Current medical management of pleural · PDF fileCurrent medical management of pleural infection ... of the definition of empyema in a nonpurulent ... Current medical management of

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10.1586/14750708.3.1.163 © 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 3(1), 163-174 163

REVIEW

Current medical management of pleural infectionDemosthenes Bouros†, Argyris Tzouvelekis & Katerina M Antoniou†Author for correspondenceDemocritus University of Thrace, Department of Pneumonology Medical School, Alexandroupolis, 68100, GreeceTel.: +30 255 107 6106Fax: +30 255 107 [email protected]

Keywords: empyema, fibrinolytics, management, parapneumonic pleural effusions, pleural infections, streptokinase, therapy, treatment, urokinase

Pulmonary infections with secondary pleural involvement have led to considerable morbidity and mortality. Their diagnosis, prognosis and medical management are challenging. The spectrum of parapneumonic pleural effusions ranges from a small pleural effusion that does not require specific therapy to multiloculated pleural empyema with pleural fibrosis, trapped lung, systemic sepsis and respiratory failure. Today’s chest physician plays a pivotal role in the timely and modern medical management of patients with parapneumonic pleural effusions and pleural empyema. However, uncertainties remain regarding the medical treatment of pleural infection which involves prolonged courses of antibiotics, attention to the patient’s nutritional state, intercostal drainage and intrapleural instillation of fibrinolytic agents. The latter is undertaken to dissolve fibrinous clots and membranes, to prevent fluid sequestration and hence to improve drainage. Our primary aim is to review the current status of knowledge regarding medical management of parapneumonic pleural effusions and pleural empyema, discuss factors which influence their clinical course and prognosis and present a number of the future perspectives.

Pleural infection develops in approximately65,000 patients each year in the USA and theUK. Parapneumonic pleural effusions (PPEs)and pleural empyema (PE) represent a frequentlydifficult diagnostic and therapeutic challenge inclinical practice due to their heterogeneity. Overthe past decade, their devastating incidence andclinical seriousness have stimulated innumerableresearch studies, with any possible therapeuticapproach. However, there are still many uncer-tainties concerning the diagnosis and treatmentof PPE and PE. Most of these studies have beenundertaken due to the attention currently beingdirected at the practice of evidence-based medi-cine with interventions that are supported bylarge, randomized controlled studies. Further-more, pressures on physicians to dischargepatients from the hospital in record time, whiledecreasing morbidity and patient-relatedcharges, are forcing the re-evaluation of currentpractices, many of which are based on anecdoteor experience. Additionally, a lack of controlledstudies concerning the management of PPE andPE was noted in recent guidelines [1–3]. This lackof evidence originates partly from hardships thatare inherent in the investigation of pleural infec-tions, which represent heterogeneous disorderswith outcomes strongly influenced by multiplefactors such as coexisting diseases, underlyinglung function, severity of associated pneumonia,extent of pleural inflammation and virulence ofcausative pathogens.

It is estimated that at least 40% of patientswith pneumonia develop an effusion [1].Delays in diagnosis and treatment are com-mon and may contribute to increased morbid-ity and mortality. There is considerablevariation in the aggressiveness and course ofparapneumonic effusions. Therefore, the spec-trum of appropriate therapy may vary from aconservative approach in uncomplicatedeffusions, to tube drainage with or withoutfibrinolytic therapy in complicated effusionsto aggressive surgical intervention in severemultiloculated empyemas.

Under appropriate conditions, the use of fibri-nolytics intrapleurally appears to enhance inter-costal tube drainage, reducing the requirementfor subsequent surgical mechanical debridement.It should be noted that it still remains to beproven whether the increase in pleural fluiddrainage has any measurable impact on out-come. Recently, there has been interest in otherintrapleural agents, including combination drugsconsisting of streptokinase, streptodornase-αand DNase.

This review discusses the current diagnosticand therapeutic options, and also presentssome of the future perspectives in the medicalmanagement minefield of parapneumoniceffusions and empyemas. Surgical treatmentmodalities represent the issue of anotherreview article and thus have been excludedfrom our data.

REVIEW – Bouros, Tzouvelekis & Antoniou

164 Therapy (2006) 3(1)

DefinitionsA PPE is an accumulation of exudative pleuraleffusion associated with bacterial pneumonia,lung abscess or bronchiectasis [1–3]. An effusionis refered to as an empyema when the concentra-tion of leukocytes becomes macroscopicallyevident as a thick, highly viscous, whitish-yellow, opaque and turbid fluid (pus). Othercommon causes include surgical procedures,traumas and esophageal perforation. Theempyema consists of fibrin, cellular debris andliving or dead bacteria. There is no consensus onthe number of white blood cell (WBC) counts,or the biochemistry for an empyema. The extentof the definition of empyema in a nonpurulentfluid with only the presence of a positive Gramstain or culture is not widely accepted [4].

Uncomplicated (simple) PPEs are usuallysmall, not loculated and not infected. Mostoften, they resolve spontaneously under anti-biotic treatment. Complicated PPEs are usuallyassociated with pleural invasion of the infectiousagent and require tube thoracostomy and possi-bly further interventions. A loculated PPE is anonfree-flowing pleural effusion. A multi-loculated PPE is a pleural effusion with morethan one loculus [1–5].

PathophysiologyThe evolution of a simple PPE to an empyemarepresents a continuous progression from asmall amount of free-flowing, noninfected,nonpurulent pleural fluid to a large amount offrank pus which is multiloculated and associ-ated with thick visceral pleura that prevents theunderlying lung from expanding if the fluid isremoved. Pleural infection may also developwithout evidence of pneumonia – also know asprimary empyema.

When a patient develops pneumonia, thepleura responds to the presence of microbes witha vigorous inflammatory response. The rate ofpleural fluid formation, consisting of an exudateof WBC and proteins, is increased. The increaseis mainly due to lung interstitial fluid and sec-ondary to increased permeability of the capilla-ries in the pleurae. When the amount of fluidentering the pleural space exceeds the capacity ofthe lymphatics to reabsorb the fluid, a pleuraleffusion develops. Initially, the pleural fluid hasnormal glucose, pH and the lactic acid dehydro-genase (LDH) levels and the WBC count arelow [5]. Mesothelial cells are actively phagocytic,initiating an inflammatory response when acti-vated by the presence of bacteria, by releasing a

battery of chemokines (C-X-C group), cytokines(interleukin [IL]-1, IL-6, IL-8, tumor necrosisfactor [TNF]-α), oxidants and proteases [6].

