Urokinase

Objective: Use of intrapleural fibrinolytic agents in the management of complicated parapneumonic effusions has been widely reported in adults. Such agents promote drainage of fluid through the thoracostomy tube and may obviate surgery. Both streptokinase and urokinase have been used for this purpose, but there are few reports of their use in the children. The objective of this study was to evaluate the role of intrapleural urokinase in the management of complicated parapneumonic effusions in children. Methods: We reviewed the hospital course of nine children, ages 6 months to 6 years, with complicated parapneumonic effusions who received intrapleural urokinase after failing to respond to IV antibiotics and closed-tube thoracostomy drainage. Four subjects had additional thoroscopic adhesiolysis before intrapleural instillation of urokinase; 20,000 IU of diluted urokinase was instilled three times a day via the thoracostomy tube for 3 days. Results: Eight subjects responded to 3 days of urokinase instillation, with increased thoracostomy tube drainage and clinical resolution of symptoms. The remaining subject responded to a second course of instillation. Two subjects needed oral analgesic for transient chest pain. AR subjects tolerated the procedure well. No bleeding, fever, anaphylaxis, or allergic reactions were noted. The coagulation parameters remained unchanged. Conclusion: Intrapleural instillation of urokinase appears to be a useful and safe adjunct in the management of complicated parapneumonic effusions in children. Its use may be considered in potential decortication patients in an effort to prevent surgery and possibly shorten hospitalization.

(CHEST 1997; 112:1579-83)

Key words: children; empyema; intrapleural; parapneumonic effusions; urokinase

Abbreviations: ESR = erythrocyte sedimentation rate

Bacterial pneumonias in children are frequently complicated by pleural effusions, with a reported incidence varying between 20% and 91%.[1,2] Morbidity remains high, with one report averaging a total hospital stay of 23 days.[3] Failure to control the pleural process may lead to progressive disease and can lead to a complicated parapneumonic effusion. Simple tube drainage is often inadequate in complicated parapneumonic effusions owing to the presence of viscous fluid with fibrinous debris clogging the tube or multiple loculations in the pleural space. Patients who do not respond to IV antibiotics and tube thoracostomy may require multiple chest tube insertions, radiographically guided catheter(s) placement, or more commonly surgical decortication.

In 1949, Tillett and Sherry[4] first described the use of fibrinolytic agents to promote drainage of the pleural space. They used streptokinase and streptodornase instillation through the thoracostomy tube. Since then, several authors have reported improvement in pleural drainage with these agents.[5-8] However, associated systemic toxic reactions, including hypertension, bleeding, fever, and chills have limited its use.[4,5,9] Since then, purified streptokinase and lately urokinase have replaced the older agents for intrapleural fibrinolytic therapy.[10-17]

Experience of use of intrapleural fibrinolytics in children is limited and the safety and efficacy of these agents are not well described.[8,15,16]

In this report, we describe our experience with the use of urokinase in the management of complicated parapneumonic effusions in children.

Materials and Methods

All pediatric cases of complicated parapneumonic effusions treated with intrapleural urokinase between October 1994 and November 1995 were reviewed. The diagnosis of complicated parapneumonic effusions and empyema was confirmed by thoracocentesis and examination of the pleural fluid.[18] Patients whose conditions did not improve clinically with IV antibiotics and closed-tube thoracostomy drainage were considered for intrapleural fibrinolytic therapy. Lack of clinical response was reflected in persistent fevers, persistently elevated WBC counts, chest auscultation findings, and persistent findings of pleural effusion on chest radiograph. All patients had minimal to absent chest tube drainage ([is less than] 10 mL in 24 h) prior to intrapleural instillation. The presence of a complicated effusion, ie, loculation, was confirmed by chest radiograph and/or CT. Diluted urokinase was administered via the thoracostomy tube as described below.

