433
53
Intrapleural Fibrinolytics
Jay T. Heidecker and Steven A. Sahn
pneumonia that requires drainage for the resolu- tion of pleural sepsis. An empyema thoracis is pus in the pleural space2 and represents the fi nal stage of a parapneumonic effusion that always requires pleural space drainage.
53.1. Pathophysiology of Parapneumonic Effusions and Empyema
Parapneumonic effusions are prototypical exu- dative effusions that occur as a result of altered microvascular permeability.4 The natural history of a parapneumonic effusion evolves over three stages: exudative, fi brinopurulent, and organiz- ing. The exudative stage begins shortly after the onset of the pneumonic process. Neutrophils bind to cell wall components on bacteria in the distal alveoli and secrete interleukin-1(IL-1), IL- 6, IL-8, tissue necrosis factor α (TNF-α), and platelet activating factor (PAF).5 IL-8 and PAF recruit neutrophils, which secrete additional cytokines that recruit more neutrophils and increase vascular permeability of both pulmo- nary and adjacent parietal pleural microvessels.
A neutrophil-predominant, protein-rich fl uid with an elevated lactate dehydrogenase (LDH) is formed in the pleural space.6 Prompt and appro- priate antibiotic therapy in this stage controls the infl ammatory process, obviating the need for pleural space drainage with or without fi brinolytics.
The fi brinopurulent stage is characterized by continued exudation of plasma proteins, Pleural space infection (complicated parapneu-
monic effusion and empyema) is common and causes signifi cant morbidity and mortality of up to 10%. The incidence of community-acquired pneumonia in the United States is estimated at 3.5 to 4 million cases per year with about 20% of patients requiring hospitalization.1 A parapneu- monic effusion develops in approximately half of hospitalized patients with pneumonia,2 translat- ing into 300,000 to 350,000 parapneumonic effu- sion annually. Most are small and resolve with antibiotics alone without pleural space sequelae.
However, the effusion can progress to a compli- cated parapneumonic effusion (CPE) or empyema.
Management ranges from observation to thora- cotomy with decortication. The use intrapleural fi brinolytics, such as streptokinase, urokinase, and tissue plasminogen activator (tPA) to augment chest-tube drainage of a CPE and empyema is widespread; however, case series, cohort studies, and small randomized, controlled trials have confl icting conclusions. Recently, a large, multi- center, randomized clinical trial [First Multi- center Intrapleural Sepsis Trial (MIST-1)] found no benefi t of intrapleural streptokinase for CPE and empyema3; therefore, the use of intrapleural fi brinolytics must be selective and needs further study.
The classifi cation of pleural space infection can be confusing. For simplicity, an uncompli- cated parapneumonic effusion is a pleural effu- sion that occurs as a result of pneumonia that resolves with antibiotic therapy alone. A CPE (pleural fl uid pH <7.20 and/or positive gram stain or culture) is a pleural effusion associated with
including coagulation factors, as well as dysregu- lation of fi brinolysis, resulting in altered fi brin turnover, septation, and loculation within the pleural space. During the development of a para- pneumonic effusion, the mesothelial cell is stim- ulated by TNF-α, IL-1, lipopolysaccharide, and interferon γ (INF-γ).7 In parapneumonic effusion and empyema, levels of plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2) are signifi - cantly elevated,8–10 inhibiting fi brinolysis and promoting fi brin formation.10,11 Fibrin strands form, causing loculation. Extensive loculation can lead to lung entrapment.12 Because the central pathology appears to be disordered fi brin turn- over, it has been postulated that intrapleural fi brinolytics would be effective in the drainage of pleural fl uid in the early fi brinopurulent stage, preventing progression to an empyema. The con- fl icting data regarding the effectiveness of intra- pleural fi brinolytics may refl ect the presence of collagen formation along this fi brin skeleton and crosslinking of fi brin strands rendering fi brino- lytics ineffective during the late fi brinoprolifera- tive and organizing phase.
The third stage of a parapneumonic effusion is the organizing stage, which results in an empyema. Progression to this stage typically occurs over 2 to 4 weeks in the absence of ade- quate treatment. The empyema fl uid (pus) becomes viscous because of fi brin, cellular debris, and coagulation proteins which often contain viable bacteria.13 Fibroblasts enter the pleural space and promote collagen deposition on the fi brin neomatrix and along the pleural surface.