The formation of parapneumonic effusionscan be divided into four stages [7,8]:

• The pleuritis sicca stage: the inflammatoryprocess extends to the visceral pleura, causinga local reaction. This leads to an audible pleu-ral rub and pleuritic chest pain originatingfrom the sensitive innervation of the adjacentparietal pleura. Numerous patients with pneu-monia report pleuritic pain without develop-ing a pleural effusion indicating that theinvolvement of the pleura may be limited tothis stage.

• The exudative stage: is characterized by asmall, sterile, neutrophil predominant exu-date, secondary to increased permeability ofthe visceral pleura. The following accumula-tion of fluid in the pleural space is probablythe combined result of the influx of pulmo-nary interstitial fluid and a local microvascularexudate. Pleural fluid has high protein levels,normal glucose, pH and LDH; however, it isnot infected. The process is reversible with theinstitution of appropriate antibiotic therapyduring the early exudative phase.

• The fibropurulent stage: if the pneumoniaprogresses, bacteria continue to multiply inthe lung with invasion and persistence in thepleural space, while endothelial injurybecomes more prominent with increased pleu-ral fluid formation. Pleural fluid biochemicalparameters change dramatically, mirroringelevated metabolic activity and cell death inleukocytes and bacteria. The latter results indecreased glucose and pH whereas LDH riseswithin pleural fluid. Pleural fluid becomesclottable, as fibrin and collagen are depositedin a continuous sheet covering the visceral andparietal pleura, compartmentalizing the pleu-ral fluid into loculations. The pleural fluidvolume may increase further due to blockageof the parietal pleura stoma by fibrin andcollagen and mesothelial cells. Early in thisstage, antibiotics alone may be effective; how-ever, in the later stages pleural-space drainageis needed.

• The organization/empyema stage: if empyemafails to resolve on treatment, the organiza-tional stage is entered, in which thick rinds offibrous tissue are deposited within thehemithorax forming a single or multiple locu-lations. The organization stage occurs with

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Current medical management of pleural infection – REVIEW

the growth of fibroblasts into the exudates, toform an inelastic pleural peel and densefibrous septations. Empyema fluid is a thick,purulent coagulum which may not be ade-quately drained by tube thoracostomy.Empyema, with the formation of frank pus,may arise from a parapneumonic effusion.However, 25% of empyemas occur aftertrauma or surgery [8]. The rapidity and extentof this process are affected by the type andvirulence of the organism [9]. Untreatedempyema rarely resolves spontaneously.Patients with empyema always requiredrainage for resolution of pleural sepsis.

The evolution of a simple PPE to anempyema represents a continuous progressionfrom a small amount of free-flowing, non-infected pleural fluid to a large amount of frankpus, which is multiloculated and associated witha thick visceral pleura.

Classification of parapneumonic pleural effusions & empyemaInnumerable classification schemes have beensuggested to classify the broad spectrum ofPPEs. A common classification divides PPEsinto three categories, namely uncomplicatedand complicated PPE and thoracic empyema,corresponding to the aforementioned stages ofPPE. The American College of Chest Physicianshas recently developed a new classification ofPPE and empyema which is based upon theradiologic characteristics of the effusion, thepleural fluid bacteriology and the pleural fluidchemistry (Box 1). The key aspects to note con-cerning this classification are the characteristicsindicating that the patient has a moderate-to-high risk of a poor outcome without drainage.Radiologic characteristics associated with a poorprognosis include an effusion that occupiesmore than 50% of the hemithorax, is loculated,

or is associated with thickened parietal pleura.The pleural fluid radiologic, bacteriologic andchemistry prognosticators associated with apoor outcome in patients with complicated PPEare also shown in Box 1 [10]. Several pleural fluidparameters have been described to assess theseverity and predict the clinical course of PPE.Patients with complicated PPE tend to have alower pleural fluid pH and glucose level and ahigher LDH activity. The superiority of the pHover glucose or LDH measurements in PPE/PEhas been confirmed in a meta-analysis of sevenstudies [10]. The decision threshold to identifycomplicated effusions and consequently toassess disease prognosis, ranged betweenpH 7.21 and 7.29. Moreover, there is a generalconsensus that pleural fluid pH is the mostimportant chemical parameter to predict thefurther course of a PPE/PE and variousrecommendations have been made as to the bestcut-off point to distinguish complicated fromuncomplicated cases [1,2,10]. However, it shouldbe kept in mind that pleural fluid pH may notbe useful in patients with systemic pH altera-tions and in infections due to Proteus species,which induce a local metabolic alkalosis due toammonia production. It is also possible to findpleural fluid pH with different macroscopiccharacteristics and pH values in loculatedpleural effusions [1–3].

Epidemiology & bacteriologyPleural infection caused by underlyingpneumonia is the most common cause ofempyema, accounting for 70% of reportedcases. Pleural empyemas occur in 5 to 10% ofpatients with PPE and appear to affect the eld-erly and debilitated more frequently, as well asmen more than women, and hospitalizedpatients with community-acquired pneumonia.Risk factors for their development includecomorbidities such as diabetes mellitus, alcoholabuse, gastroesophageal reflux, rheumatoidarthritis, chronic lung disease and intravenousdrug abuse [1,3]. Clinical factors that predict thepresence of anaerobic pneumonia include poordental hygiene, sedative drug use, alcoholism,seizures and mental retardation [3]. Empyemamay develop as a complication of pneumonia,or may follow surgery, trauma or iatrogenicprocedures [3,4]. It may also occur as a ‘primaryinfection’ without evidence of parenchymallung infection. Rare causes of empyema includepostobstructive pneumonitis due to foreignbody aspiration or tumor [1,3].

Box 1. Indicators of a poor prognosis with complicated parapneumonic effusions.

• Fluid is pus.• Positive Gram stain or culture.• Pleural fluid pH of less than 7.20.• Pleural fluid glucose less than 60 mg/dl.• Pleural fluid lactic acid dehydrogenase

over three times the upper limit of normal for serum.

• Loculated pleural fluid.


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The role of the pathogen in the underlyingpneumonia and the likelihood of the patientdeveloping PPE are not clear, since there are nocomparative studies from a single institution.The bacteriology of empyema is extremely var-ied and there are significant differences betweenorganisms responsible for community- andhospital-acquired infection. Before the adventof modern antibiotics the most common causesof community-acquired pleural infection werestreptococcal (Streptococcus milleri and Strepto-coccus pneumoniae) and staphylococcal species.The current series of empyemas support thecontinuing role of these organisms while docu-menting the emergence of anaerobes andGram-negative organisms as common patho-gens. Conversely, cases of hospital-acquiredinfection are most commonly caused by methi-cillin-resistant Staphylococcus aureus (MRSA),other Staphylococci and Enterobacteria [3,4].

