U.K. Controlled trial of intrapleural streptokinase for pleural infection. Intrapleural urokinase in the management of parapneumonic empyema: a randomised controlled trial. Randomised controlled trial of intrapleural streptokinase in community acquired pleural infection. Intrapleural urokinase versus normal saline in the treatment of complicated parapneumonic effusions and empyema. A randomized, double-blind study. Intrapleural streptokinase for empyema and complicated parapneumonic effusions. Early use of intrapleural fibrinolytics in the management of postpneumonic empyema. A prospective study. Intrapleural streptokinase versus urokinase in the treatment of complicated parapneumonic effusions: a prospective, double-blind study.
Intrapleural fibrinolytic agents are used in the drainage of infected pleural-fluid collections. This use is based on small trials that did not have the statistical power to evaluate accurately important clinical outcomes, including safety. We conducted a trial to clarify the therapeutic role of intrapleural streptokinase.
                In this double-blind trial, 454 patients with pleural infection (defined by the presence of purulent pleural fluid or pleural fluid with a pH below 7.2 with signs of infection or by proven bacterial invasion of the pleural space) were randomly assigned to receive either intrapleural streptokinase (250,000 IU twice daily for three days) or placebo. Patients received antibiotics and underwent chest-tube drainage, surgery, and other treatment as part of routine care. The number of patients in the two groups who had died or needed surgical drainage at three months was compared (the primary end point); secondary end points were the rates of death and of surgery (analyzed separately), the radiographic outcome, and the length of the hospital stay.
                The groups were well matched at baseline. Among the 427 patients who received streptokinase or placebo, there was no significant difference between the groups in the proportion of patients who died or needed surgery (with streptokinase: 64 of 206 patients [31 percent]; with placebo: 60 of 221 [27 percent]; relative risk, 1.14 [95 percent confidence interval, 0.85 to 1.54; P=0.43), a result that excluded a clinically significant benefit of streptokinase. There was no benefit to streptokinase in terms of mortality, rate of surgery, radiographic outcomes, or length of the hospital stay. Serious adverse events (chest pain, fever, or allergy) were more common with streptokinase (7 percent, vs. 3 percent with placebo; relative risk, 2.49 [95 percent confidence interval, 0.98 to 6.36]; P=0.08).
                The intrapleural administration of streptokinase does not improve mortality, the rate of surgery, or the length of the hospital stay among patients with pleural infection.
                Copyright 2005 Massachusetts Medical Society. We compared the effectiveness of intrapleural urokinase versus normal saline via a thoracostomy tube in the treatment of parapneumonic empyema in a randomised controlled study. Forty-nine patients with parapneumonic empyema were randomly assigned to receive either intrapleural urokinase or normal saline treatment. The daily volume instilled through a chest tube was 100 ml in both groups. Urokinase (100,000 IU/day) was diluted in normal saline before instillation. The mean duration for defervescence was shorter (7 +/- 3 vs 13 +/- 5 days, p<0.01) and the mean volume of drained fluid during the five-day treatment period was significantly greater in the urokinase group (1.8 +/- 1.5 vs 0.8 +/- 0.8 litres, p<0.001) than in the control group. The subsequent decortication rate was 60% and 29.1%, respectively (p<0.001). The duration of hospitalisation was also shorter in the urokinase group (14 +/- 4 vs 21 +/- 4 days, p<0.001) than in the saline group. We conclude that intrapleural instillation of urokinase in the management of parapneumonic empyema provides a better outcome and reduces the need for decortication. Standard treatment for pleural infection includes catheter drainage and antibiotics. Tube drainage often fails if the fluid is loculated by fibrinous adhesions when surgical drainage is needed. Streptokinase may aid the process of pleural drainage, but there have been no controlled trials to assess its efficacy.