The result is an inelastic visceral pleural peel that limits lung expansion. Due to collagen deposition and the maturity of the visceral pleural peel, a fi brinolytic agent would not be expected to be useful in a mature empyema.
53.2. Management of Complicated Parapneumonic Effusions
Most CPEs require pleural space drainage, in addition to antibiotic therapy. Success rates of image-guided, small-bore catheters and standard chest tubes for CPEs are similar.14,15 Ultrasono- graphic and computed tomography (CT)16- directed, small-bore chest tubes can be placed
into small loculations that may be diffi cult to reach with blind insertion, such as apical locula- tions, loculations abutting the mediastinum, and loculations with underlying lung consolidation.
Each loculus should be drained, if possible.
Small-bore chest tubes should be fl ushed regu- larly via a three-way valve17; intrapleural fi brino- lytics can easily be administered through a side port of most small-bore chest tubes.
53.2.1. Management of Empyema
For the patient with empyema, initial therapy should include drainage of the pleural space and intravenous antibiotics. The optimal mode of drainage is controversial. Although success with small-gauge, image-guided pigtail catheters is reported,14 a large-bore (28F–32F) chest tube is the preferred initial drainage modality of non- loculated empyema.18 However, in pooled data from 21 case series reporting treatment of CPE and empyema, patients treated with tube thora- costomy as the primary intervention required a second intervention 40% of the time.19 Wait and colleagues20 found that early treatment of locu- lated empyema with video-assisted thoras- copic surgery (VATS) resulted in a signifi cantly decreased hospital stay compared to streptoki- nase in a small series of patients; however, the methodology was biased toward the VATS arm.
A Cochrane review of all trials comparing medical and surgical therapy for empyema excluded most series for methodological reasons21–23 and, there- fore, could not reach defi nitive conclusions.24 The most important aspect of management of empyema is the prompt initiation of effective drainage of the pleural space. Delays in complet- ing drainage, regardless of the initial approach selected, contribute to increased morbidity.25
53.2.2. Evaluation of Chest-tube Drainage
When tube thoracostomy is the initial manage- ment choice for CPE and empyema, chest-tube output should be monitored accurately. When drainage approaches 50cc/day or the patient’s symptoms have not improved, a posterior- anterior (PA) and lateral chest radiograph or CT scan should be performed to assess adequacy of drainage and tube position. If there is residual
fl uid, the tube should be fl ushed with sterile saline to ensure patency.17 If kinked, it can be withdrawn slightly to relieve the obstruction. There are commercial dressings available that secure a small-bore chest tube to the chest wall without kinking. Computed tomography is able to dem- onstrate whether the chest tube is correctly posi- tioned in the fl uid collection and whether there are additional loculations that are not in com- munication with the tube. In some instances, however, tube thoracostomy alone is inadequate.
The options available to manage inadequate drainage include additional chest tubes, intra- pleural fi brinolytics, VATS, limited thoracotomy, standard thoracotomy with decortication, and open surgical drainage. The choice of an addi- tional drainage modality depends upon the pres- ence of ongoing pleural sepsis, maturity of the empyema, degree of restriction of lung function from a mature pleural peel, familiarity with the treatment modalities, and debility of the patient.
53.2.3. Intrapleural Fibrinolytics
Intrapleural fi brinolytics have been used when there is occlusion of the chest tube with thick, viscous material or when there are multiple pleural loculations that fail to drain.13 The three primary fi brinolytics that have been used are streptokinase, urokinase, and tissue plasmino- gen activator (tPA). Streptokinase is dosed by adding 250,000 units to 20 to 100mL of normal saline. If urokinase is chosen, 100,000 units are used; however, it is not currently available in the United States.26 In children, 4mg tPA in 50mL saline has been used.27 The fi brinolytic is instilled into the pleural space, and the chest tube is clamped for 2 to 4h.28,29 The chest tube is then unclamped and returned to suction. Daily or up to three times per day instillations have been employed. We favor three instillations daily so we can assess a patient’s response relatively rapidly and avoid an unnecessarily delay of surgery if there is an inadequate response to the fi brinolytic. Mechanistically, administration of intrapleural fi brinolytics would appear to be an effective approach in disrupting pleural locula- tions if given when fi brin stranding predominates prior to fi brin strand crosslinking and collagen deposition.