Urokinase Administration

Coagulation parameters and platelet counts were obtained prior to and after initiation of urokinase therapy, 20 mL of sterile urokinase solution, concentration 1,000 IU/mL (Abbott Laboratories; Chicago) was freshly reconstituted in the pharmacy with sterile water and instilled via the thoracostomy tube. Patients were rotated in several positions to facilitate pleural distribution. The tube was then clamped for 2 h. At the end of 2 h, the tube was unclamped and suctioned resumed at - 15 cm [H.sub.2]O. The procedure was repeated three times a day for 3 days, for a total dose of 180,000 IU of urokinase. The dose and protocol were chosen based on previous experience.[16]

During this period, clinical course was evaluated by monitoring for fever, chest tube drainage, WBC counts, erythrocyte sedimentation rate (ESR), and daily- chest radiographs. Patients were also observed for signs of anaphylaxis, respiratory decompensation, chest pain, and bleeding.

Results

Fourteen children were treated for complicated parapneumonic effusions in the study period. Nine children received intrapleural urokinase therapy. Of the remaining, three underwent open thoracotomy and two responded to antibiotics and closed-tube drainage. Table 1 summarizes the clinical information on the nine patients treated with urokinase. Age range was 6 months to 6 years, with a mean of 3.3 [+ or -] 0.8 years (all results are expressed as mean [+ or -] SEM). Bacterial pathogen(s) were isolated in five of nine patients. Mean duration of illness prior to referral to our center was 8.2 [+ or -] 1.2 days. One patient (case 5) received two courses of urokinase.

[TABULAR DATA NOT REPRODUCIBLE IN ASCII]

Four patients had thoracoscopy for lysis of adhesions and placement of chest tubes. Two of these patients underwent early thoracoscopy within 48 h), in view of extensive loculations demonstrated in the chest cavity by CT, upon presentation. The other two underwent thoracoscopy after failure to respond to antibiotic therapy and closed-tube drainage. Urokinase administration was instituted in these four patients as an adjunct.

All patients had an increase in the chest tube drainage within 24 h following instillation of urokinase, with volume of drainage considerably greater than that instilled (Table 2). Most of the improved drainage was within 48 h. All patients had improved conditions clinically with defervescence of fever and decrease in WBC counts and ESR (Table 2). None of the patients required open thoracotomies. Mean duration before initiating urokinase therapy was 7.1 [+ or -] l.4 days. The chest tube was removed at a mean of 3.7 [+ or -] 0.5 days after urokinase instillation. Mean discharge day after urokinase was 5.0 [+ or -] 1.4 days; mean hospital stay was 15.5 [+ or -] 1.4 days (Fig 1).

[TABULAR DATA NOT REPRODUCIBLE IN ASCII]

Two patients reported transient chest pain during urokinase therapy, which was easily controlled with oral acetaminophen. None of the patients developed fever, bleeding, or any allergic reactions. The coagulation parameters remained within normal limits in all patients before and after urokinase therapy.

Discussion

Persistent or loculated parapneumonic effusions and empyemas remain a therapeutic problem in children. It has long been recognized that fibrin deposits and clots may impair drainage through the thoracostomy tube. Inadequate treatment at this "fibrinopurulent" stage can lead to organization and sear formation involving the pleural cavity and lung. This may require decortication and/or prolonged open drainage. Intrapleural fibrinolytic agents offer a promising alternative.

Streptokinase is a bacterially derived protein that complexes with plasminogen in the blood to become a plasminogen activator. This complex then activates plasminogen. When plasminogen is cleaved, a trypsin-like protein, plasmin, is generated. Plasmin hydrolyzes fibrin to a soluble state.[19,20] In contrast, urokinase, which is a protein similar to streptokinase and derived from human urine, is a direct plasminogen activator.

In 1949, Tillett and Sherry 4 first reported successful use of intrapleural streptococcal fibrinolysins (streptokinase) and streptococcal deoxyribonuclease on fibrinous, purulent, and sanguineous pleural effusions. Since then, there have been several reports of "enzymatic debridement" of pleural empyemas in the adult literature.

