Streptokinase

Objective: To evaluate the role of intrapleural streptokinase in the management of complicated parapneumonic effusions in children.

Design: Prospective comparative study.

Setting: Cheng Kung University Hospital, a tertiary medical center in Tainan, Taiwan.

Patients and methods: We enrolled as our prospective study group 20 consecutive children with complicated parapneumonic effusions who received intrapleural streptokinase treatment between August 2000 and July 2002. We also retrospectively analyzed a comparison group of 22 consecutive children with complicated parapneumonic effusions who received chest tube drainage without streptokinase treatment from January 1992 to July 2000. We then compared the clinical manifestations and outcome of these two patient groups. The patient population (21 boys and 21 girls) ranged in age from 9 to 130 months (mean age, 41.5 [+ or -] 26.3 months [mean [+ or -] SD]). The characters of pleural effusion showed no difference between the two groups. Nineteen patients had positive findings for Streptococcus pneumoniae, 2 patients had positive findings for Staphylococcus aureus, 2 patients had positive findings for Pseudomonas aeruginosa, and 19 patients had undetermined pathogens. All patients were treated with appropriate antibiotics.

Results: More pleural fluid was drained from the streptokinase group than from the comparison group during streptokinase treatment (816 [+ or -] 481 mL vs 279 [+ or -] 238 mL, p < 0.01). The duration of fever after chest tube insertion was also significantly lower in the study group (5.3 [+ or -] 3.1 days vs 7.9 [+ or -] 4.6 days, p < 0.05). Only two patients in the streptokinase group required surgical intervention compared with nine patients in the comparison group (p < 0.05). No major side effects were noticed after streptokinase instillation.

Conclusion: Intrapleural fibrinolytic treatment with streptokinase is safe and effective, and it can obviate the need for surgery in most cases. The combination treatment should be attempted early on, when complicated parapneumonic effusion is first diagnosed.

Key words: children; empyema; fibrinolytic treatment; parapneumonic effusion; streptokinase

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Pleural effusions are common complications of pediatric bacterial pneumonias. They occur with a frequency ranging from 21 to 91%. (1,2) Failure to control the pleural process may lead to progressive disease and can result in complicated parapneumonic effusions. (3) The natural history of a complicated parapneumonic effusion is to develop a single loculus or multiple loculations and then progress to an empyema cavity in untreated or inadequately treated patients. (4) Simple chest tube drainage is often inadequate in complicated parapneumonic effusions due to the presence of viscous fluid with fibrinous debris clogging the tube or multiple loculations in the pleural space. Fibrin deposition within the pleural cavity may develop within a few days. (5) Thus, patients with poor response to antibiotics and tube thoracostomy may require multiple chest tube insertions, radiographically guided catheter placement or, uncommonly, surgical decortication. (3)

The optimal management of complicated parapneumonic effusions is controversial because there are so few prospective randomized trials. (4) Chemical fibrinolysis in the management of complicated parapneumonic effusions has been employed since 1949, with the initial use of a mixture of streptokinase and streptodornase. (6) Although intrapleural fibrinolytic therapy has been reported for > 50 years, the results of only a few trials (7-9) in adult patients have been published. In pediatric patients, however, experience is limited. (10-13) In recent years, the efficacy of fibrinolytic treatment with urokinase for childhood empyema has been demonstrated. (14-16) However, less information is available on the use of streptokinase in pediatric patients. (10,12,17) Currently, there is still insufficient evidence to support the routine use of intrapleural fibrinolytic therapy in the treatment of parapneumonic effusion and empyema. (18) Experience with and knowledge of the efficacy of intrapleural fibrinolytics in children with empyema are therefore limited. In this study, we investigated the effects of intrapleural instillations of streptokinase in the management of parapneumonic effusion and empyema in children.

PATIENTS AND METHODS

From January 1992 to April 2002, a total of 42 pediatric patients with complicated parapneumonic effusion who had received chest tube drainage were enrolled in this study, 20 prospectively and 22 retrospectively. From August 2000 to July 2002, 20 consecutive patients who had received intrapleural streptokinase therapy in addition to the chest tube drainage were enrolled as the study group. The comparison group consisted of 22 consecutive patients from January 1992 to July 2000 who had received only conventional chest tube therapy. In all cases, chest tubes were inserted to drain pleural fluid with at least one of the following characteristics: pH < 7.2, glucose < 40 mg/dL, total protein > 5 g/dL, lactate dehydrogenase > 1,000 IU/L, grossly purulent appearance, or positive Gram stain. (19) The pleural effusions were classified as empyema if frank pus was obtained at drainage and/or if the pleural fluid Gram stain or culture finding were positive. In order to compare the disease severity, we used Light's classification to score our patients. (20) Appropriate antibiotics were used initially (mainly a combination of penicillin, cephalosporins, aminoglycosides, and/or vancomycin) and then adjusted after the culture results were obtained. Surgical intervention (decortication or lobectomy) was performed after 7 days of persistent fever (body temperature > 38.0[degrees]C) despite appropriate therapy or because of a lung abscess proved by CT of the chest. The criteria for chest tube insertion and indication for surgery remained the same during the whole study period.