The literature regarding the effectiveness of intrapleural fi brinolytics is confl icting. Many case series have suggested improvement in clinical and radiographic outcomes with intrapleural strepto- kinase or urokinase.29–39 Small randomized, con- trolled trials report improvement in the volume of fl uid drained,26,28,40–42 radiographic appearance of the pleural space,26,28,38 decreased hospital stay,26,41 and decreased need for surgery26,40,41 in patients receiving intrapleural fi brinolytics (streptokinase or urokinase). The patients in these studies were heterogenous. In some studies, only patients with empyema were studied; in others, a mixed popula- tion of empyemas and CPE were represented. A summary of the case series and randomized studies involving intrapleural fi brinolytics is shown in Tables 53.1 and 2.
While there have been numerous studies docu- menting apparent effi cacy of intrapleural fi brino- lytics, the majority of the reports are small retrospective case series. A Cochrane review of three randomized, controlled trials of good methodological quality26,28,41 found that intra- pleural fi brinolytics appeared to decrease hospi- tal stay, need for surgery, and time to defervesence, and showed improvement in the chest radio- graph. However, these fi ndings were not uniform and the number of patients was small. Therefore, the Cochrane review did not recommend use of intrapleural fi brinolytics for the management of CPE and empyema.43
A double-blind, randomized clinical trial in the United Kingdom of 454 patients (MIST-1) examined the utility of intrapleural streptokinase in patients with empyema (pus) or CPE (pH of
<7.20 or positive gram stain with signs of infec- tion, such as fever, elevated white-cell count, or elevated C-reactive protein). Results in 427 patients enrolled did not show a difference in mortality rates, need for surgery, or hospital stay.3 However, 83% of the patients had empyema, cor- responding to the organizational stage of a para- pneumonic effusion. The median time from initial symptoms of pneumonia to randomization of 14 days refl ects an advanced pathophysiologi- cal stage of the parapneumonic effusion. There- fore, it would not be anticipated that these patients would have a positive response from intrapleural fi brinolytic therapy. We believe that the results from the MIST-1 trial should not be applied to all
TABLE 53.1. Studies with at least 10 patients involving fibrinolytics in adults.
Level of
Reference evidence Design Agent N (type) Comments
Bergh (1977)30 4 Retrospective Streptokinase 12 empyemas 83% increased drainage or CXR improvement case series 250,000U/day
Henke (1992)31 4 Retrospective Streptokinase 12 CPE 67% increased drainage or CXR improvement case series 250,000U/day
Taylor (1994)32 4 Retrospective Streptokinase 11 empyemas 73% increased drainage or clinical, CXR, US
case series 250,000U/day improvement
Laisaar (1996)33 4 Retrospective Streptokinase 1 CPE 68% increased drainage clinical or CXR case series 250,000U/day 21 empyemas improvement
Roupie (1996)34 4 Retrospective Streptokinase 16 empyemas 88% increased drainage or CT imiprovement case series 250,000U/day
Moulton (1989)35 4 Retrospective Urokinase 80– 11 empyemas 91% clinical improvement case series 150,000U several
times/day
Park (1996)36 4 Retrospective Urokinase 10 empyemas 60% improved lung expansion on CXR case series 80,000U t.i.d.
