfrom two to six (median three), and thevolume of empyema fluid drained per

patient ranged from 100 ml to 4870 ml(median 900ml). Streptokinase was welltolerated in all patients.Conclusions - Intrapleural streptokinaseis an effective adjunct in the managementof complicated empyema and may reducethe need for surgery.

(Thorax 1994;49:856-859)

Thoracic empyemas continue to cause sub-stantial morbidity and mortality1 despite theadvent of antimicrobial therapy in the 1940s.Failure of conventional first line therapy -

namely, intercostal tube drainage and anti-biotics - occurs when pleural fluid is no longerfree flowing. Inadequate drainage is usuallyassociated with the fibrinopurulent stage of theempyema process, in which empyema fluidbecomes multiloculated by the formation offibrin strands. Fibrin deposition within thepleural cavity may take only a few days.2 Thuspatients may present with multiloculated effu-sions which are not amenable to tube drainage

Clinical data of 1) patients in study

Patient Sex Age Predisposing Pleural Days fism Number of Volume of Duration of Factors Outcomeno. (years) factor culture first drainage to strepwokinase fluid drained stay after complicating

streptokinase instiUations (ml) streptokinase recovery afterinstillation (days) steptokinase

1 F 25 Smoker 7 3 over 4 days 1180 5 Well at 56 weeks2 M 26 Myocarditis Clostridium 43 3 over 3 days 1160 - Severe Surgery, died

perfringens, cardiac postoperativelyPneumocystis failurecarinii

3 M 26 Smoker 28 3 over 4 days 360 - Surgery, successfuldecortication

4 M 39 Drug abuser 63 2 over 3 days 100 4 - Well at 8 weeks (lost tofollow up)

5 M 40 Smoker - 42 3 over 4 days 900 6 Well at 30 weeks6 M 48 Infected Escherichia 5 3 over 5 days 280 21 Malnourished, Well at 6 weeks

pulmonary coli, fractured tibiainfarction Bacteriodes and fibula

7 M 55 Cardiac Staphylococcus 10 6 over 20 days 4870 42 Cardiac, renal Well at 18 weeksfailure aureus failure and surgery

for strangulatedinguinal hernia

8 M 59 Mycobactenium 90 5 over 35 days 1980 - Surgery, successfultubereulosis decortication

9 F 63 Rheumatoid - 2 2 over 2 days 100 7 - Well at 5 weeksarthritis,methotrexate

10 M 66 - 49 4 over 7 days 1160 12 Well at 24 weeks11 F 74 Asthma Streptococcus 4 2 over 2 days 580 40 Malnourished, Well at 22 weeks

miXeri fractured wrist

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Intrapleural streptokinase in the management of empyema

Figure 1 Chest radiographs ofpatient I (A) at presentation and (B) 40 weeks after treatment with streptokinase.

alone. In an attempt to facilitate drainage andobviate surgery, enzymatic debridement of thepleural cavity with streptokinase is a non-invasive therapeutic option. Intrapleural in-stillation of streptokinase was first described in1949 by Tillet and Sherry.3 Its use did notgain acceptance, however, because of the rareoccurrence of intrapleural haemorrhage andsystemic fibrinolysis.45 With the availability ofpurer fibrinolytic formulations there has been aresurgence in the use of intrapleural fibrinolytictherapy' in countries outside the UK. Wehave reviewed our experience ofenzymatic lysisof adhesions in the pleural cavity with strepto-kinase in 11 patients with complicated em-pyemas.

MethodsPATIENTSEleven adults (eight men) ofmean age 47 years(median 48, range 25-74) with multiloculatedempyemas were treated with intrapleural strep-tokinase. All patients had post-pneumonic em-pyemas and had failed to respond satisfactorilyto antibiotics and intercostal tube drainage.Pleural ultrasound examinations confirmed thepresence of multiple loculations in all patients.In order to maximise fluid drainage prior tothe instillation of streptokinase, all catheters(either 8 FG pigtail nephrostomy tube with 10side holes or 14 FG double-lumen: Merck,Hampshire, UK) were inserted under ultra-sound or fluoroscopic control into the largestloculation of fluid and were regularly flushedonce or twice daily with 20 ml normal salineto maintain patency. Suction had been appliedto the drains ofsix patients before streptokinasewas given. Two patients (nos 2 and 11) hadmore than one drain in situ at the time ofstreptokinase instillation; the second catheterwas inserted under ultrasound guidance intothe largest loculation which was separate fromthe area already drained. The underlying pre-disposing factors and pleural pathogens arelisted in the table. Despite ultrasound guidedplacement of catheters, the use of suction, and

the maintenance of tube patency, drainage wasconsidered to be inadequate and so strepto-kinase was instilled into the pleural cavity.

