American Journal of Respiratory and Critical Care Medicine

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.

It is estimated that about 1 million persons in the United States develop parapneumonic effusions yearly (1). Complicated parapneumonic effusions (CPE) are those parapneumonic effusions that require drainage of the pleural space for the resolution of fever and sepsis and the prevention of evolution of pleural empyema (PE) (2-5).

The optimal treatment of CPE and PE remains controversial. There is increasing evidence that medical treatment of CPE and PE is an effective and safe mode of management, produces less morbidity than surgical intervention, is preferred by doctors and patients, and does not require surgical expertise. However, fibrinous septa and clots that obstruct the chest tube often limit less invasive drainage techniques. Fibrinolytic agents, such as streptokinase (SK) and urokinase (UK) have been injected intrapleurally to combat these problems, and their use is increasingly reported (6-29). Although these agents were first used half a century ago (6), studies have not been designed to answer the question of whether their activity is based on the lysis of pleural fibrinous adhesions or is a result of the volume effect (i.e., the lysis of adhesions as a result of increased intrapleural pressure from the fluid volume instilled in treatment. Most reported studies of the utility of fibrinolytics have been uncontrolled. Only one controlled, randomized study has been reported on the intrapleural instillation of SK versus NS (26). UK has never been tested in a comparative, randomized, double-blind trial to clarify its effectiveness and mode of action in CPE and PE.

The present study was the first to compare the intrapleural instillation of UK and NS in patients with CPE and PE in a randomized, prospective, double-blind manner in terms of effectiveness and the role of the instilled volume.

Patients

We prospectively studied 31 consecutive patients (24 men and seven women) with CPE (21 subjects) or PE (10 subjects) in whom pleural effusion did not resolve with chest-tube drainage. The median age of the patients was 56 yr (range: 21 to 78 yr) (Table 1). Diagnosis was based on the current definitions of CPE and PE (1-4) and was confirmed with chest computed tomography (CT) and/or ultrasonography (US). Patients with CPE had a pleural fluid pH < 7.0, lactate dehydrogenase (LDH) > 1,000 U, glucose < 40 mg/dl, a positive Gram stain or culture, and multiloculated pleural effusion (Category 5 according to Light's classification) (3). Patients with PE had frank pus on thoracentesis, and multiple locules (Category 7 of Light's classification) (3).

Table 1. DEMOGRAPHIC DATA OF PATIENTS AND  PLEURAL FLUID ANALYSIS

SubjectsUrokinaseControl
Patient characteristics
Number (M/F)15 (11/4)16 (13/3)
Median age, yr 5457
Range21–7825–77
Pleural Fluid AnalysisUrokinaseControlp Value*
Parameter
pH7.0 ± 0.37.02 ± 0.2NS
Glucose, mg/dl25 ± 1020 ± 19NS
LDH, IU 1,280 ± 120 1,160 ± 150NS
WBC, × 103/ml17,500 ± 2,30019,200 ± 3,200NS
Type of Pleural Effusion
Complicated Parapneu- monic effusion, number  of patients
1110NS
Pleural empyema, number of  patients 4 6

Definition of abbreviations: LDH = lactate dehydrogenase; NS = not significant; WBC = white blood cell count.

*Mann–Whitney U test.

Chi-square test.

Exclusion criteria were age > 90 yr, bronchopleural fistula, a known sensitivity to UK, and contraindication to thrombolytic therapy, such as a history of hemorrhagic stroke, intracranial neoplasm, cranial surgery or head trauma within 14 d or major thoracic or abdominal surgery within 10 d before the study began. Clinically, all patients had prolonged fever, cough, dyspnea, and sputum production despite combination antibiotic therapy.

Protocol

Patients were randomly assigned to receive UK (15 subjects) or NS (16 subjects; control group) in a double-blind manner. All patients initially had a closed intercostal drainage with a size 28- to 32-Fr chest tube attached to a waterseal system (Argyle; Sherwood Medical Company, Tullamore, Ireland). For intrapleural instillation of UK we used the method we have described previously (23). In brief, a solution of 100.000 IU of UK in 100 ml NS was instilled via the chest tube. In the control group, 100 ml of NS was instilled through the chest tube. The solutions were prepared by the hospital nursing staff, and neither the treating physicians nor the patient were aware of the identity of the treatment. The chest tube in both groups was clamped after instillation for 3 h before being reopened to −20 cm H2O suction for 18 h. The treatment was continued for three once-daily instillations of UK or NS. Chest tubes were removed after the fourth day of treatment, provided that the net pleural drainage had fallen to < 50 ml during the previous 24 h. In case of treatment failure the codes were broken and further intervention was undertaken with 3 d of instillation of UK in the control group, and video-assisted thoracoscopic surgery (VATS) in case of UK failure in both groups.