Bouros (1994)37 4 Prospective Streptokinase 15 CPE 95% clinical or CXR improvement case series 250,000U/day 5 empyemas
Jerjes-Sanches 4 Prospective Streptokinase 30 empyemas 93% increased drainage, CXR or pft
(1996)38 multicenter 250,000U/day improvement
series
Bouros (1996)39 4 Prospective Urokinase 13 CPE 95% increased drainage or improved CXR or US case series 50,000U/day 7 empyemas
Lim (1999)21 3b Prospective Streptokinase 19 CPE Decreased mortality 3% vs. 24% with SK + sequential 250,000U/day 63 empyemas surgery vs. nothing; trend toward mortality cohort vs. SK + surgery benefit in SK vs. nothing but not significant
vs. no treatment
Chin (1997)29 2b Case control Chest tube alone or 12 CPE Increased drainage but no improvement in fever, streptokinase 40 empyemas need for surgery, hospital stay, or mortality
250,000U/day
Davies (1997)28 2b Randomized, Streptokinase 11 CPE Increased drainage and CXR improvement in controlled 250,000U/day 13 empyemas streptokinase group
trial vs. NS
Wait (1997)20 1b Randomized Streptokinase 20 CPE or VATS decrease hospital days and increase series 250,000U/day empyemas success of drainage
vs. VATS
Bouros (1999)26 1b Randomized, Urokinase 21 CPE Urokinase decrease hospital days, increase controlled 100,000U/day 10 empyemas success 87% vs. 25%, decrease VATS need
trial × 3 days vs. NS 14% vs. 38%
Tuncozgur (2001)41 1b Randomized, Urokinase 49 CPE or Urokinase decrease hospital stay 14 vs. 21 days controlled 100,000U/day empyemas and need for surgery 29% vs. 60%
trial × 5 days vs.
placebo
Diacon (2004)40 1b Randomized, Streptokinase 7 CPE Streptokinase increase success and decrease controlled 250,000U/day 37 empyemas need for surgery 14% vs. 32%; all patients
trial vs. NS got rinse of NS or SK
Bouros (1997)42 1b Randomized, Streptokinase 39 CPE Both improve drainage, no difference in amount double-blind 250,000U/day 11 empyemas of drainage or need for surgery
trial vs. urokinase
100,000U/day
Maskell (2005)3 1b Randomized, Streptokinase 355 empyemas No difference in need for surgery, mortality, double-blind 250,000U bid hospital stay, residual pleural thickening;
trial × 3 days vs. 75 CPE study population skewed with high
placebo percentage mature empyema
Cameron (2004)43 1a High-quality Evaluated the 144 patients Fibrinolytics appear to decrease need for surgery (Cochrane meta-analysis RCTs available with CPE or and length of stay; unable to give firm review) at time empyema recommendations due to low number of patients Abbreviations: CPE, complicated parapneumonic effusion; CXR, chest radiograph; NS, normal saline; pft, author, please supply definition; RCT, random- ized, controlled trial; tPA, tissue plasminogen activator; US, ultrasound.
patients with CPEs because the group that poten- tially would be responsive (those in the early fi bri- nopurulent stage) was under-represented in this trial. The message from MIST-1 is that there is no role for intrapleural fi brinolytics in the late fi bri- nopurulent or organizational stage of a parap- neumonic effusion. The value of intrapleural fi brinolytics can only be judged when given earlier in the pathophysiological process. Further studies assessing the effi cacy of intrapleural fi brinolytics must recognize that parapneumonic effusion and empyema represent a heterogeneous spectrum of disorders. Trials should not enroll patients with mature empyema as these patients bias the results toward a negative treatment effect.
The use of intrapleural fi brinolytics is not without adverse effects. There are case reports of localized pleural and systemic bleeding44,45 and acute respiratory distress syndrome after intra- pleural instillation of streptokinase and uroki- nase.46 Streptokinase is a bacterial protein and, therefore, can induce neutralizing antibodies.
These antibodies could theoretically interfere with its effi cacy and cause an anaphylactic reaction if streptokinase is given in subsequent hospitalizations. Patients who have received streptokinase should receive a card indicating their exposure and should receive urokinase or tPA for future thrombolysis.