Diagnosis & investigationsPhysicians should be alert for PPE in anypatient with pulmonary infection who has apleural effusion at presentation. The clinicalpresentation of patients with PPE includes fever,pleurodynia, cough and dyspnea. However, upto 10% of patients with PPE and empyema arerelatively asymptomatic, whereas 60 to 80%have underlying comorbidities. Diagnosticthoracentesis is recommended before theadministration of antibiotics to improve thediagnostic yield of pleural fluid culture. Currentguidelines advise that pleural fluid should besampled in every patient where pleural infectionis considered a possibility, except in very smalleffusions (<10 mm) which can only beobserved [11]. The presence of frank pus atthoracentesis is diagnostic of empyema, regard-less of other tests. A foul-smelling pleural fluidsuggests the presence of anaerobic bacteria [3].

Pleural fluid analysisPleural fluid chemistryIn a suspected pleural infection, nonpurulentfluid should be sent for biochemical analysis(protein, LDH, glucose and pH). PPE are exu-dates and identified by application of Light’scriteria [11]. Several pleural fluid parameters havebeen described to assess the severity and serve aspredictors of disease clinical course and prog-nosis. Pleural fluid pH is the most powerful pre-dictor of which pleural effusions will run a‘complicated course’ and become multiloculated,progressing to empyema. It should be

determined with the same care as for arterial pHlevel using a heparinized syringe and measuredin the blood–gas laboratory. The decision thresh-old to identify complicated effusions rangesbetween pH 7.21 and 7.29 [10]. A pleural pH inthis range appears to represent the threshold forconsideration of drainage. Pleural effusions witha nonacidic pH (>7.30) will usually resolve with-out the need for chest tube drainage, whereasthose with an acidic pH (<7.20) are described ascomplicated and require intercostal drainage forresolution. Although low glucose (<35 mg/dl)and high LDH (>1000 IU/l) are supportive ofpleural infection, their addition to pleural fluidpH does not increase the diagnostic accuracy andshould only be used when pH measurement isunavailable [3]. Finally, in a recently publishedconsensus statement, a pH of less than 7.20 wasrecommended as the most reliable prognosti-cator that predicts poor outcome and leads tochest-tube drainage [1].

Pleural fluid cytologyPPE/PE are polymorphonuclear-dominatedeffusions. The absence of which suggests analternative diagnosis (i.e., predominance oflymphocytes in an exudate is most often associ-ated with tuberculosis or malignancy). The dis-covery of food particles in the pleural fluidsuggests the presence of an esophageal–pleuralfistula [3].

RadiologyRadiology is pivotal in the evaluation andappropriate management of PPE. A chest radio-graph showing a pleural-based opacity that hasan abnormal contour or does not flow freely onlateral decubitus views, confirms the presenceof pleural fluid, which in the setting of pleuralinfection is often loculated with multiple air-fluid levels. The lateral decubitus film candetect pleural effusion as small as 5 ml and isused in the diagnosis of a thoracentesis. How-ever, the widespread availability of thoracicultrasonography has largely superseded the lat-ter technique. ultrasonography allows preciseassessment of loculations and is the method ofchoice to guide thoracentesis or place a chesttube (Figure 1). Furthermore, it can detect smallamounts of pleural fluid and reliably distin-guishes small effusions from pleuralthickening [3]. Moreover, ultrasonography isassociated with a low complication rate and hasa success rate in attempted fluid aspirationapproaching 100%.



Although diagnosis can be facilitated by thora-centesis under ultrasonography guidance, opti-mal management requires a chest CT scans withcontrast, which enhances the pleural surface andassists in delineating pleural fluid loculi [13]. ACT scan can show pleural abnormalities at anearlier stage than other modalities. It is useful indistinguishing pleural from parenchymal abnor-malities and lung abscesses from empyema.Moreover, it is valuable in determining the pre-cise location and extent of pleural disease. Finally,magnetic resonance imaging (MRI) may be use-ful in identifying loculated collections and chestwall involvement. Nevertheless, its use in theclinical evaluation of pleural infection is limited.

Methods for treatment of PPE/PEThe benefit of draining large pleural effusionsand empyemas has been recognized since thetime of Hippocrates. Nonetheless it is widelyacceptable that the presence of loculations mayimpede the free drainage of effusions and pre-vent lung re-expansion. Currently there are sev-eral medical therapeutic choices for the moderntreatment of the PPE/PE (Box 2). Nonsurgical

treatment options to reduce the impact ofadhesions and loculae, in addition to appropriateantibiotic therapy, include single and multiplethoracentesis and/or single and multiple inter-costal tube thoracostomies with or without intra-pleural fibrinolytic agents. Surgical optionsinclude direct-vision and video-assisted thoraco-scopic surgical adhesolysis, limited and fullthoracotomy with adhesolysis and possibledecortication for severe pleural thickening.Authors have focused on the current level ofknowledge regarding medical management ofPPEs and PEs and conducted a systematic reviewof the literature concerning its efficacy andsafety. Surgical therapeutic modalities wereexcluded from our data since they represent thefocus of another review article and should beanalyzed separately.

Antibiotic therapyAntibiotic therapy is indicated for all patientswith PPE or PE. Early institution of appropriateantibiotic therapy may minimize the develop-ment of PPE and eradicate small effusions beforethey develop into complicated PPE and PE. The

Figure 1. Ultrasonographic image of the pleural space of a patient with a complicated parapneumonic effusion with multiple pleural adhesions and loculations.


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choice of antibiotic should be based on the resultsof blood and pleural fluid cultures and sensitivi-ties, depending primarily on whether the pneu-monia is community or hospital acquired.Nonetheless, it is worth mentioning that culturesare positive in less than 30% of cases,complicating the early institution of the appro-priate regimen. Thus, initial treatment shouldfollow the existing guidelines for treatment ofcommunity- or hospital-acquired pneumonia [13];however, with the following in mind: antibioticsthat exhibit satisfactory penetration into the pleu-ral fluid include the penicillins, cephalosporins,aztreonam, clindamycin and ciprofloxacin [14].Community-acquired pneumonia requires anti-biotic cover for community pathogens and anaer-obes; choices include a second-generationcephalosporin or intravenous aminopenicillin,plus therapy for anaerobic infection (clinda-mycin). In hospital-acquired empyema, treat-ment for both Gram positive and Gram negativeaerobic organisms as well as anaerobes is neededand additionally highly resistant bacteria shouldbe considered. Options include antipseudomonalquinolones (carbapenems), antipseudomonalpenicillins, third-generation cephalosporins oreven vancomycin for MRSA species. A change tooral antibiotics may be considered following clin-ical improvement and resolution of fever. Theoptimal duration of antibiotic treatment isunclear, although it is likely to be at least3 weeks [15]. However, there is still debate overthe use of intrapleural antibiotics. Several studieshave stated positive results but none of themincluded a randomized control group [15].