All patients received antibiotics. If Gram stain or cultures were negative, these drugs consisted of intravenous ceftazidime (2 g twice daily), aztreonam (1 g four times daily), and clindamycin (600 mg thrice daily). When cultures were positive, the antibiotic scheme was modified accordingly. The study protocol was approved by the ethics committee of our institution.

Assessment

The effectiveness of treatment with either UK or NS was primarily assessed by: (1) chest radiography; (2) chest US and/or CT; (3) daily monitoring of the volume of fluid drained from the chest tube; and (4) clinically (time of resolution of systemic symptoms and signs). Body temperature was recorded every 4 h. Clinical improvement of the most common symptoms (dyspnea, debilitation, and discomfort) was assessed subjectively by the patient on a daily basis. We used a simple reporting scale with a socre of 1 if symptoms were better, 2 if they were the same, and 3 if they were worse.

Secondary variables were: (1) the time until the white blood cell (WBC) count was < 10.000/ml; and (2) deviation of the platelet count, prothrombin ratio, and fibrinogen from predicted values, and the presence of fibrin degradation products (FDP). These varibles were measured at baseline, daily for the first 3 d of treatment, and then at discharge.

Chest radiography (face and lateral) was done twice weekly and again at discharge. Repeat US and/or CT for the detection of remaining pleural effusion was undertaken if there was residual shadowing on radiography and the patient's daily drainage volume was less than 50 ml. The total duration of hospitalization and the duration of chest drainage were recorded.

The decision of whether or not to continue fibrinolytic therapy or to proceed to VATS was made by the attending physician on the basis of clinical judgment. Criteria to proceed to VATS consisted of progressive or persistent sepsis syndrome in the presence of substantial residual pleural fluid. Chest radiographs were evaluated independently by two experts without knowledge of the randomization group of the patient. The size of the pleural fluid collection was measured at baseline and at the end of the 3-d treatment period. In order to score the changes in chest radiographs, we used the method we described previously (13, 23, 25). In brief, the dimensions of pleural fluid loculations were estimated by measuring the two maximal diameters at right angles to each other on chest radiographs and in CT scans. The overall reduction in pleural fluid volume was categorized as 0 (no change), 1 (less than one-third improvement), 2 (improvement of between one- and two-thirds), and 3 (more than two-thirds improvement). In case of interobserver disagreement, the lower score was used.

The overall success rate (complete drainage) was defined by the number of patients who had a daily fluid drainage ⩽ 50 ml after completion of the 3-d treatment, without residual pleural fluid collection as shown by chest imaging (chest radiography, US, or CT).

Follow-up

All patients were followed for a mean of 14 mo (range: 7 to 28 mo) with clinical examination, chest radiography, and/or US or CT of the thorax.

Statistical Analysis

Results are expressed as mean ± SD. Wilcoxon's rank-sum test was used for comparisons of same-group paired data; the Mann–Whitney U test was used for intergroup comparisons; the chi-square test was used for comparisons of group proportions with qualitative data.

A value of p < 0.05 was considered significant.

Thirty-one patients entered the study and were randomly assigned in an age stratified way into the two study groups. The two groups were well matched. Baseline patient characteristics and pleural fluid analysis are presented in Table 1.

Blood and Pleural Fluid Analysis

In both groups, pleural fluid analysis on initial thoracentesis showed the fluid to be exudative. Macroscopically turbid fluid was found in all cases. The pleural fluid WBC count on initial thoracentesis (measured with a Coulter T660 hematologic analyzer; Coulter, Hialeah, FL) was increased in both groups (17,500 ± 2,300/mm3 in the UK group and 19.200 ± 3,200/mm3 in the NS group, p > 0.05). As determined with a blood-gas analyzer (AVL 995; Schauffhausen, Switzerland), pH was found to be low in both the UK and NS groups (7.0 ± 0.3 and 7.02 ± 0.2, respectively, p > 0.05). Glucose (determined with the photometric method) was < 40 mg/dl in both groups (25 ± 10 and 20 ± 19 mg/dl [mean ± SD]) for the UK and NS groups, respectively (p > 0.05). LDH (determined with the photometric method [normal range: 80 to 230 IU/L]) was 1,280 ± 120 IU and 1,160 ± 150 IU for the UK and NS groups, respectively (p > 0.05) (Table 1).