ADMINISTRATION OF STEPTOKINASEAliquots of 250 000 units streptokinase in100 ml normal saline were instilled into thepleural cavity via the small catheter and thetube(s) clamped. Patients were then rotated invarious positions to improve the dispersal ofstreptokinase and the clamp(s) were releasedafter four hours. Maximum drainage wasachieved by assiduously maintaining the pat-ency of the catheters by flushing. Maximumexpansion was achieved by placing the drainson to negative pressure (10-20 cm H20) suc-tion before drain removal. The response tostreptokinase was assessed by (a) clinical out-come (reduction in pain, dyspnoea, cough, andfever, and improvement in general wellbeing);(b) quantity of output from drain after un-clamping; and (c) subsequent pleural ultra-sound and serial chest radiography. Repeatinstillation of streptokinase was performed ifresidual fluid was present 24 hours after theprevious instillation.

ResultsComplete resolution with re-expansion of theunderlying lung was effected in eight patients.The mean follow up period was 20 weeks (range5-56 weeks, median 20 weeks). All eight remainwell and further resolution of minimal pleuralthickening was shown in subsequent chestradiographs (figs 1-3). One patient, a 59 yearold man with thickened visceral pleura in whomcomplete re-expansion did not occur followingdrainage of a chronic tuberculous empyemaof 10 weeks duration, underwent successfuldecortication. A 26 year old man with a 10week history of unresolved empyema drained360 ml fluid after streptokinase. In view ofpersisting thickened visceral pleura identifiedon ultrasound examination, however, de-cortication was performed. A 26 year old man

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Taylor, Rubens, Pearson, Bames

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Figure 2 Chest radiographs ofpatient S (A) withcatheter in situ revealing multiple fluid levels beforetreatment with streptokinase, (B) after two instillations ofstreptokinase, and (C) 13 weeks after administration ofstreptokinase.

with myocarditis who was on the waiting listfor cardiac transplantation had a pyo-pneumothorax. Following streptokinaseinstillation, the empyema drained but thepneumothorax persisted. He therefore under-went surgery for non-resolution ofthe pneumo-thorax but died perioperatively from cardiacfailure.The number ofstreptokinase instillations per

patient ranged from two to six with a median

Figure 3 Chest radiographs ofpatient 11 (A) atpresentation, (B) with catheter in situ before streptokinaseadministration, and (C) 11 weeks after treatment withstreptokinase.

of three. The volume ofempyema fluid drainedper patient following streptokinase (after sub-traction of the injected volumes) ranged from100 ml to 4870 ml with a median of 900 ml(table). Streptokinase was well tolerated by allpatients. One patient, a 74 year old woman,complained of mild ipsilateral chest pain afterboth instillations of streptokinase. There wasno evidence of intrapleural haemorrhage orclinical manifestation ofsystemic coagulopathy.

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Intrapleural streptokinase in the management of empyema

DiscussionWe have given intrapleural streptokinase to11 patients with empyemas which have notresolved with intercostal tube drainage andantibiotic therapy. The next therapeutic man-oevre would usually have been surgery. In ourexperience streptokinase promoted drainage ofloculated empyemas, permitting clinical res-olution and obviating thoracic surgery. In viewof the considerable morbidity and mortalityassociated with decortication,9 the applicationof this non-invasive therapeutic option appearsto be beneficial. Streptokinase effected com-plete resolution ofthe empyema in two patients(nos 7 and 11) who were at high risk of seriousmorbidity and mortality if they had undergonethoracotomy and decortication. In two pa-tients, failure of streptokinase to achieve com-plete clinical resolution may be attributed toconsiderable pleural thickening which had de-veloped before streptokinase therapy. It seemslikely that, ifenzymatic therapy is initiated earlyin the evolution ofan empyema - tha; is, beforefibrinopurulence is established and or-ganisation occurs - more extensive surgicalprocedures could be avoided.