Nutritional supportMalnutrition is common in cases of empyema.The availability of nutritional support represents acrucial aspect of the management of the underly-ing lung disease. Adequate nutrition with addi-tional support is likely to be beneficial for patientswith empyema since many require supplementarynasogastric feeding and parenteral nutrition [2].

Intercostal drainageIndications for chest tube drainage are thediagnosis of empyema, the identification oforganisms on pleural fluid Gram stain or cultureand a pleural fluid pH of less than 7.20 (Box 1).Drainage may also be considered for sympto-matic (dyspnea) relief in very large parapneu-monic effusions. In many centers relatively large(25–28 F) chest tubes are usually used to drainPPE, especially PE, with a success rate thatranges between 6 and 76%. Their failure todrain PPE is usually attributed to misplacement,malfunctioning or loculation of the pleuralfluid. However, there is a recent increasing inter-est in using smaller bore catheters (<14 F) in thecontext of less discomfort to the patient andfewer complications [3]. Nonetheless, it shouldbe noted that there is a lack of evidence compar-ing drain sizes in pleural infection. Therefore,the ideal chest tube size remains unclear and hasnot been addressed in randomized trials. Inser-tion of the chest tube should ideally be carriedout under ultrasonography or CT guidance, aseffusions are frequently loculated. The decisionto remove a chest tube is usually dependantupon clinical and radiologic response to alltreatment modalities. The authors recommendthat the chest tube is removed when daily drain-age falls below 50 ml/24 h and the fluid is clearand yellow. Once again, data supporting theprecise timing of removal is elusive and the over-all improvement in the patient’s clinical state isthe most important factor. Complications ofchest tube drainage include hemorrhage,pneumothorax, subcutaneous emphysema orpain. Mortality ranges from 0 to 24% [3].

Fibrinolytic agentsThe treatment of complicated PPE with anti-biotics alone has been advocated, with or with-out chest tube drainage. It is now generallyaccepted that clearance of loculations is the cor-nerstone of successful treatment. The firstattempt to use intrapleural thrombolytic therapyoccured over than 50 years ago using enzymesfrom streptococcal cultures in patients withempyema drainage failure alone [16]. The wide-spread availability of fibrinolytic agents has seenthe emergence of several clinical trials support-ing their beneficial use in the treatment ofPPE/PE over the last few years. Fibrinolyticagents have the potential to lyze fibrin clots andadhesions to promote pleural fluid drainage.Streptokinase is a nonenzymatic proteinproduced by the Lancefield group C strain of

Box 2. Methods for medical treatment of parapneumonic effusions and pleural empyema.

• Antibiotics.• Daily thoracentesis.• Tube thoracostomy (standard chest tube).• Image-guided percutaneous catheter insertion.• Intrapleural fibrinolytic debridement.• Suction drainage.• Medical thoracoscopy (pleuroscopy).



the β-hemolytic streptococci (exotoxin), whichindirectly activates the fibrinolytic system [17–20].Urokinase is a direct plasminogen activator, iso-lated initially from human urine. For each mole-cule of urokinase, one molecule of plasmin isproduced, thus making more efficient use of thepreexisting plasminogen [18–21].

Clinical trials of intrapleural fibrinolyticsIntrapleural instillation of fibrinolytic agents(usually streptokinase or urokinase) has beenshown, in a number of small studies, to be aneffective and safe mode of treatment in compli-cated PPE and PE, minimizing the need for sur-gical intervention [1,22]. However, the latterstatement should be treated with caution sincethese studies have not addressed this outcomeadequately and therefore it could be misleading.

The mean success rate in the publisheduncontrolled series of streptokinase is approxi-mately 82% (range: 44–100%) [17,23–41] and thatof urokinase is 84% (55–100%) [36,37,40–51].Todate, six controlled and/or randomized trials ofintrapleural fibrinolytics have been reported.Bouros and colleagues performed a double-blind, randomized, controlled trial comparingstreptokinase 250,000 µl versus urokinase100,000 µl and ultimately suggested thatstreptokinase and urokinase could be used withequivalent efficacy and safety [36]. The first rand-omized, double-blind placebo-controlled trialwas reported by Davies and colleagues in 24patients with pleural infection. Patients wererandomized to receive either streptokinase orsaline placebo [37]. Clinical end points did notshow a significant difference between the inter-vention and control groups. In addition, Bourosand colleagues compared urokinase and salineplacebo in 31 patients with pleural infection, in adouble-blind, parallel study which showed suc-cessful pleural drainage was significantly morefrequent in those receiving urokinase [52]. How-ever, the study was not large enough to addressissues such as mortality, surgery rate or safety.

The fourth randomized, controlled study wasconducted by Tuncozgur and colleagues [53].Patients were randomized for treatment witheither urokinase or normal saline. The authorsconcluded that urokinase provides a better out-come and reduces the need for decortication.The next placebo-controlled trial was reportedlast year. The study by Diacon and colleagues [42]

was an important addition as the first rand-omized placebo-controlled trial of intrapleuralstreptokinase that employed pragmatic clinical

outcomes (need of surgery or death) as primaryend points [42,55]. Streptokinase-treated patientspresented with a higher clinical success rate andfewer referrals for surgery. The authors statedthat intrapleural streptokinase adjunctive tochest tube drainage reduces the need for surgeryand improves the clinical treatment success inpatients with PE.

Due to the limited number of patientsenrolled in the aforementioned studies, a recentmeta-analysis from the Cochrane library conc-luded on the basis of the above observation, thatwhile fibrinolytics reduced hospital stay andtime-to-defervescence and offered some benefitin terms of radiographic improvement and treat-ment failure, the evidence was not consistent andgiven the small sample size, the benefit of fibri-nolytics remained unproven [18]. The authorsstated that results from this meta-analysis arevalid only when data from all studies are pooled,evidence that renders major uncertainty on thereliability and scientific rigidity of this observa-tion given the heterogeneity and diversity of thestudied conditions and populations. Ultimately,they highlight the need for further randomizedcontrolled trials in a considerable number ofpatients to safely recommend intrapleuralfibrinolysis as an important adjunctive treatmentto intercostal tube drainage.

