BMJ  2006;332:133-134 (21 January), doi:10.1136/bmj.332.7534.133

Editorial

Intrapleural streptokinase for pleural infection

A step forward in managing pleural effusions?

Parapneumonic pleural effusions and pleural empyema are clinically challenging conditions, both therapeutically and diagnostically, because of their heterogeneity.¹ They range from small, uncomplicated, pleural effusions that do not require specific treatment to multiloculated effusions and empyema with pleural fibrosis, trapped lung, systemic sepsis, respiratory failure, and metastatic infection.^{1 2} Drainage of pleural pus has always been regarded as the key to successful management,^1-3 but newer techniques are now also available to clinicians: image guided small bore catheter insertion, intrapleural instillation of fibrinolytics, and medical thoracoscopy. In the face of these newer approaches several management algorithms and guidelines have been published,^{1 3} but there are still many unanswered questions about diagnosis and treatment. One of the most important concerns the use of fibrinolytics.

Until recently five small randomised controlled trials of intrapleural fibrinolytics had been reported.^4-8 A double blind trial comparing streptokinase 250 000 IU and urokinase 100 000 IU in 50 patients has shown that both these fibrinolytic agents are equally effective, but urokinase is safer.⁴ Another compared streptokinase and saline (as placebo) given through a chest tube in 24 patients.⁵ Clinical endpoints did not show a significant difference between the intervention and the control groups, though the volume of pleural fluid drained and the improvement in the chest radiograph were significantly greater in the streptokinase group. In a subsequent double blind randomised trial we compared urokinase and intrapleural saline as placebo in 31 patients with pleural infection.⁶ Patients were randomised after failed chest tube drainage alone. Subsequently, significantly more of the patients receiving urokinase had successful pleural drainage (87% v 25%, P < 0.001). In another randomised controlled study in 49 patients who received either urokinase or normal saline,⁷ it was found that urokinase provided a better outcome and reduced the need for decortication. In a double blind trial of 53 patients Diacon et al reported that after seven days streptokinase produced a higher clinical success rate than placebo (82% v 48%, P = 0.01) and fewer referrals for surgery (43% v 9%, P = 0.02).⁸ However, no significant radiological or functional differences were observed between the groups during follow-up over six months. The authors concluded that intrapleural streptokinase given as an adjunct to chest tube drainage reduces the need for surgery and improves the clinical outcome.

A meta-analysis from the Cochrane library⁹ evaluated four trials^4-7 and concluded that fibrinolytics reduce hospital stay, shorten the period of fever, produce radiological improvement, and reduce the incidence of treatment failure (defined as death). However, none of these trials was powered to assess the endpoints of mortality and the need for surgery.

In contrast to these results are the findings of a recent UK based, double blind trial comparing intrapleural streptokinase (250 000 IU twice daily for three days) with placebo.¹⁰ Maskell et al studied 454 patients with pleural infection and their primary endpoint was the number of patients in the two groups who had died or needed surgical drainage at three months. This number was 64 (31%) out of 206 patients in the streptokinase group and 60 (27%) out of 221 in the placebo group (relative risk 1.14; 95% confidence interval 0.85 to 0.54; P = 0.43). In terms of mortality, rate of surgery, radiographic outcomes, and length of hospital stay streptokinase was of no benefit.

The findings of this study and the authors' suggestion that fibrinolytics should be avoided are limited by certain major weaknesses.¹¹ Firstly, this study enrolled heterogeneous groups of patients from a number of centres, possibly with different experience in treating pleural infection. All stages of parapneumonic pleural effusions and empyema formation were eligible for inclusion. Yet in some cases, such as those with late "organised" stage disease or fibrous peels, management with fibrinolytics would not be expected to have any effect. In such cases even video assisted thoracoscopic surgery is ineffective and has a high conversion rate to open thoracotomy.^{1 2} Similarly, in patients with early, non-loculated parapneumonic pleural effusions fibrinolytics are not expected to produce any benefit. Secondly, the authors included patients of advanced age, many of whom had coexisting conditions (65%), whereas the earlier studies included younger patients with less comorbidity.^4-6 Thirdly, Maskell et al's study used smaller chest tubes than the 28 or 32 French gauge tubes used in the other randomised trials, without imaging guidance insertion. Fourthly, important therapeutic interventions, such as referral for surgical drainage, was done without following a specific protocol, again unlike in the previous controlled studies.^4-7

Nevertheless, the study of Maskell et al does remind us that fibrinolytic therapy is not indicated for all patients. A definitive procedure should be done within one week of the patient first being seen, which suggests that after 3-5 unsuccessful instillations of a fibrinolytic under proper imaging evaluation a patient should be referred for further intervention. If possible this should be medical thoracoscopy or video-assisted thoracoscopic surgery.^{12 13} A comparative trial of intrapleural fibrinolytics versus medical thoracoscopy in complicated and loculated parapneumonic pleural effusions is ongoing in Europe. In the meantime, the available evidence suggests that fibrinolytics should be used by experienced physicians using large enough image guided catheters in selected patients with loculated parapneumonic pleural effusions but avoided in those with pleural empyema.

Department of Pneumonology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
(bouros{at}med.duth.gr)

Interstitial Lung Disease Unit, Imperial College and Royal Brompton Hospital, London

Pulmonary Disease Program, Saint Thomas Hospital, Nashville, TN 372, USA

---

Competing interests: None declared.

References

1. Bouros D, Plataki M, Schiza S. Parapneumonic pleural effusion and empyema. In: Bouros D, ed. Pleural diseases. New York: Dekker, 2004: 353-90.
2. Bouros D, Hamm H. Infectious pleural effusions. Eur Respir Mon 2002;22: 204-18.
3. Davies CWH, Gleeson FV, Davies RJO. BTS guidelines for the management of pleural infection. Thorax 2003;58 (suppl II): ii18-ii28.[Free Full Text]
4. 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 1997;155: 291-5.[Abstract]
5. Davies RJ, Traill ZC, Gleeson FV. Randomised controlled trial of intrapleural streptokinase in community acquired pleural infection. Thorax 1997;52: 416-21.[Abstract]
6. 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 1999;159: 37-42.[Abstract/Free Full Text]
7. Tuncozgur B, Ustunsoy H, Sivrikoz MC, Dikensov O, Topal M, Sanli M, et al. Intrapleural urokinase in the management of parapneumonic empyema: a randomised controlled trial. Int J Clin Pract 2001;55: 658-60.[ISI][Medline]
8. 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 2004;70: 49-53.
9. Cameron R, Davies HR. Intra-pleural fibrinolytic therapy versus conservative management in the treatment of parapneumonic effusions and empyema. Cochrane Database Syst Rev 2004;2: CD002312.
10. Maskell NA, Davies CW, Nunn AJ, Hedley EL, Gleeson FV, Miller R, et al. UK controlled trial of intrapleural streptokinase for pleural infection. First Multicenter Intrapleural Sepsis Trial (MIST1) Group. N Engl J Med 2005;352: 865-74.[Abstract/Free Full Text]
11. Bouros D. A trial of intrapleural streptokinase. N Engl J Med 2005;352: 2243-5.[Free Full Text]
12. 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 2002;16: 151-4.[CrossRef][ISI][Medline]
13. Petrakis IE, Kogerakis NE, Drositis IE, Lasithiotakis KG, Bouros D, Chalkiadakis GE. Video-assisted thoracoscopic surgery for thoracic empyema: primarily, or after fibrinolytic therapy failure? Am J Surg 2004;187: 471-4.[CrossRef][ISI][Medline]

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