Other agents may be better suited to disrupt pleural loculations. Single-chain urokinase
appears to work only on plasminogen that is bound to fi brin strands47; and therefore, it is not active against free-fl oating plasminogen within the pleural space. This selective binding may offer two distinct benefi ts. First, by being active only on bound plasminogen, it activates plasmin- ogen that can cleave fi brin strands, causing locu- lations instead of being utilized on free-fl oating fi brinogen. Second, binding to plasminogen on fi brin strands may shield it from plasminogen activator inhibition and prolong its effects.47,48 Further study is needed to clarify the apparent advantage of single-chain urokinase compared to streptokinase and other urokinase prepara- tions. Tissue plasminogen activator may be more effective in disrupting loculations than uroki- nase or streptokinase preparations, as it does not require binding to plasminogen to be active. Ret- rospective cohorts of children with empyema and CPE suggest that tPA may increase drainage without signifi cant bleeding risk.27,49 However, there is a paucity of literature in adults reporting its use.50 Given its increased cost, widespread use of tPA for CPE and empyema cannot currently be advocated. There may be a role for fi brinolytics in combination with deoxyribonuclease (DNase) or collagenases. The initial use of intrapleural streptokinase was from bacterial cultures that contained both streptokinase as well as strepto- coccal DNase.51 In comparison to streptokinase alone, the addition of DNase caused marked TABLE 53.2. Studies with at least 10 patients involving fibrinolytics in children.
Level of
Reference evidence Design Agent N (type) Comments
Hawkins (2004)60 4 Retrospective tPA 58 empyemas 93% successful without need for additional case series in children treatment
Weinstein (2004)27 3a Retrospective Early, late, or no 8 empyemas Decreased chest-tube time in patients with cohort tPA 4mg 45 CPE; all early tPA, no operations required; sequential
in children no tPA, then after 1999 all early or late tPA Yao (2004)57 3a Prospective & Streptokinase 19 CPE Streptokinase increase drainage, decrease
retrospective 12,000U/kg/day 23 empyemas fever days 5.3 vs. 7.9 days, decrease surgery
cohort in children 10% vs. 41%
Singh (2004)59 1b Randomized, Streptokinase 40 empyemas No difference in clinical or sonographic controlled 15,000U/kg/day in children outcome
trial × 3 days vs. NS
Thomson (2002)56 1b Randomized, Urokinase 40,000U 60 CPE or Urokinase decrease hospital stay 7.2 vs. 9.4 multicenter, bid × 3 days vs. empyemas days; only 5 VATS needed 3 in placebo 2 in double-blind, placebo in children urokinase
controlled trial
Abbreviations: CPE, complicated parapneumonic effusion; CXR, chest radiograph; NS, normal saline; tPA, tissue plasminogen activator; US, ultrasound.
reduction in the viscosity of the pus in vitro52 and has been successfully used in humans.53Mecha- nistically, these two agents used together would lyse fi brin strands and decrease viscosity of the pus, promoting better drainage. However, before widespread use of these combinations can be advocated, randomized studies or large, well- designed cohort trials would be required.
In the absence of high-grade evidence from adequately performed trials, we limit the use of fi brinolytic therapy to patients with late exuda- tive or early fi brinopurulent parapneumonic effusions who do not drain rapidly and completely following chest-tube insertion. Parapneumonic effusions in these early stages are more likely to be amenable to fi brinolytic therapy compared with effusions in the organized stage (empyema).
Once we have verifi ed that the chest tube remains within a loculation by CT scan, we dose strepto- kinse three times per day, clamping the tube for 2h. If we do not achieve radiographic improve- ment with three doses, we either insert an addi- tional chest tube under ultrasound or CT guidance or consider surgical drainage. If an additional chest tube(s) does not result in adequate drainage, surgery should be performed without delay if there are no absolute contraindications.
52.2.4. Conclusion
Based on the evidence available, the authors rec- ommend that intrapleural fi brinolytics should not be used for mature empyema (level of evi- dence 1a to 1b; recommendation grade A), may be considered for early fi brinopurulent compli- cated parapneumonic effusion (level of evidence 1b to 2b; recommendation grade B), but their use should not delay surgical intervention where appropriate.
52.2.5. Empyema in Children
Management of empyema in children is similar to adults with some notable exceptions. First, the epidemiology of empyema differs in children and adults. Most children with empyema are healthy.
They have less altered mental status, airway pro- tection issues, and aspiration, and are, in general, not at risk for anaerobic pathogens. The majority of children present with cough, dyspnea, respira- tory distress, and fever; poor feeding is a rare presentation.54 In the western world, children virtually never die from empyema; the difference in mortality between adults and children with empyema is related to the comorbidities in adults.