                Twenty four patients with infected community acquired parapneumonic effusions were studied. All had either frankly purulent/culture or Gram stain positive pleural fluid (13 cases; 54%) or fluid which fulfilled the biochemical criteria for pleural infection. Fluid was drained with a 14F catheter. The antibiotics used were cefuroxime and metronidazole or were guided by culture. Subjects were randomly assigned to receive intrapleural streptokinase, 250,000 i.u. daily, or control saline flushes for three days. The primary end points related to the efficacy of pleural drainage--namely, the volume of pleural fluid drained and the chest radiographic response to treatment. Other end points were the number of pleural procedures needed and blood indices of inflammation.
                The streptokinase group drained more pleural fluid both during the days of streptokinase/control treatment (mean (SD) 391 (200) ml versus 124 (44) ml; difference 267 ml, 95% confidence interval (CI) 144 to 390; p < .001) and overall (2564 (1663) ml, 95% CI 465 to 2545; p < 0.01). They showed greater improvement on the chest radiograph at discharge, measured as the fall in the maximum dimension of the pleural collection (6.0 (2.7) cm versus 3.4 (2.7) cm; difference 2.9 cm, 95% CI 0.3 to 4.4; p < 0.05) and the overall reduction in pleural fluid collection size (p < 0.05, two-tailed Fisher's exact test). Systemic fibrinolysis and bleeding complications did not occur. Surgery was required by three control patients but none in the streptokinase group.
                Intrapleural streptokinase probably aids the treatment of pleural infections by improving pleural drainage without causing systemic fibrinolysis or local haemorrhage. Intrapleural administration of fibrinolytic agents has been shown to be effective and safe in the treatment of loculated parapneumonic pleural effusions. However, controlled studies of the possible role of the activity of urokinase (UK) through the volume effect are lacking. We therefore investigated the hypothesis that UK is effective through the lysis of pleural adhesions and not through the volume effect. Thirty-one consecutive patients with multiloculated pleural effusions were randomly assigned to receive either intrapleural UK (15 patients) or normal saline (NS) (16 patients) for 3 d, in a double-blind manner. All patients had inadequate drainage through a chest tube (< 70 ml/24 h). UK was given daily through the chest tube in a dose of 100.000 IU diluted in 100 ml of NS. Controls were given the same volume of NS intrapleurally. Response was assessed by clinical outcome, fluid drainage, chest radiography, pleural ultrasonography (US) and/or computed tomography (CT). Clinical and radiographic improvement was noted in all but two patients in the UK group but in only four in the control group. The net mean volume drained during the 3-d treatment period was significantly greater in the UK group (970 +/- 75 ml versus 280 +/- 55 ml, p < 0.001). Pleural fluid drainage was complete in 13 (86.5%) patients in the UK group (two patients were treated through video-assisted thoracoscopy) but in only four (25%) in the control group. Twelve patients in the control group were subsequently treated with UK and six of them had complete drainage; the remaining six patients had complete drainage after video-assisted thoracoscopy. Our results suggest that UK is effective in the treatment of loculated pleural effusions through the lysis of pleural adhesions and not through the volume effect. We conducted a single-center, randomized, placebo-controlled trial to determine whether streptokinase instillations adjunctive to chest tube drainage reduce the need for surgery and improve outcome in patients with pleural empyema. Fifty-three patients (frank pus aspirated, 81%; microbiological agent cultured, 62%; mean effusion pH, 6.6 +/- 0.4) received antibiotic treatment, chest tube drainage, and once-daily pleural rinses with either normal saline or normal saline with streptokinase (250,000 IU). Nine patients were excluded for various reasons before pleural rinses were started. Streptokinase (n = 22) was instilled over 4.5 +/- 2 days and saline (n = 22) was instilled over 3 +/- 1.3 days. One patient in each group died during treatment. Clinical treatment success and need for referral to surgery were the main outcome measures. No difference was observed after 3 days. After 7 days, streptokinase-treated patients had a higher clinical success rate (82 vs. 48%, p = 0.01) and fewer referrals for surgery (45 vs. 9%, p = 0.02). No significant radiologic or functional differences were observed between groups during follow-up over 6 months. We conclude that intrapleural streptokinase adjunctive to chest tube drainage reduces the need for surgery and improves the clinical treatment success in patients with pleural empyema. A prospective randomized study was conducted in order to analyze the role of fibrinolytics in the treatment of complicated parapneumonic effusion.