With this aim in mind, the Multicenter Intra-pleural Sepsis Trial (MIST) was recently con-ducted by Maskell and colleagues [43]. Thisdouble-blind trial is the largest randomizedstudy of fibrinolytics and included 454 patientswith pleural infection. Patients were randomlyassigned to receive either intrapleural strepto-kinase or placebo twice daily for 3 days. Therewas no difference in mortality or rates of surgery(primary end points). Furthermore, no statisticalsignificant difference was notable between thestreptokinase and placebo groups in terms ofradiographic outcome, length of hospital stayand improvement in lung function severalmonths after discharge. Therefore, the largestrandomized trial states no beneficial effect of theapplication of fibrinolytics in the treatment ofpleural infection. Nonetheless, a critical reviewof the trial suggests that the largest weakness wasthe late use of streptokinase in the clinicalcourse, with median time from first symptom torandomization of approximately 2 weeks. Fur-thermore, for chest tube insertion and follow-upno image guidance was used, the experience wasprobably not the same through all centers andthe catheters used were a small bore to drain


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cases with empyema. Nevertheless, these resultsand the conclusion of the meta-analysisdescribed above, underscore the point that anyvalue of intrapleural fibrinolysis remains largelyunproven at the present time. Taking intoaccount these limitations, until new welldefined, randomized, controlled trials evaluatingthe validity of fibrinolytic therapy in loculatedPPE are available, our view is that they can beused by experienced physicians using the appro-priate sized image-guided catheters, avoidingcases of PE [54–56].

Side effects, contraindications, regimens & efficacyMost reported side effects due to intrapleuralfibrinolytic agents are immunologic and occurwith intrapleural streptokinase. The initial use ofnonpurified solutions of streptokinase resulted infrequent febrile reactions, general malaise andleukocytosis. Newer preparations cause far fewerallergic reactions, ranging from 0 to 20% forfever [18–20]. Evidence for local and systemic hem-orrhage is scarce [35]. Systemically administeredstreptokinase generates an antibody response thatcan neutralize later administration of streptoki-nase [57–64]. Urokinase is nonantigenic but maystill cause acute reactions (due to immediatehypersensitivity and histamine release) withfever [65] and cardiac arrhythmia [66]. A case ofacute hypoxemic respiratory failure followingintrapleural instillation of both streptokinase andurokinase for empyema drainage has also beenreported [67].

Contraindications for intrapleural administra-tion of fibrinolytics are still elusive. However, athorough review of the literature revealed absoluteand relative contraindications (Box 3) [18].

Fibrinolytic regimens include streptokinase250,000 IU daily, or 250,000 IU over 12 h, orurokinase 100,000 IU daily retained for 2 to

4 h in the pleural space are the recommendedregimens [2]. The effective half-life of bothfibrinolytics is less than 30 min and it is plaus-ible that fibrin deposition occurs during theperiod between doses [69,70]. It may therefore beappropriate to administer more frequently thandaily [44].

Early administration of fibrinolytic agentsbefore significant collagen is deposited in thepleural space dramatically increases theireffectiveness [55,56]. Measurement of pleural fluiddrainage, laboratory findings (WBC count) andradiographic results are used to monitor treat-ment efficacy [21]. The criteria for abandoningconservative therapy with fibrinolytics andadopting a surgical approach are still ambiguous.In the case of fever persistence, signs of pleuralsepsis, markedly elevated WBC count with anelevated proportion of polymorphonuclear cells,or inadequate drainage after three to five instilla-tions, the clinician should reevaluate whether ornot alternative therapy should be employed. Inthis situation, further invasive intervention, suchas thoracoscopy is recommended [70].

Other agentsOver the last few years, an emerging interestregarding the application of streptodornase, thecoagent originally used has occurred [5]. As anadjuvant or single fibrinolytic agent, it has beenshown to liquify pus more effectively in vitrothan streptokinase [71,72]. In vivo case reports andseries are sparse [70,71]. Tillett’s original empiricaldose of streptodornase was 60,000 units/instilla-tion, with the more recent literature suggesting25 to 50,000 units. One case study used 23doses of streptokinase 100,000 units/streptodor-nase 25,000 units without side effect [16]. Largertrials are needed to demonstrate the benefit andsafety of streptodornase.

Recent studies indicate the usefulness of atissue-plasminogen activator (t-PA, Alteplase) asa therapeutic agent for PPE/PE. A downregula-tion of endogenous t-PA in pleural fluid orinhibition of plasminogen and plasmin by plas-minogen activator inhibitors-1 and -2 and othermediators [66,75,76], could support the patho-genesis of fibrin deposition in exudative pleuraleffusions. However, there are only a few casereports and a retrospective study in pediatricpatients documenting promising results [76–78].These data underline the necessity for rand-omized controlled trials to be conducted in orderto shed further light into the efficacy, dosing andsafety of intrapleural alteplase in the treatment of

Box 3. Absolute and relative contraindications of fibrinolytic treatment.

Absolute• History of allergic reaction to the agent.• Bronchopleural fistula.• Trauma or surgery within 48 h.Relative• Major thoracic or abdominal surgery within 7 to 14 days.• History of hemorrhagic stroke.• Cranial surgery or trauma within 14 days.• Coagulation defects.• Previous streptokinase thrombolysis (for streptokinase only).• Streptococcal infection (for streptokinase only).



patients with CPE and PE [79,80]. In line withthis, an ongoing trial by this authors’ studygroup estimating the efficacy of alteplase inPPE/PE will address the latter important issues.

Empyema pus has a very high content ofDNA. Investigators have postulated that DNaseis effective in reducing the pus viscosity, and thusimproving drainage [81]. Commercially availablehuman recombinant (hr)DNase digests DNA bydepolymerization of polymerized deoxyribonu-cleoproteins of bacteria and may potentiallydecrease the viscosity of PE pus without the riskof allergic reactions that occur with streptococcalextracts. Simpson and colleagues used an in vitroassay to determine the relative effects of strep-tokinase versus hrDNase on the viscosity of pusfrom patients with soft tissue abscesses and PEand documented a beneficial effect of hrDNasein comparison with streptokinase [82,83].

Medical thoracoscopy (pleuroscopy)Thoracoscopy was introduced by Jacobaeus in1910, primarily as a diagnostic procedure in twocases of exudative (tuberculous) pleuritis. Thora-coscopy was rediscovered by thoracic surgeons atthe beginning of this decade and termed surgicalthoracoscopy, which is more precisely known asvideo-assisted thoracoscopic surgery (VATS) [84].VATS may be more effective than chest tubedrainage and less invasive than open thoracot-omy for the lung complication, pleuralempyema. Conversely, medical thoracoscopy orpleuroscopy when compared with VATS, has theadvantage that it can be performed under local

anesthesia or conscious sedation in an endoscopysuite using nondisposible rigid instruments. Thistechnique plays a bridging role between medicaland surgical management and has assumed agreat importance over the last decade. It is con-siderably less invasive and expensive. Today, theleading diagnostic indication for medical thora-coscopy is an exudative pleural effusion ofunknown origin offering a yield of more than90% in malignancy or tuberculous pleurisy. Theeffectiveness of this modern and minimally inva-sive technique in comparison with VATS in thetreatment of PPE and/or PE has not yet beenclearly determined [85].

