Management of Parapneumonic Effusions

Annotation for Point E

Early recognition of a persistent pleural collection (<3 days) offers the potential to use fibrinolytics to release the trapped fluid via a chest tube. Although conceptually intuitive considering the pathophysiology of empyema, fibrinolytic therapy remains controversial. The first report of fibrinolytic therapy in the pleural space was by Tillett and Sherry⁴⁷ in 1949. They infused purified hemolytic streptococcal concentrates, presumed to contain streptokinase and deoxyribonuclease (DNase). Although apparently safe, there was no documented improvement in patient outcome during the ensuing 60 years. The first randomized trial, by Davies et al.⁴⁸ in 1997, demonstrated radiographic improvement in 24 patients but no discernable clinical benefit. This was followed by a number of underpowered randomized studies in Europe, suggesting that urokinase demonstrated a therapeutic value.^49-51 These conflicting results led to the MIST I study,⁴¹ involving 52 hospitals in the United Kingdom with 412 randomized patients. The data indicated that 72 hours of streptokinase treatment resulted in no improvement in mortality, rate of surgery, or length of stay and was associated with an increased rate of serious adverse events. This study was criticized for including a heterogeneous mix of patients with different comorbidities and different stages of pleural disease.⁵² The most recent Cochrane review in 2009⁶ noted that there was a discordance between earlier studies and the MIST I data and concluded that fibrinolytics should be used selectively because there has not been a proven benefit in high-quality trials; however, the authors acknowledged that there may be certain subgroups of patients who benefit from this therapy. Clinical studies in other arenas indicated that tissue plasminogen activator (tPA) was a more effective and safer agent than streptokinase or urokinase as a fibrinolytic agent.⁵³ Other studies suggested that the addition of DNase to streptokinase improves evacuation of an empyema.^54,55 Subsequently, MIST II, using tPAwith or without DNase, has been completed.⁵⁶  Unfortunately, this study (n = 210; four study groups) was only powered sufficiently to evaluate radiographic changes.⁵⁷ But consistent with MIST I, tPA showed no benefit over no fibrinolytic treatment. This is level I therapeutic evidence. The combination of tPA and DNase, however, was beneficial in both the primary end point (radiographic clearance) and secondary end points (need for thoracotomy, hospital length of stay). The authors responsibly conclude, ‘‘Our study shows that combination intrapleural t-PA and DNAse therapy improves the drainage of pleural fluid in patients with pleural infection … This combined treatment may therefore be useful in patients in whom standard medical management has failed and thoracic surgery is not a treatment option. However, appropriate trials are needed to accurately define the treatment effects.’’

Thus, the debate continues regarding the role of fibrinolytics in the management of pleural collections. Most intensivists have observed effective eradication of early empyema in some patients but agree that the appropriate population remains ill defined. On the basis of the pathophysiology of empyema and the morbidity of thoracotomy for delayed intervention, most think that fibrinolytic treatment should be attempted for early empyema with simple collections separated by thin septa documented by CT scan (Fig. 2) if tube thoracotomy drainage fails. Image-guided direct infusion of fibrinolytics into the collection is superior to delivery via the failed chest tube. The precise agent, dosage, and timing of infusion remain to be analyzed; the combination of tPA and DNase seems to be the most effective regimen at this time.⁵⁶