                From 2001 to 2004, 127 consecutive patients were managed for thoracic empyema. In all cases the cause was bacterial pneumonia. Seventy patients were managed with sole tube thoracostomy (group A) and 57 with combination of tube thoracostomy and streptokinase instillation (group B). Groups were statistically compared for the age, gender, duration of symptoms, quality of pleural fluid, chest imaging, complete drainage, length of hospital stay and mortality. Multivariate analysis was used in order to define the factors that affect outcome.
                Tube thoracostomy was successful in 47 (67.1%) cases (group A), while fibrinolysis led to a favorable outcome in 50 cases (87.7%) (P<0.05). The length of stay in thoracic surgical department was significantly longer for group A (P<0.001). Mortality rate in group A was significantly higher (P<0.001). Multiple regression analysis disclosed as sole independent favorable factor for pleural drainage, the use of fibrinolysis during the course of chest tube drainage (P=0.006, odds ratio 4.29, 95% CI 1.51-12.14).
                Fibrinolytic agents are a useful adjunct in the management of complicated parapneumonic effusions. Intrapleural fibrinolytics, if used early in the fibrinopurulent stage of a parapneumonic effusion, decrease the rate of surgical interventions (VATS or open decortcation) and the length of hospital stay with minor associated morbidity. Intrapleural administration of fibrinolytics has been shown in small numbers of patients with complicated parapneumonic effusions (CPE) and pleural empyema to be effective and relatively safe. Although streptokinase (SK) is recommended as the fibrinolytic of choice, there are no comparative studies among fibrinolytics. We therefore compared the efficacy, safety, and the cost of treatment two of the most used thrombolytics, SK and urokinase (UK). Fifty consecutive patients with CPE or empyema were randomly allocated to receive either SK (25 patients) or UK, in a double-blind fashion. All patients had inadequate drainage through chest tube (< 70 ml/24 h). Both drugs were diluted in 100 ml normal saline and were infused intrapleurally through the chest tube in a daily dose of 250,000 IU of SK or 100,000 IU of UK. The chest tube was clamped for 3 h after instillation. Response was assessed by clinical outcome, fluid drainage, chest radiography, pleural ultrasound, and/or computed tomography. Clinical and radiologic improvement was noted in all but two patients in each group, who required surgical intervention. The mean volume drained during the first 24 h after instillation was significantly increased; 380 +/- 99 ml for the SK group (p < 0.001) and 420.8 +/- 110 ml for the UK group (p < 0.001). The total volume (mean +/- SD) of fluid drained after treatment was 1,596 +/- 68 ml for the SK group, and 1,510 +/- 55 ml for the UK group (p > 0.05). The SK instillations (mean +/- SD) were 6 +/- 2.16 (range, 3 to 10) and those of UK 5.92 +/- 2.05 (range, 3 to 8). High fever as adverse reaction to SK was observed in two patients. The total cost of the drug in the UK group was two times higher than that of SK ($180 +/- 47 for SK and $320 +/- 123 for UK). The mean total hospital stay after beginning fibrinolytic therapy was 11.28 +/- 2.44 d (range, 7 to 15) for the SK group and 10.48 +/- 2.53 d (range, 6 to 18) for the UK group (p = 0.32). We conclude that intrapleural SK or UK is an effective adjunct in the management of parapneumonic effusions and may reduce the need for surgery. UK could be the thrombolytic of choice given the potentially dangerous allergic reactions to SK and relatively little higher cost of UK.
Intrapleural fibrinolytic therapy confers significant benefit in reducing the requirement for surgical intervention for patients in the early studies included in this review but not in the more recently published Maskell study. The reasons for this difference are uncertain. Separate subgroup analysis of proven loculated/septated effusions from the available data in our meta-analysis suggests a potential overall treatment benefit with fibrinolytics, but these results should be treated with caution as the data are incomplete and the benefit is not significant in the subgroup of high quality trials (Cochrane Grade A). Intrapleural fibrinolytics have not been shown to significantly increase adverse events, but the confidence interval is too wide to firmly exclude this possibility.