Expert commentary & outlookDespite the widespread availability of numerousmedical treatment strategies, pleural infection isstill associated with a high mortality and mor-bidity. Factors that should be included in the cli-nician’s ‘wish list’ are early etiologic diagnosisbased on clinical, radiologic and pleural fluidfindings and prompt institution of the appropri-ate treatment. Antibiotic therapy is indicated forall patients with PPE or PE. Early institution ofappropriate antibiotic therapy may minimize thedevelopment of PPE and eradicate small effu-sions before they develop into complicated PPEand PE. Once pleural infection is diagnosed,intercostal drainage should be applied, althoughthere is no therapeutic effect after the develop-ment of multiloculated effusions. Regardingfibrinolytic agents, their validity has to be re-evaluated in the context of large prospective,

Highlights

• Early etiologic diagnosis of pleural infection based on clinical, radiological and pleural fluid findings represents the cornerstone of the appropriate medical treatment.

• Antibiotic therapy is indicated for all patients with parapneumonic pleural effusions (PPEs) or pleural empyema (PEs). Early institution may minimize the development of PPE and eradicate small effusions before they develop into complicated PPE and PE.

• Indications for chest tube drainage are the diagnosis of empyema, the identification of organisms on pleural fluid Gram stain or culture and a pleural fluid pH < 7.20. It may also be used for symptomatic (dyspnea) relief in very large pleural effusions.

• Intrapleural instillation of fibrinolytic agents has been shown, in a number of 'small' studies, to be an effective and safe mode of treatment in complicated PPE and PE, minimizing the need for surgical intervention. However, based on the findings of the largest randomized controlled study, their benefit and efficacy still remain unproven. Their validity has to be re-evaluated in the context of large prospective well-defined studies.

• Medical thoracoscopy represents a novel and promising application in the field of medical management of PPE/PE, since it combines video-assisted thoracoscopic surgery efficacy with less side effects and cost. However, effectiveness of this modern and minimally invasive technique in comparison with VATS in the treatment of PPE and/or PE has not been yet clearly determined.

• The role of newer fibrinolytics, like tissue-plasminogen activator and human recombinant deoxyribonuclease, should also be investigated in PPE.


172 Therapy (2006) 3(1)

well-defined studies since the limited number ofpatients included in the above trials combinedwith the recent results by Maskell and colleagues,pose major limitations and render uncertaintyon their applicability and efficacy. Until largerprospective studies capable of accurately assess-ing whether the benefits of fibrinolytic therapytranslate into a reduction in mortality, our cur-rent view is to limit their use in centers whereVATS is not available or in patients not capableof surgical management.

A comparative study of intrapleuralfibrinolytics versus medical thoracoscopy incomplicated and loculated PPE is about to startin Europe. The role of newer fibrinolytics, suchas t-PA and hrDNase, should also be investigatedin PPE.

AcknowledgementThis work was supported by a grant from the Society forPulmonary and Intensive Care Research at the DemocritusUniversity of Thrace, Greece.

Bibliography1. Bouros D, Plataki M, Schiza S.

Parapneumonic pleural effusion and empyema. In: Pleural Diseases. Bouros D. Dekker, NY, USA, 353–390 (2004).

2. Bouros D, Hamm H. Infectious pleural effusions. Eur. Respir. Mon. 22, 204–218 (2002).

3. Davies CWH, Gleeson FV, Davies RJO. BTS guidelines for the management of pleural infection. Thorax 58, 18–28 (2003).

4. Sahn SA. Use of fibrinolytic agents in the management of complicated parapneumonic effusions and empyemas. Thorax 53(Suppl.), S65–S72 (1998).

5. Fraedrich G, Hofmann D, Effenhauser P, Jander R. Instillation of fibrinolytics enzymes in the management of pleural empyema. Thorac. Cariovasc. Surg. 30, 36–38 (1982).

6. Strange C, Sahn SA. The definitions and epidemiology of pleural space infection. Semin. Respir. Inf. 14, 3–8 (1999).

7. Light RW. Pleural diseases (4th Edition). Lippincott Williams & Wilkins. PA, USA (2001).

8. Antony VB, Mohammed KA. Pathophysiology of pleural infections. Semin. Respir. Inf. 14, 9–17 (1999).

9. Sahn SA. Management of complicated parapneumonic effusions. Am. Rev. Respir. Dis. 148, 813–817 (1993).

10. Heffner JE, Brown LK, Barbieri C, DeLeo JM. Pleural fluid chemical analysis in parapneumonic effusions. A meta-analysis. Am. J. Respir. Crit. Care Med. 151, 1700–1708 (1995).

11. Light RW, Macgregor MI, Luchsinger PC, Ball WC Jr. Pleural effusions: the diagnostic separation of transudates and exudates. Ann. Intern. Med. 77, 507–513 (1972).

12. Kearney SE, Davies CW, Davies RJ, Gleeson FV. Computed tomography and ultrasound in parapneumonic effusions and empyema. Clin. Radiol. 55, 542–547 (2000).

13. Mandell LA, Bartlett JG, Dowell SF, File TM Jr, Musher DM, Whitney C, Infectious Diseases Society of America. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin. Infect. Dis. 37, 1405–1433 (2003).

14. Hoover EL, Hsu HK, Webb H, Toporoff B, Minnard E, Cunningham JN. The surgical management of empyema thoracis in substance abuse patients: a 5-year experience. Ann. Thorac. Surg. 46, 563–566 (1988).

15. Chapman SJ, Davies RJ. The management of pleural space infections. Respirology 9, 4–11 (2004).

16. Tillett WS, Sherry S, Read CT. The use of streptokinase-streptodornase in the treatment of postneumonic empyema. J. Thorac. Surg. 21, 275–297 (1951).

17. Aye RW, Froese DP, Hill LD. Use of purified streptokinase in empyema and hemothorax. Am. J. Surg. 161, 560–562 (1991).

18. Bouros D, Schiza S, Siafakas N. Utility of fibrinolytic agents for draining intrapleural infections. Semin. Respir. Med. 14, 39–47 (1999).

19. Bouros D, Plataki M, Antoniou KM. Parapneumonic effusion and empyema: best therapeutic approach. Monaldi Arch. Chest Dis. 56, 144–148 (2001).