Coagulation profiles, including prothrombin time, active partial thrombin time, and platelet counts were checked in all patients before fibrinolytic agents were placed. A total dosage of 12,000 U/kg/d of streptokinase in 50 mL of 0.9% saline solution was instilled into the drainage tube; the tube was clamped on the completion of the instillation. (12) Throughout the process, patients were rotated into several positions to facilitate pleural distribution. After 2 h, the tubes were unclamped and placed back on 5 to 20 cm of [H.sub.2]O suction. The drainage effusion amount was then recorded. Therapy lasted from 3 to 5 days. The duration of therapy was based on careful analysis by the authors of clinical pictures, the amount of chest tube drainage, and chest radiographs. Patients were clinically monitored for signs and symptoms of anaphylaxis, chest pain, bleeding, and hypertension.

We used the Student t test to compare continuous variables, such as age, duration of fever, WBC count, C-reactive protein, total protein, glucose, lactate dehydrogenase, total admission day, and pleural effusion amount, between the study group and the comparison group. For comparison of category variables such as sex classification of parapneumonic effusion, and number of surgeries, we used the [chi square] test. For numbers < 5, we used the Fisher exact test. Statistical significance was set at p < 0.05.

RESULTS

The patients (21 boys and 21 girls) ranged in age from 9 to 130 months (mean, 41.5 [+ or -] 26.3 months [[+ or -] SD]). There were no significant differences between the study and comparison groups in patient demographics, classification of parapneumonic effusion, pleural fluid analyses from thoracentesis, or initial antibiotic treatment (Table 1). Twenty-three patients (55%) had culture-proved bacterial pathogens, and bacteria were found in the Gram stain results of pleural fluid in 8 of the patients. The pathogens were Streptococcus pneumoniae in 19 patients, Staphylococcus aureus in 2 patients, and Pseudomonas aeruginosa in 2 patients. The sensitivity of penicillin for S pneumoniae was rated sensitive in nine patients, intermediate in nine patients, and resistant in one patient. We also compared patients with culture-confirmed pathogens between the study group and comparison group. Again, patient demographics, classification of parapneumonic effusion, and pleural fluid analyses were not different between these two subgroups (Table 2).

A summary of the clinical outcomes is given in Table 3. The duration of fever after hospital admission was shorter in the study group than the comparison group (13.8 [+ or -] 5.3 days vs 17.9 [+ or -] 7.0 days, p < 0.05). The duration of lever after chest tube insertion was also shorter in the study group than the comparison group (5.3 [+ or -] 3.1 days vs 7.9 [+ or -] 4.6 days, p < 0.05). The study group drained more pleural fluid during the days of streptokinase treatment (816 [+ or -] 481 mL vs 279 [+ or -] 238 mL, p < 0.01). Although the total number of inpatient days for those in the study group who were admitted to the hospital (admission days) was shorter than for those in the comparison group, the difference was not significant (16.6 [+ or -] 5.7 days vs 18.2 [+ or -] 8.3 days). Only two patients (10%) in the streptokinase group required surgical intervention, compared with nine patients (40%) in the comparison group (p < 0.05). If we compare the clinical outcomes only in patients with positive bacteria culture results, the result was similar to the entire patient group comparison. A summary of clinical outcomes in patients with positive bacteria culture results is shown in Table 4.

None of the patients experienced clinical deterioration, bleeding complications, anaphylaxis, or hypertension during or after intrapleural streptokinase therapy. Three patients (15%) complained of chest pain or becoming irritable after instillation of streptokinase. These discomforts were easily managed by the administration of acetaminophen.