Bergh et al[6] reported use of intrapleural fibrinolytics in 38 patients, including 12 with empyema, none of whom needed subsequent decortication. In the series of Fraedrich et a][21] of 27 empyemas treated math intrapleural fibrinolytics, only 40% of the empyemas were cured without further surgical intervention. Temes et al[14] reviewed 26 adults referred for decortication who were offered intrapleural fibrinolytics prior to surgery, 62% of patients showed complete resolution. Recently, Jerges-Sanchez et a][15] reported a 92% success rate in treating loculated pleural effusions math intrapleural streptokinase in a multicenter, open, prospective study involving 48 adults with hemothorax and empyema.

Rosen et al[8] reported the successful and safe use of intrapleural streptokinase in five children. However, questions regarding the safety of streptokinase continue to be raised over the years. In early reports,[4-6] as many as 75% of patients treated with intrapleural fibrinolytics reported side effects, including fever, malaise, headaches, nausea, and arthralgias. Incidence of these reactions decreased after introduction of purified streptokinase. Apart from the systemic reactions described above, there are two major concerns: bleeding and development of systemic antibodies to streptokinase. Godley and Bell[9] reported a major bleed in a patient with empyema and bronchopleural fistula. The issue of whether intrapleural instillation leads to systemic production of antistreptokinase antibodies is yet to be determined, though it should remain an important consideration for a patient who might receive thrombolytic or fibrinolytic therapy in later life.

Urokinase was first introduced in 1987. Being a human-derived protein, the incidence of allergic reactions is very low and the development of systemic antibodies is also probably very low. The efficacy and safety of intrapleural urokinase use in adults have been well investigated. Moulton et al[10] treated 13 patients with intrapleural urokinase, 6 of whom had empyemas; 12 patients showed complete resolution. Pollack and Passik[13] reported three of nine patients showing partial and five of nine showing complete resolution of empyema with intrapleural urokinase. Lee et al[11] prospectively treated 10 loculated empyemas successfully with intrapleural urokinase via a percutaneously placed drainage catheter. No adverse effects were noted in any of these studies. To our knowledge, the issue of systemic antiurokinase antibodies has not been studied.

To date, there are only sporadic case reports on the use of intrapleural urokinase in children.[16,17] To our knowledge, this is the first series describing the use of intrapleural urokinase in the pediatric literature.

All subjects tolerated the procedure well without complications. There was a successful outcome, ie, improved chest tube drainage in eight of nine patients with 3 days of urokinase. The remaining patient responded to a second course of urokinase without complications. In four patients, intrapleural urokinase was used as an adjunct to thoracoscopic lysis of adhesions and thoracostomy tube placement. Again there was no bleeding at site of surgery during urokinase treatment. The issue of possible systemic antibodies to urokinase was not studied.

We are not aware of any dosage recommendations for intrapleural fibrinolytics in children. Pollak and Passik[13] used up to 250,000 U of urokinase in their nine adult patients. Rosen et al[8] had used 200,000 to 1,500,000 U (12,300 to 136,000 U/kg per dose) of streptokinase in the five children they studied with no complications. We used 180,000 IU of urokinase over 3 days in our patients (range, 3,896 to 9,836 Iu/kg/d with a mean dose of 6,332 [+ or -] 901 IU/kg/d).

None of our patients required open surgical procedures and the average length of hospitalization, 15.5 days, is considerably shorter than those in older reports of pediatric empyemas.[3,22] However, we cannot conclude that urokinase instillation would decrease the need for surgery or shorten hospital stay on the basis of our retrospective case series alone. Our data suggest that a controlled prospective trial would be important to clarify the effects of urokinase on these outcomes.

We conclude that intrapleural urokinase instillation as a fibrinolytic agent appears to be a safe adjunctive tool in the management of complicated parapneumonic effusions in children. Its use should be considered in potential decortication candidates in an effort to avoid surgery with its attendant morbidity. This therapy may be most beneficial when used in the early stage of loculation and fibrosis (fibrinopurulent stage). Additional study is needed to assess timing of administration, ideal dosing of intrapleural urokinase, and potential long-term side effects.

References

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