It is unclear whether immediate drainage is nec- essary in pediatric patients who have complicated (by pleural fl uid analysis, ultrasound, or CT scan appearance) parapneumonic effusions. Pediatric patients with exudative parapneumonic effusions have been treated successfully with antibiotics alone54 or with serial thoracentesis as opposed to chest-tube drainage.55 Small-bore chest tubes appear effective in draining pediatric empyema and resulted in a signifi cant decrease in hospital stay in one study.56 Intrapleural fi brinolytics, including tPA,27,49 appear to decrease febrile days, the need for surgical intervention,57 and hospital stay.56 Fibrinolytics also appear to be safe in chil- dren.58 As death is rare in pediatric empyema in the western world, assessment of this end point is problematic (Table 53.2).
53.2.6. Conclusion
Based on the paucity of studies and confl icting conclusions of the two randomized, controlled trials,56,59 there is insuffi cient evidence to provide a recommendation on the use of fi brinolytics in children; however, the use of intrapleural fi brino- lytics appears to be safe.
Intrapleural fi brinolytics should not be used for management of mature empyema (level of evidence 1a to 1b; recommendation grade A).
Intrapleural fi brinolytics may be consid- ered for management of early fi brinopurulent complicated parapneumonic effusion (level of evidence 1b to 2b; recommendation grade B), but their use should not delay surgical inter- vention where appropriate.
There is insuffi cient evidence to provide a rec- ommendation on the use of fi brinolytics for management of empyema in children.
References
1. Bernstein JM. Treatment of community-acquired pneumonia – IDSA guidelines. Infectious Diseases Society of America. Chest 1999;115:9S–13S.
2. Strange C, Sahn SA. The defi nitions and epidemi- ology of pleural space infection. Semin Respir Infect 1999;14:3–8.
3. Maskell NA, Davies CW, Nunn AJ, et al. U.K. con- trolled trial of intrapleural streptokinase for pleural infection. N Engl J Med 2005;352:865–874.
4. Sahn SA. The pathophysiology of pleural effu- sions. Annu Rev Med 1990;41:7–13.
5. Kroegel C, Antony VB. Immunobiology of pleural infl ammation: potential implications for patho- genesis, diagnosis and therapy. Eur Respir J 1997;
10:2411–2418.
6. Light RW, Girard WM, Jenkinson SG, et al.
Parapneumonic effusions. Am J Med 1980;69:
507–512.
7. Antony VB, Hott JW, Kunkel SL, et al. Pleural mesothelial cell expression of C-C (monocyte che- motactic peptide) and C-X-C (interleukin 8) che- mokines. Am J Respir Cell Mol Biol 1995;12:
581–588.
8. Philip-Joet F, Alessi MC, Philip-Joet C, et al. Fibri- nolytic and infl ammatory processes in pleural effusions. Eur Respir J 1995;8:1352–1356.
9. Idell S, Girard W, Koenig KB, et al. Abnormalities of pathways of fi brin turnover in the human pleural space. Am Rev Respir Dis 1991;144:
187–194.
10. Idell S, Zwieb C, Boggaram J, et al. Mechanisms of fi brin formation and lysis by human lung fi bro- blasts: infl uence of TGF-beta and TNF-alpha. Am J Physiol 1992;263:L487–L494.
11. Idell S, Zwieb C, Kumar A, et al. Pathways of fi brin turnover of human pleural mesothelial cells in vitro. Am J Respir Cell Mol Biol 1992;7:414–
426.
12. Strange C, Tomlinson JR, Wilson C, et al. The his- tology of experimental pleural injury with tetra- cycline, empyema, and carrageenan. Exp Mol Pathol 1989;51:205–219.
13. Sahn SA. Management of complicated parapneu- monic effusions. Am Rev Respir Dis 1993;148:
813–817.
14. Silverman SG, Mueller PR, Saini S, et al. Thoracic empyema: management with image-guided cath- eter drainage. Radiology 1988;169:5–9.
15. vanSonnenberg E, Nakamoto SK, Mueller PR, et al. CT- and ultrasound-guided catheter drainage of empyemas after chest-tube failure. Radiology 1984;151:349–353.
16. Klein JS, Schultz S, Heffner JE. Interventional radiology of the chest: image-guided percutane- ous drainage of pleural effusions, lung abscess, and pneumothorax. AJR Am J Roentgenol 1995;164:
581–588.