DISCUSSION

Although intrapleural streptokinase therapy has been reported to be a successful treatment for complicated parapneumonia effusion in children, (12-14) this is the first study to demonstrate that intrapleural streptokinase therapy is also effective in children with culture-proved empyema. Our data demonstrate that instillation of streptokinase dramatically increased the volume of chest tube drainage concurrent with clinical improvement (reduction of fever). Pleural empyema is a collection of pus between the lungs and the chest wall. Approximately 50% of cases complicate pneumonia. (21) There are a variety of treatment options ranging from IV antibiotics alone to chest tube drainage, video-assisted thoracostomy, thoracotomy, or surgical decortication and debridement, depending in part on the stage of the empyema and the severity. (21) Without adequate treatment, acute empyema will progress through the exudate stage, the fibropurulent stage, and on to the organization stage. (4,13) Multiloculation of empyema is usually formed in the fibrinopurulent stage and is regarded as a significant cause of failure in percutaneous catheter drainage. Furthermore, the pneumonia may be difficult to control and may progress to necrotizing pneumonia or lung abscess. In such eases, surgical intervention such as decortication or lobectomy may be needed. Any therapy that can reduce the chance of surgery may be preferable. (4,14) Shoseyov et al (22) also reported the repeated ultrasound-guided needle thoracocentesis is as efficacious as conventional chest tube drainage. Intrapleural administration of fibrinolytic agents has been proven to effectively lyse fibrinous pleural material and break down septas. (1-3,7,8,9)

Streptokinase is a purified proteolytie enzyme produced by a bacterial protein of group C [beta]-hemolytic streptococci. It converts plasminogen to plasmin that degrades fibrin clots as well as figrinogen. (23) Fibrinolytic therapy is therefore more likely to be successful during the fibrinopurulent stage and the early organization stage of parapneumonic effusion, and unlikely to be successful in an organized empyema cavity when fibrin adhesions are matured and a visceral pleural peel has been developed. (4) In the present study, two patients in the streptokinase group required surgery compared with nine patients in the comparison group (p < 0.05). This trend was also observed in patients with bacterial culture-confirmed parapneumonic effusion. Based on our data, the early use of intrapleural streptokinase obviated the need for surgery in most cases of pneumonia with parapneumonic effusion.

Common side effects of bleeding complication and chest wall pain have been described during intrapleural infusion. (4,12) In addition, streptokinase has been reported to be antigenic and can lead to antibody formation in systemic thrombolytic streptokinase therapy. If re-exposed to streptokinase, it may cause anaphylactoid reactions in patients. (12,24) However, our data showed that only 15% of the patients who received intrapleural streptokinase treatment had minor side effects such as chest pain or irritability. These discomforts improved after acetaminophen was used. Our results suggest that the intrapleural dosage of the streptokinase (12,000 U/kg) in children is safe.

In our study, the streptokinase group had an increasing volume of chest tube drainage, a decreasing time of defervescence, and a shorter hospital stay. This is consistent with the current theory that streptokinase can dissolve loculations and septations, permitting the free flow of pleura1 fluid. (6,23) An alternative explanation is that streptokinase induces the further production of fluid in the lung and pleura. (12) In this study, the clinical improvements of our patients supported the former explanation.

Although not evaluated in prospective studies, most experts recommended the drainage of the pleural space in all clinical settings if bacteria were detected with a pleural fluid culture or Gram stain. Unfortunately, the sensitivity of the Gram stain for detecting pleural effusions is low. (25) Only 19% of our patients were Gram positive, perhaps because most patients in this series had been previously treated with antibiotics at outpatient clinics.

The limitation of this study is that this was not a prospective randomized trial. Although we used retrospective patients as a comparison group, the treatment policy was the same during the whole study period. In addition, because we did not use video-assisted thoracoscopic surgery in this institution, we found the early use of intrapleural streptokinase obviated the need for surgery in most cases of pneumonia with parapneumonic effusion. Further studies with larger populations are needed to confirm this result.

CONCLUSION

This is the first study to demonstrate that intrapleural streptokinase therapy is also effective in children with culture-proved empyema. In previous reports, intrapleural fibrinolytic therapy was applied only when patients responded poorly to systemic antibiotic treatments with chest tube drainage. The relatively later intrapleural fibrinolytic therapy given these patients contributed to the high failure rate. The success rate of intrapleural streptokinase therapy was far greater than that of conventional treatment. This treatment was also significantly successful in culture-proved patients. However, it is necessary that the optimal dosage, duration of therapy, and effects of other fibrinolytic agents be carefully determined.

ACKNOWLEDGMENT: The authors thank Bill Franke for editorial assistance.

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* From the Departments of Pediatrics (Drs. Yao, J-M. Wu, and Liu) and Surgery (Dr. M-H. Wu), National Cheng Kung University Hospital and Institute of Clinical Medicine (Dr. Wang) National Cheng Kung University Medical College, Tainan; and Department of Occupational Medicine (Dr. Chuang), Kaoshiung Medical University Hospital, Kaoshiung, Taiwan.

Financial support was provided by Taiwan Cardiac Children's Foundation.

Manuscript received April 7, 2003; revision accepted September 23, 2003.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Jieh-Neng Wang, MD, Department of Pediatrics, Institute of Clinical Medicine, National Cheng Kung University Hospital, 138 Sheng-Li Rd, Tainan 704, Taiwan; e-mail: jiehneng@mail.ncku.edu.tw

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