All patients tolerated intrapleural strepto-kinase well; only one complained of mild chestdiscomfort shortly after each streptokinase in-stillation. Other authors'0 have described thesuccessful use of lignocaine given intra-pleurally 15 minutes before streptokinase ad-ministration. It is of note that previous reportsof anaphylaxis and febrile reactions developedin patients in whom streptokinase had been leftin the pleural cavity for longer time periods(up to 24 hours).6"' It is likely that the shorterinstillation time of four hours, combined withthe use of only highly purified preparations,contributed to the lack of adverse reactionsin this series. As in more recent studies,71'intrapleural haemorrhage did not occur. It isof note that steroid cover was not given inanticipation of possible systemic reactions torepeated streptokinase instillations which weregiven at intervals during a period of 20 and 35days to two patients (nos 7 and 8 respectively);all such instillations were well tolerated. Ra-diological intervention with placement of smallcatheters under ultrasound or fluoroscopic con-trol into specific loculations has optimised the

outcome of this technique. Subsequent as-sessment with serial pleural ultrasound ex-aminations has provided information on thepresence or absence of fluid or pleural thick-ening. Indeed, the success of this techniquemay be attributed partly to the use of ultra-sound guided drainage of large loculations,although it is noteworthy that, in this study,adequate drainage was not achieved byultrasound guided placement of drains alone.

In summary, intrapleural purified strepto-kinase may .be used as an adjunct to initialchest tube drainage when there is a residualcollection of pleural fluid. Streptokinase en-hances the drainage of fluid which is loculatedor is too viscous to be drained by tube thoraco-stomy alone. Subsequent surgical interventionis not jeopardised by the prior use of strep-tokinase. The optimum time for the in-troduction of intrapleural streptokinase in themedical management of complicated empyemaremains controversial. Multicentre controlledtrials will be necessary to clarify the role of thistechnique and such a trial is underway.

1 Strange C, Sahn SA. Management ofparapneumonic pleuraleffusions and empyema. In: Wallace RJ, ed. Infectiousdisease clinics of North America. Philadelphia: Saunders,1991:539-59.

2 Landay MJ, Christensen EE, Bynum LJ, Goodman C.Anaerobic pleural and pulmonary infections. AJR 1980;134:233-40.

3 Tillet WS, Sherry S. The effect in patients of streptococcalfibrinolysin (streptokinase) and streptococcal des-oxyribonuclease on fibrinous, purulent and sanguinouspleural exudations. J Clin Invest 1949;28: 173-90.

4 Berglin E, Ekroth R. Intrapleural instillation ofstreptokinase:effects on systemic fibrinolysis. Thorac Cardiovasc Surg1981;29:124-6.

5 Godley PJ, Bell RC. Major haemorrhage following ad-ministration of intrapleural streptokinase. Chest 1984;86:486-7.

6 Fraedrich G, Hofmann D, Effenhauser P, Jander R. In-stillation of fibrinolytic enzymes in the treatment of pleuralempyema. Thorac Cardiovasc Surg 1982;30:36-8.

7 Aye RW, Froese DP, Hill LD. Use of purified streptokinasein empyema and haemothorax. Am J Surg 1991;161:560-2.

8 Bergh NP, Ekroth R, Larsson S, Nagy P. Intrapleural strep-tokinase in the treatment of haemothorax and empyema.Scand3 Thora" Cardiovasc Surg 1977;11:265-8.

9 Muskett A, Burton NA, Karwande SV, Collins MP. Man-agement of refractory empyema with early decortication.Am J Surg 1988;156:529-32.

10 Henke CA, Leatherman JW. Intrapleurally administeredstreptokinase in the treatment of acute loculated non-purulent parapneumonic effusions Am Rev Respir Dis1992;145:680-4.

11 Tillet WS, Sherry S, Read CT. The use of streptokinase-streptodomase in the treatment of post-pneumonic em-pyema. J Thorac Surg 1951;21:275-97.

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