17. Davies CW, Gleeson FV, Davies RJ. BTS guidelines for the management of pleural infection. Thorax 2003;58(suppl 2):ii18–ii28.
18. Light R. Parapneumonic effusions and empyema:
current management strategies. J Crit Illness 1995;10:832–839.
19. Colice GL, Curtis A, Deslauriers J, et al. Medical and surgical treatment of parapneumonic effu- sions: an evidence-based guideline. Chest 2000;118:
1158–1171.
20. Wait MA, Sharma S, Hohn J, et al. A randomized trial of empyema therapy. Chest 1997;111:1548–
1551.
21. Lim TK, Chin NK. Empirical treatment with fi bri- nolysis and early surgery reduces the duration of hospitalization in pleural sepsis. Eur Respir J 1999;13:514–518.
22. Sasse S, Nguyen TK, Mulligan M, et al. The effects of early chest tube placement on empyema resolu- tion. Chest 1997;111:1679–1683.
23. Lee SH LS, Lee SY, Park SM, et al. A comparative study of three therapeutic modalities in loculated tuberculous pleural effusions. Tuberculosis Respir Dis 1996;43:683–692.
24. Coote N. Surgical versus non-surgical manage- ment of pleural empyema. Cochrane Database Syst Rev 2002:CD001956.
25. Ashbaugh DG. Empyema thoracis. Factors infl u- encing morbidity and mortality. Chest 1991;99:1162–
1165.
26. Bouros D, Schiza S, Tzanakis N, et al. Intrapleural urokinase versus normal saline in the treatment of complicated parapneumonic effusions and empyema. A randomized, double-blind study. Am J Respir Crit Care Med 1999;159:37–42.
27. Weinstein M, Restrepo R, Chait PG, et al.
Effectiveness and safety of tissue plasminogen activator in the management of complicated parapneumonic effusions. Pediatrics 2004;113:
e182–e185.
28. Davies RJ, Traill ZC, Gleeson FV. Randomised controlled trial of intrapleural streptokinase in community acquired pleural infection. Thorax 1997;52:416–421.
29. Chin NK, Lim TK. Controlled trial of intrapleural streptokinase in the treatment of pleural empyema and complicated parapneumonic effusions. Chest 1997;111:275–279.
30. Bergh NP, Ekroth R, Larsson S, et al. Intrapleural streptokinase in the treatment of haemothorax and empyema. Scand J Thorac Cardiovasc Surg 1977;11:265–268.
31. Henke CA, Leatherman JW. Intrapleurally admin- istered streptokinase in the treatment of acute
loculated nonpurulent parapneumonic effusions.
Am Rev Respir Dis 1992;145:680–684.
32. Taylor RF, Rubens MB, Pearson MC, et al. Intra- pleural streptokinase in the management of empyema. Thorax 1994;49:856–859.
33. Laisaar T, Puttsepp E, Laisaar V. Early adminis- tration of intrapleural streptokinase in the treat- ment of multiloculated pleural effusions and pleural empyemas. Thorac Cardiovasc Surg 1996;
44:252–256.
34. Roupie E, Bouabdallah K, Delclaux C, et al.
Intrapleural administration of streptokinase in complicated purulent pleural effusion: a CT- guided strategy. Intensive Care Med 1996;22:
1351–1353.
35. Moulton JS, Moore PT, Mencini RA. Treatment of loculated pleural effusions with transcatheter intracavitary urokinase. AJR Am J Roentgenol 1989;153:941–945.
36. Park CS, Chung WM, Lim MK, et al. Transcatheter instillation of urokinase into loculated pleural effusion: analysis of treatment effect. AJR Am J Roentgenol 1996;167:649–652.
37. Bouros D, Schiza S, Panagou P, et al. Role of strep- tokinase in the treatment of acute loculated para- pneumonic pleural effusions and empyema.
Thorax 1994;49:852–855.
38. Jerjes-Sanchez C, Ramirez-Rivera A, Elizalde JJ, et al. Intrapleural fi brinolysis with streptokinase as an adjunctive treatment in hemothorax and empyema: a multicenter trial. Chest 1996;109:1514–
1519.