All patients were hypoxemic (PaO2 with breathing of room air at sea level < 75 mm Hg). Hematologic and biochemical parameters did not differ significantly for the two groups of patients.

Microbiology and Predisposing Conditions

A positive pleural fluid Gram stain and/or culture, or a positive blood culture, was found in 12 cases. Streptococcus pneumoniae was identified in four cases, Staphylococcus aureus in two, and Pseudomonas aeruginosa in two. Bacteroides urealyticus, Hemophilus influenzae, Peptostreptococcus sp., Fusobacterium sp., Proteus mirabilis, Escherichia coli, and Peptococccus sp. were identified in one case each. In three cases, mixed pathogens were identified.

Underlying diseases or predisposing conditions for parapneumonic infection were found in many cases, and included: alcoholism in three cases, lung cancer in three, and diabetes mellitus in four. Malnutrition, cancer of the esophagus, bronchiectasis, severe gastroesophageal reflux, positivity for human immunodeficiency virus (HIV), intravenous drug abuse, epilepsy, and upper abdominal surgery were diagnosed in one case each. No significant differences were observed between the UK and NS groups of patients in terms of microbiology or predisposing conditions.

Response to Therapy

Reduction in fever, dyspnea, debilitation and discomfort was noted in all but two patients in the UK group (86.5%), but in only 4 (25%) in the NS group. Defervescence was observed in a mean (SD) time of 6 (± 4) d in the UK group and 12 (± 5) d in the NS group (p < 0.01) (Table 2 and Figure 1).

Table 2. CLINICAL AND CHEST RADIOGRAPHIC IMPROVEMENT  PARAMETERS AFTER TREATMENT (MEAN  ±  SD)

Parameter Mean (SD)Urokinase (n = 15)Normal Saline (n = 16)p Value*
Duration of hospitalization, d13 (4)18 (5)< 0.01
Duration of pleural drainage, d8 (4)12 (6)< 0.05
Time before defervescence, d6 (4)12 (5)< 0.01
Mean chest radiographic improvement  score (at third day of treatment)2.7 (0.59)1.2 (0.92)< 0.001
Success rate, %
 First 3-d intrapleural treatment86.525< 0.001
 Surgical intervention (VATS), %13.537.5< 0.05
Positive cultures, number of pathogens87< 0.05

*Mann–Whitney U test.

Chi-square test.

The mean (SD) volume of pleural fluid drained during the 24 h before instillation began was 48 ± 23 ml for the UK group and 55 ± 31 ml for the NS group (p > 0.05); the mean volume drained during the first 24 h after instillation was significantly greater in the UK group (410 ± 99 ml versus 105 ± 10 ml; p < 0.001). During the first three days after intrapleural treatment, the mean net total fluid drained was also greater in the UK than in the control group (970 ± 75 ml and 280 ± 55 ml, respectively, p < 0.001). Similarly, the total fluid drained was greater in the UK group (1,240 ± 120 ml versus 350 + 80 ml, respectively; p < 0.001) (Figure 2). The mean duration of pleural drainage was 8 (± 4) d in the UK group and 12 (± 6) d in the control group (Table 2).

The improvement in chest radiographs after 3 d of intrapleural instillation of UK or NS was significantly greater in the UK group. A chest radiographic improvement score of 3 (excellent improvement) was noted in 12 patients in the UK group but in only two in the NS group; a score of 2 (moderate improvement) was seen in two patients in the UK group and four in the NS group; one patient in the UK group and seven patients in the NS group had minimal improvement (a score of 1), and three patients in the NS group showed no improvement (a score of 0) (Figure 3). The overall improvement in the chest radiographic score after the completion of 3 d of treatment was 2.7 ± 0.59 for the UK group and 1.2 ± 0.9 for the NS group (p < 0.001). The overall success rate was 86.5% in the UK group and 25% in the control group (p < 0.001). The mean total hospital stay after the beginning of therapy was 13 ± 4 d (range: 7 to 19 d) for the UK group and 18 ± 5 d (range: 9 to 26 d) for the NS group (Table 2).