20. Bouros D, Schiza S, Siafakas N. Fibrinolytics in the treatment of parapneumonic effusions. Monaldi Arch. Chest Dis. 54, 558–563 (1999).

21. Heffner JE, McDonalds J, Barbieri C, Klein J. Management of complicated parapneumonic effusions. An analysis of physician practice patterns. Arch. Surg. 130, 433–438 (1995).

22. Cameron R, Davies HR. Intrapleural fibrinolytic therapy versus conservative management in the treatment of parapneumonic effusion and empyema. Cochrane Database Syst. Rev. 2, CD002312 (2004).

23. Bergh NP, Ekroth R, Larsson S, Nagy P. Intrapleural streptokinase in the management of hemothorax and empyema. Scand. J. Thorac. Cardiovasc. Surg. 11, 265–168 (1977).

24. Fraedrich G, Hofmann D, Effenhauser P et al. Instillation of fibrinolytic enzymes in the treatment of pleural empyema. Thorac. Cardiovasc. Surg. 30, 36–38 (1982).

25. Mitchell ME, Alberts WM, Chandler KW, Goldman AL. Intrapleural streptokinase in management of parapneumonic effusion. Reports of series and review of literature. J. Fla. Med. Assoc. 76, 10119–10122 (1989).

26. Wilsie-Ediger SK, Salzman G, Reisz G, Foreman MG. Use of intrapleural streptokinase in the treatment of thoracic empyema. Am. J. Med. Sci. 300, 296–300 (1990).

27. Henke CA, Leatherman JW. Intrapleurally administered streptokinase in empyema in the treatment of acute loculated non-purulent parapneumonic effusions. Am. Rev. Respir. Dis. 145, 680–684 (1992).

28. Alfageme I, Munoz F, Pena N, Ubrias S. Empyema of the thorax in adults. Etiology, biologic findings, and management. Chest 103, 839–843 (1993).

29. Bouros D, Schiza S, Panagou P, Drositis J, Siafakas NM. Role of streptokinase in the treatment of acute loculated parapneumonic pleural effusions and empyema. Thorax 49, 852–855 (1994).

30. Taylor RFH, Reubens MB, Pearson MC, Barnes NC. Intrapleural streptokinase in the management of empyema. Thorax 49, 856–859 (1994).

31. Chin NK, Lim TK. Treatment of complicated parapneumonic effusions and pleural empyema: a four year prospective study. Singapore Med. J. 37, 631–635 (1996).

32. Roupie E, Bouabdallah K, Delclaux C et al. Intrapleural administration of streptokinase in complicated purulent pleural effusion: a CT-guided strategy. Intensive Care Med. 22, 1351–1353 (1996).



33. Jerjes-Sanchez C, Ramirez-Rivera A, Elizalde JJ et al. Intrapleural fibrinolytics with streptokinase as an adjunctive treatment in haemothorax and empyema. A multicentre trial. Chest 109, 1514–1519 (1996).

34. Laisaar T, Puttsepp E, Laisaar V. Early administration of intrapleural streptokinase in complicated multiloculated pleural effusions and pleural empyemas.Thorac. Cardiovasc. Surg. 44, 252–256 (1996).

35. Temes RT, Follis F, Kessler RM, Pett SB, Wernly J. Intrapleural fibrinolytics in the management of empyema thoracis. Chest 110, 102–106 (1996).

36. Bouros D, Schiza S, Patsourakis G, Chalkiadakis G, Panagou P, Siafakas NM. Intrapleural streptokinase versus urokinase in the treatment of complicated parapneumonic effusions. A prospective, double-blind study. Am. J. Respir. Crit. Care Med. 155, 291–295 (1997).

37. Davies RJ, Traill ZC, Gleeson FV. Randomised controlled trial of intrapleural streptokinase in community acquired pleural infection. Thorax. 52, 416–421 (1997).

38. Wait MA, Sharma S, Hohn J, Dal Nogare A. A randomized trial of empyema therapy. Chest 111, 1548–1551 (1997).

39. Chin NK, Lim TK. Controlled trial of intrapleural streptokinase in the treatment of pleural empyema and complicated parapneumonic effusion. Chest 111, 275–279 (1997).

40. Lim TK, Chin NK. Empirical treatment with fibrinolytics and early surgery reduces the duration of hospitalization in pleural sepsis. Eur. Respir. J. 13, 514–518 (1999).

41. Souza A, Offner P, Moore E, Biffl W, Haenel J, Francoise R, Brush J. Optimal management of complicated empyema. Am. J. Surg. 180, 507–511 (2000).

42. Diacon AH, Theron J, Schuurmans MM, Van De Wal BW, Bolliger C. Intrapleural streptokinase for empyema and complicated parapneumonic effusions. Am. J. Respir. Crit. Care Med. 170, 49–53 (2004).

43. Maskell NA, Davies CW, Nunn AJ et al. UK controlled trial of intrapleural streptokinase for pleural infection. First Multicenter Intrapleural Sepsis Trial (MIST1) Group N. Engl. J. Med. 352, 865–874 (2005).

44. Moulton JS, Moore PT, Mencini RA. Treatment of loculated pleural effusion with Transcatheter intracavitary urokinase. Am. J. Rad. 153, 941–995 (1989).

45. Lee KS, Im JK, Kim YH, Huwang SH, BaeWK, Lee BH. Treatment of thoracic multiloculated empyemas with intracavitary UK: a prospective study. Radiology 179, 771–775 (1991).

46. Couser JI, Berley J, Timm EG. Intrapleural urokinase for loculated effusions. Chest 101, 1467–1469 (1992).

47. Robinson LA, Moulton A, Flemming WH, Alonso A, Galbraith TA. Intrapleural fibrinolytic treatment of multiloculated thoracic empyemas. Ann. Thorac. Surg. 57, 803–814 (1994).

48. Pollack JS, Passik CS. Intrapleural UK in the treatment of loculated pleural effusions. Chest 105, 868–873 (1994).

49. Moulton JS, Benkert RE, Weisiger KH, Chambers JA. Treatment of complicated pleural fluid collections with image-guided drainage and intracavitary urokinase. Chest 108, 1252–1259 (1995).

50. Bouros D, Schiza S, Tzanakis N, Drositis I, Siafakas N. Intrapleural streptokinase in the treatment of complicated parapneumonic effusions and empyemas. Eur. Respir. J. 9, 1656–1659 (1996).

51. Park CK, Chung WM, Lim MK, Cho CH, Suh CH, Chung WK. Transcatheter instillation of urokinase into loculated pleural effusions: analysis of treatment effect. Am. J. Roentgenol. 167, 649–652 (1996).