39. Bouros D, Schiza S, Tzanakis N, et al. Intrapleural urokinase in the treatment of complicated parap- neumonic pleural effusions and empyema. Eur Respir J 1996;9:1656–1659.
40. Diacon AH, Theron J, Schuurmans MM, et al.
Intrapleural streptokinase for empyema and com- plicated parapneumonic effusions. Am J Respir Crit Care Med 2004;170:49–53.
41. Tuncozgur B, Ustunsoy H, Sivrikoz MC, et al.
Intrapleural urokinase in the management of parapneumonic empyema: a randomised con- trolled trial. Int J Clin Pract 2001;55:658–660.
42. Bouros D, Schiza S, Patsourakis G, et al. Intrapleu- ral streptokinase versus urokinase in the treat- ment of complicated parapneumonic effusions: a prospective, double-blind study. Am J Respir Crit Care Med 1997;155:291–295.
43. Cameron R, Davies HR. Intra-pleural fi brinolytic therapy versus conservative management in the treatment of parapneumonic effusions and empyema. Cochrane Database Syst Rev 2004:
CD002312.
44. Porter J, Banning AP. Intrapleural streptokinase.
Thorax 1998;53:720.
45. Temes RT, Follis F, Kessler RM, et al. Intrapleural fi brinolytics in management of empyema thoracis.
Chest 1996;110:102–106.
46. Frye MD, Jarratt M, Sahn SA. Acute hypoxemic respiratory failure following intrapleural throm- bolytic therapy for hemothorax. Chest 1994;105:
1595–1596.
47. Idell S, Mazar A, Cines D, et al. Single-chain uro- kinase alone or complexed to its receptor in tetra- cycline-induced pleuritis in rabbits. Am J Respir Crit Care Med 2002;166:920–926.
48. Antony VB. Fibrinolysis in the pleural space:
breaking the bonds that bind. Am J Respir Crit Care Med 2002;166:909–910.
49. Ray TL, Berkenbosch JW, Russo P, et al. Tissue plasminogen activator as an adjuvant therapy for pleural empyema in pediatric patients. J Intensive Care Med 2004;19:44–50.
50. Walker CA, Shirk MB, Tschampel MM, et al. Intra- pleural alteplase in a patient with complicated pleural effusion. Ann Pharmacother 2003;37:376–
379.
51. Tillett W, Sherry S. The effect in patients of strep- tococcal fi brinolysin (streptokinsae) and strepto- coccal deoxyribonuclease on fi brinous, purulent, and sanguinous pleural exudations. J Clin Invest 1949;28:173–190.
52. Simpson G, Roomes D, Heron M. Effects of strep- tokinase and deoxyribonuclease on viscosity of human surgical and empyema pus. Chest 2000;117:1728–1733.
53. Simpson G, Roomes D, Reeves B. Successful treatment of empyema thoracis with human recombinant deoxyribonuclease. Thorax 2003;58:365–
366.
54. Chan W, Keyser-Gauvin E, Davis GM, et al.
Empyema thoracis in children: a 26-year review of the Montreal Children’s Hospital experience. J Pediatr Surg 1997;32:870–872.
55. Shoseyov D, Bibi H, Shatzberg G, et al. Short-term course and outcome of treatments of pleural empyema in pediatric patients: repeated ultra- sound-guided needle thoracocentesis vs chest tube drainage. Chest 2002;121:836–840.
56. Thomson AH, Hull J, Kumar MR, et al. Ran- domised trial of intrapleural urokinase in the treatment of childhood empyema. Thorax 2002;
57:343–347.
57. Yao CT, Wu JM, Liu CC, et al. Treatment of com- plicated parapneumonic pleural effusion with intrapleural streptokinase in children. Chest 2004;
125:566–571.
58. Kilic N, Celebi S, Gurpinar A, et al. Management of thoracic empyema in children. Pediatr Surg Int 2002;18:21–23.
59. Singh M, Mathew JL, Chandra S, et al. Random- ized controlled trial of intrapleural streptokinase
in empyema thoracis in children. Acta Paediatr 2004;93:1443–1445.
60. Hawkins JA, Scaife ES, Hillman ND, et al. Current treatment of pediatric empyema. Semin Thorac Cardiovasc Surg 2004;16:196–200.