Treatment Failure

Two (13.5%) patients in the UK group and 12 (75%) in the control group had inadequate pleural fluid evacuation. In order to promote pleural fluid drainage, all 12 patients in the control group were subsequently given intrapleural instillation of UK for 3 d, using the same technique we used in the UK group. Six of the 12 patients had complete pleural fluid drainage, whereas the remaining six still had inadequate drainage. These six patients and the two patients in the UK group underwent VATS and had successful lysis of pleural adhesions and empyema evacuation. It is noteworthy that all of these patients had PE (Table 2).

Complications of Therapy

There were no complications of tube thoracostomy. Measurement of platelets, prothrombin ratio, and fibrinogen, and identification of the presence of FDP at baseline and daily during the first 3 d of intrapleural therapy was done in 10 patients in the UK group and in eight patients in the control group. One patient in the UK group had an increased prothrombin time, decreased fibrinogen, and FDP, which resolved after pleural fluid drainage. In the UK group there was no significant deviation of the studied clotting parameters from their baseline values during treatment. Local or systemic hemorrhage was not observed in either study group.

Long-Term Results

All patients successfully treated with intrapleural fibrinolysis, NS, or VATS were doing well at follow-up, showing no recurrences of disease. Limited residual pleural thickening, progressively improving during the follow-up period, was observed in four patients in the UK group and seven in the NS group. In the rest of the patients, chest radiographs returned to normal in a period of 1 to 4 mo. All patients who had VATS had an uneventful postoperative period, with no recurrences observed during follow-up.

We report here the results of the first randomized controlled trial to assess the efficacy of intrapleural instillation of UK in the drainage of CPE and PE, and discuss the possible role of the instilled volume effect in treating these conditions. The results of this study show that UK increases chest-tube drainage and improves the chest radiographic appearance to a significantly greater degree than NS. Previous, uncontrolled studies have shown that UK is an effective and safe mode of treatment (18, 25, 29). However, the question of whether fibrinolytic agents act through the lysis of pleural adhesions or are effective because of the instilled volume, which in most studies is 100 ml, has not been answered. The results of the present study suggest that UK acts through lysis of adhesions rather than by breaking them down through the volume effect. Although our findings do not conclusively prove that volume does not play some role in the outcome of treatment for CPE or PE, since 25% of the patients in the control group had a good result, previous reports (13, 16, 22, 26) of the effectiveness of fibrinolytic agents, even with minimal volumes ranging as low as 20 ml to dilute the fibrinolytic agent, support our findings. The significant increase in the volume of drained pleural fluid in the UK group could be partly attributed to the ability of fibrinolytic agents to independently increase the volume of pleural fluid. Indeed, Strange and collegues (30, 31) have shown in a rabbit model of pleural sepsis that intrapleural instillation of fibrinolytic agents increased plasminogen-dependent fibrinolytic activity in the pleura and reduced number of pleural adhesions, as well as increasing the volume of pleural fluid independently of drainage. It was implied that this increase in pleural fluid production could be deleterious, since it might delay tube removal or further needed intervention (27). However, the design of our study does not support this possibility, in accord with the findings of Strange and colleagues (30, 31).

The success rate of UK in our series was 86.5%. In previous studies the success rate of fibrinolytics ranged from 44% to 100% (32). The success rate for UK has been reported (18, 25-29) to range from 63% to 100%. In a randomized comparative study of SK and UK, we found that the two drugs were comparably highly effective in treating CPE and PE (25). Fibrinolytic agents are most effective if used early in the evolution of parapneumonic effusions, before extensive collagen is deposited in the pleural space in the fibrinopurulent stage of the disease (2, 26). The present study also suggested the early use of intrapleural UK as more effective than when chest-tube drainage fails. Indeed, we found that drainage in the UK group was successful in 86.5% of patients, as opposed to only 50% in the control group, which received UK later, after an initial trial with NS had failed. This observation is in agreement with that of Davies and colleagues (26). It is of interest that the two patients in the UK group who did not respond to fibrinolysis had empyema. Also, all patients with empyema in the control group failed to respond to treatment and needed VATS.

