© 2004 American Thoracic Society
Ongoing Search for Effective Intrapleural Therapy for EmpyemaIs Streptokinase the Answer?University College London and Osler Chest Unit Oxford, United Kingdom Empyema is one of the oldest and severest of diseases, and drainage of pleural pus has always been regarded as the key to its successful management (1). Hippocrates observed that "if an empyema does not rupture, death will occur" (2). Incision and drainage were strongly advocated by Osler who viewed empyema as an abscess. Despite the effectiveness of surgical drainage in evacuating pus, there is a long history of reservations on subjecting patients to surgery. Dupuytren, Napoleon's surgeon, developed an empyema but chose to "die at the hands of God than of surgeons" (2). Today 65,000 patients in the U.S.A. and UK suffer from an empyema or a complicated parapneumonic effusion each year, with a mortality up to 20% and an estimated hospital cost of $500 million (1, 3). Modern-day surgery (thoracoscopic surgery or thoracotomy with decortication) remains the last resort for empyema in many countries because of limited surgical resources, risks of surgery, and philosophy of individual physicians. There is thus an ongoing need for non-surgical adjunct therapies to promote pus drainage. Empyema is characterized by fibrinous septations which defy complete evacuation of infected fluid by tube thoracostomy—often resulting in ongoing sepsis despite parenteral antibiotics (1). Local instillation of fibrinolytics to lyze adhesions and enhance drainage, although theoretically sound and widely practiced, has little evidence-based support. The study by Diacon and coworkers (4), in this issue of the Journal (pp. 49–53), is an important addition as the first randomized placebo-controlled trial of intrapleural streptokinase in pleural infection that employed pragmatic clinical outcomes (need of surgery or death) as primary endpoints. Clinicians' enthusiasm for fibrinolytics in empyema stems from two potentially deceptive observations. One, there have been numerous uncontrolled observational reports, the methodological limitations of which are well known, advocating the use of streptokinase. Two, clinicians and patients are often "reassured" that "streptokinase is working" by the marked (up to 9-fold [5]) increase in pleural fluid drainage following fibrinolytic administration. However, drainage volume, the commonest principal endpoint in previous studies (5–7), is not an ideal clinical or research outcome measure. Indeed, a non-randomized controlled study showed that increased fluid output following streptokinase did not translate into improved morbidity (8). In animal studies, intrapleural streptokinase can induce pleural fluid accumulation (9), casting further doubts on the validity of drainage volume as an endpoint. In their study, Diacon and coworkers have taken an important step forward by putting streptokinase to the "real test"—against clinical outcomes. Did the jury reach a verdict? In this study, 53 patients with pleural infection were randomized to receive intrapleural streptokinase or saline daily. The need for surgery was judged by clinicians blinded to the treatment agents. The results were mixed, and interpretions dependent on the reader's bias. On one hand, streptokinase provided no benefits over placebo in mortality (one in each group) or in reducing the need for surgery at Day 3. At Day 7, however, fewer patients in the streptokinase group required surgery than the controls (9% versus 45%, p = 0.02) (4). Are these results the "smoking gun" that supporters of streptokinase have been waiting for? Careful analysis of the data, with a healthy dose of skepticism, suggest no for two reasons, both of which underscore important design issues of clinical trials for empyema. First, the significant difference at Day 7 was due to an unusually high failure rate in the control group (50%, versus 25–34% in previous studies [6, 8]). The discrepancy probably arose from the chosen criteria for referring patients for surgery. Surgery and deaths are no doubt the most important outcome measures, but the threshold for surgical drainage varies significantly among clinicians. Diacon and coworkers referred patients for surgery for either ongoing sepsis or a lack of satisfactory radiological improvement beyond seven days (4). This contrasts with previous studies where patients referred for surgery satisfied both criteria (6, 10). Many control patients who underwent surgery in the study of Diacon and coworkers had no significant sepsis: 4 of those 10 patients had resolution of fever days before surgery; none were reported to have persistently raised inflammatory markers. The need of surgery for the lack of radiographic improvement, in the absence of sepsis, is arbitrary. Interestingly, the authors showed that residual radiographic opacity in the remaining patients resolved spontaneously without surgery with no long-term sequelae (4). In future, establishing the optimal timing and criteria for surgical referral is necessary for best patient care and will allow standardization of clinical outcome measures and comparison of results between trials. Second, the power of this study was limited. The advantage of the streptokinase group at Day 7 (p = 0.026) was dependent on a single patient and would become statistically insignificant had one extra streptokinase patient required surgery (p = 0.06) or one more control patient avoided surgery (p = 0.052), or both (p = 0.11). The results thus require verification in larger studies and cannot be regarded as definitive at present. Empyema patients are heterogenous in their bacteriology, clinical presentations, and predisposing co-morbidities. Multicenter collaborations are needed to provide sufficient power to draw reliable conclusions. One example is the recently completed Multicentre Intrapleural Sepsis Trial, which randomized 450 patients with pleural infection from 72 British centers to receive twice-daily doses of streptokinase or placebo for three days. Its results are awaited. Withstanding these concerns, the positive results by Diacon and coworkers provide hope and a platform for the ongoing search of adjunct intrapleural therapy for empyema. Although streptokinase lyzes adhesions, it is not bacteriocidal (8) and does not reduce viscosity of pus (11). Pus is thick because of its high DNA content from degranulated cells. It is plausible that a combination of agents that reduce pus viscosity (e.g., DNase [11]) and those that break down loculations may be necessary to enhance pus drainage. Manipulating the key molecules in the pleural fibrosis (e.g., transforming growth factor-ß [12]) and fibrinolytic cascades (e.g., urokinase plasminogen activator [13]) show a glimpse of promise in providing targets for novel adjunct therapies. Osler once stated, "empyema needs a surgeon and three inches of cold steel, instead of a fool of a physician" (14). He underwent rib resections for his own empyema. A century later, tube thoracostomy and antibiotics form the first line treatment for empyema (3), but surgical drainage stays a key armament if the patient fails to respond (15). Despite widespread optimism, the value of adjunctive intrapleural streptokinase remains unproven. FOOTNOTES Conflict of Interest Statement: Y.C.G.L. receives royalties for a reference text on pleural disease that he co-edited; he receives no payment as the co-editor of the International Pleural Newsletter; Y.C.G.L. is an honorary respiratory consultant at the Osler Chest Unit, Oxford, UK, where two of his colleagues (Drs R.J.O. Davies and F.V. Gleeson) are members of the steering committee for the MIST trial on streptokinase, but Y.C.G.L. was not involved in the study; Y.C.G.L. is a co-investigator of a multi-center trial of deoxyribonuclease and fibrinolytics in empyema that is currently under planning. REFERENCES
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