52. 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. Am. J. Respir. Crit. Care Med. 159, 37–42 (1999).

53. Tuncozgur B, Ustunsoy H, Sivrikoz MC et al. Intrapleural urokinase in the management of parapneumonic empyema: a randomized controlled trial. Int. J. Clin. Pract. 55, 658–660 (2001).

54. Lee YC. Ongoing search for effective intrapleural therapy for empyema: is streptokinase the answer? Am. J. Respir. Crit. Care Med. 170, 1–2 (2004).

55. Heffner JE. Multicenter trials of treatment for empyema – after all these years. N. Engl. J. Med. 352, 926–928 (2005).

56. Bouros D. A trial of intrapleural streptokinase. N. Engl. J. Med. 352(21), 2243–5 (2005).

57. Jennings K. Antibobies to streptokinase. Br. Med. J. 312, 393–394 (1996).

58. Lynch M, Littler WA, Pentecost BL, Stockley RA. Immunoglobulin response to intravenous streptokinase in acute myocardial infraction. Br. Heart J. 66, 139–142 (1991).

59. Patel S, Jalihal S, Dutka DP, Morris QK. Streptokinase neutralization titres up to 866 days after intravenous streptokinase for acute myocardial infraction. Br. Heart J. 70, 119–121 (1993).

60. Jalihal S, Morris GK. Antistreptokinase titres after intravenous streptokinase. Lancet 335, 184–185 (1990).

61. Elliott JM, Cross DB, Cederholm Williams SA, White HD. Neutralizing antibodies to streptokinase four years after intravenous thrombolytic therapy. Am. J. Cardiol. 71, 640–645 (1993).

62. Buchalter MB, Suntharalingam G, Jennings I et al. Streptokinase resistance: when might streptokinase administration be ineffective? Br. Heart J. 68, 449–453 (1992).

63. Lee HS, Cross S, Davidson R, Reid T, Jennings K. Raised levels of antistreptokinase antibody and neutralization of streptokinase or anistreplase. Eur. Heart J. 14, 84–89 (1993).

64. Laisaar T, Pullerits T. Effect on intrapleural streptokinase administration on antistreptokinase antibody level in patients with loculated pleural effusions. Chest 123(2), 432–435 (2003).

65. Cohen ML, Finch U. Transcatheter intrapleural urokinase for loculated pleural effusion. Chest 105, 1874–1876 (1994).

66. Alfageme I, Vasquez R. Ventricular fibrillation after intrapleural urokinase. Intensive Care Med. 23, 352 (1997).

67. Frye MD, Jarratt M, Sahn SA. Acute hypoxemic respiratory failure following intrapleural thrombolytic therapy for hemothorax. Chest 105, 1595–1596 (1994).

68. Strange C, Allen ML, Harley R, Lazarchick J, Sahn SA. Intrapleural streptokinase in experimentanl empyema. Am. Rev. Respir. Dis. 147, 962–966 (1993).

69. Mooder VJ, Sherry S. Thrombolytic therapy: current status. N. Engl. J. Med. 318, 1585–1594 (1998).

70. Bouros D, Antoniou KM, Chalkiadakis G, Drositis J, Petrakis I, Siafakas N. The role of video-assisted thoracoscopic surgery in the treatment of parapneumonic empyema after the failure of fibrinolytics. Surg. Endosc. 16, 151–154 (2002).

71. Simpson G, Roomes D, Heron M. In vitro effects of streptokinase and deoxyribonuclease on viscosity of human surgical and empyema pus. Respirology 5, 72 (2000) (Abstract).

72. 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. Lung 178, 13–18 (2000).


174 Therapy (2006) 3(1)

73. Simpson G, Reeves B. Successful treatment of empyema thoracis with human recombinant DNA. Respirology 5, 73 (2000) (Abstract).

74. Nishiwaki Y, Nakamura S, Serizawa A. A case on intractable empyema successfully treated by intrathoracic infusion of streptokinase-streptodornase. Jap. J. Chest Dis. 55, 152–157 (1996).

75. Meier AH, Smith B, Raghavan A, Moss RL, Harrison M, Skasgard E. Rational treatment of empyema in children. Arch. Surg. 135, 907–913 (2000).

76. Bishop NB, Pon S, Ushay HM, Greenwald BM. Alteplase in the treatment of complicated parapneumonic effusion. A case report. Pediatrics 111, E188–E190 (2003).

77. Walker CA, Shirk MB, Tchampel MM, Visconti JA. Intrapleural alteplase in a patient with complicated pleural effusion. Ann. Pharmacother. 37, 376–379 (2003).

78. Wells RG, Havens PL. Intrapleural fibrinolysis for parapneumonic effusion and empyema in children. Radiology 228, 370–378 (2003).

79. O’Brien JD, Baisden CE, Hodges B, Cummings C, Rajab H. Safety and efficacy of intrapleural alteplase (t-PA) for empyema and loculated pleural effusion. Chest Meeting Abstracts 126(Suppl.), 725S (2004).

80. Thommi G, Shehan C, Meyers P, and Mcleay M. Safety profile of various doses of alteplase instilled intrapleurally in the management of complicated pleural effusions/empyema. Chest Meeting Abstracts 126(Suppl.), 892S (2004).

81. Hamm H, Light RW. Parapneumonic effusion and empyema. Eur. Respir. J. 10, 1150–1156 (1997).

82. Simpson G, Roomes D, Heron M. Effects of streptokinase and deoxyribonuclease on viscosity of human surgical and empyema pus. Chest 117, 1728–1733 (2000).

83. Simpson G, Roomes D, Reevew B. Successful treatment thoracis with human recombinant deoxyribonuclease. Thorax 58, 365–366 (2000).

84. Loddenkemper R. Thoracoscopy-state of the art. Eur. Respir. J. 11, 213–221 (1998).

85. Blanc FX, Atassi K, Bignon J, Housset B. Diagnostic value of medical thoracoscopy in pleural disease: a 6-year retrospective study. Chest 121, 1677–1683 (2002).

AffiliationsDemosthenes Bouros, MD, FCCP

Democritus University of Thrace, Department of Pneumonology, Medical School, Alexandroupolis, 68100, GreeceTel.: +30 255 107 6106Fax: +30 255 107 [email protected]

Argyris TzouvelekisRoyal Brompton Hospital, Interstitial Lung Disease Unit, Imperial College, Faculty of Medicine, London, SW3 6LR, United [email protected]

Katerina M AntoniouRoyal Brompton Hospital, Interstitial Lung Disease Unit, Imperial College, Faculty of Medicine, London, SW3 6LR, United [email protected]

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