The efficacy of fibrinolysis depends on the existence of a functioning and properly placed chest tube. Once patients are selected for fibrinolytic therapy on the basis of failure of chest-tube drainage, efficacy of therapy is monitored through the patient's clinical response and chest radiography.

Davies and coworkers (26) contacted a randomized, prospective controlled trial in which they compared the efficacy of SK (250,000 IU in 20 ml of saline, with a 2-h dwell time, daily for 3 d) with NS flushes in 24 patients with either empyema (n = 13) or fluid that fulfilled the biochemical criteria for CPE. Patients receiving SK had greater daily and total pleural fluid drainage, as well as more evidence of chest-radiographic improvement at discharge. Three patients in the control group required surgery, compared with none in the SK group. The duration of hospitalization in the two groups was similar. Systemic fibrinolysis or local hemorrhage did not occur.

In contrast to these results, the duration of hospitalization in the present study was longer in the control group, as was the duration of pleural drainage. Similarly, the time to defervescence was significantly less in the UK group (Table 2). These differences could be attributed to the characteristics of the studied population.

In another controlled, nonrandomized trial, Chin and Lim (27) treated 40 patients with empyemas and 12 with CPE with either drainage alone (29 patients) or SK and drainage (23 patients). Decortication was done in 17%, and overall mortality was 15%. A significantly larger volume of pleural fluid was drained from patients in the SK treatment group (1.5 L) than from those in the drainage treatment group (1 L). The authors concluded that SK increased the drainage of pleural fluid but did not reduce morbidity, mortality, or the need for surgical intervention.

Wait and coworkers (28) randomized a small series of patients with empyema to receive either SK (nine patients) or VATS. They found that the VATS group had a higher primary treatment success (10 of 11 patients [91%] versus four of nine [44%] who were given SK), shorter durtation of lower chest-tube drainage (5.8 versus 9.8 d), and shorter hospitalization (8.7 versus 12.8 d). The hospital cost for the two groups was comparable. The results of the present study, although a different fibrinolytic agent (UK) was used, are not in agreement with the foregoing reports regarding the success rate and need for surgery with fibrinolytic therappy. We found that only three subjects in the control group had complete pleural fluid drainage.

Intrapleural fibrinolytic treatment does not appear to alter systemic coagulation parameters. In fact, we did not find any clinical or statistically significant deviation of the hematologic parameters examined in our study. Our observations are in accord with those in previous reports. Berglin and coworkers (33) did not observe any effects on systemic fibrinolytic activity, β2-macroglobulin levels, or thrombin times with the intrapleural instillation of SK in 10 consecutive patients with empyemas or hemothoraces. In addition, they reported a slight increase in plasminogen, β2-antiplasmin levels, and fibrinogen, but these alterations probably represented an acute-phase reaction. In any event, these changes were not consistent with generalized fibrinolysis. Berglin and coworkers concluded that SK can be given safely even in the early posttraumatic or postoperative period. However, an instance of major hemorrhage following intrapleural instillation of SK in a dose of 500,000 IU has been reported in a patient who was also taking carbenicillin and prophylactic heparin (34). This dose was higher than the 250,000 IU dose that is usually recommended for intrapleural fibrinolysis. Temmes and coworkers (16) also observed a single instance of major local bleeding that required thoracotomy in a patient treated with intrapleural SK. Recently, Davies and colleagues (35) reported that intrapleural administration of SK at up to 1.500.000 IU in 3 d did not cause significant activation of systemic fibrinolysis in humans.

In conclusion, ours is the first study to clearly show that intrapleural UK at a daily dose of 100.00 IU for 3 d is safe and effective in improving chest-tube drainage and reducing the hospital stay of patients with CPE and PE. Our study shows that patients who receive intrapleural UK have a decreased need for further surgery and a decreased need for hospitalization compared with patients who receive saline intrapleurally. The results of the study support the hypothesis that UK acts through the lysis of pleural adhesions, and not through the volume of the instilled fluid.

Supported in part by a grant from the ASTRA Hellas.

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Correspondence and requests for reprints should be addressed to Demosthenes Bouros, M.D., FCCP, Associate Professor of Pneumonology and Clinical Pharmacology, Medical School University of Crete, Departments of Pneumonology and Clinical Pharmacology, University General Hospital, Heraklion 711 10, Crete, Greece. E-mail:

Presented in part at the annual meeting of the European Respiratory Society, September 20–24, 1997, Berlin, Germany.

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