CASE REPORTS

Tissue Plasminogen Activator as AdjunctiveTherapy of Empyema in a Child

Amy Stevens, MDand Joseph D. Tobias, MD

Stevens A, Tobias JD. Tissue plasminogen activator as adjunctive Pleural effusions complicate 20–57% of bacterialtherapy of empyema in a child. J Intensive Care Med 2001;16: pneumonias [1,2]. The early exudative phase of a287–289.

parapneumonic effusion consists of a thin, easilyPleural effusions and empyemas may complicate 20–57% of drained, sterile fluid. This is followed by a fibrino-bacterial pneumonias. Clinical experience supports the use purulent stage with increased cellularity, a high pro-of fibrinolytic agents as a means of dissolving fibrin, releasing

tein content, and the deposition of fibrin on pleuralloculations and adhesions, thereby allowing for free drainagesurfaces with loculations. If the fibrinopurulentvia thoracostomy tubes. Currently available thrombolytic

agents include urokinase, tissue plasminogen activator (TPA), stage is left untreated, fibroblasts and capillaries canand streptokinase. Due to manufacturer-related issues, the invade the pleural membranes, forming an inelasticsupply of urokinase has become somewhat limited while pleural peel with subsequent scarring around thestreptokinase has the potential for allergic reactions in pediat-

lung that can result in reduced lung functional [3].ric patients. The authors report the use of TPA as an adjunctClosed tube drainage and intravenous antibioticsto other therapies for treatment of empyema in a 6-year-old

boy with pneumococcal pneumonia. comprise the initial therapy for patients with a pleu-ral fluid collection. However, many patients presentafter the initial phase of the parapneumonic effu-sion has passed and loculations with fibrinous de-bris are already present. These pose a barrier totherapeutic drainage by clogging chest tubes andblocking access to fluid collections. This may resultin the need for multiple chest tubes or, when closeddrainage is unsuccessful, surgical intervention ei-ther by thoracotomy or thoracoscopy. Failure torespond to conservative therapy with closed tubethoracostomy drainage necessitates thoracotomy in18–35% of patients [4]. Although surgical decortica-tion is the definitive therapy, it is associated witha longer postoperative recovery and the obviousrisks entailed by any surgical procedure.

As the parapneumonic effusion contains fibro-purulent material, a logical step for potential ther-apy was the use of fibrinolytic agents to disruptthe fibrin strands and release loculations, therebyallowing for more effective closed tube drainage.Intracavitary fibrinolytic agents (streptokinase, uro-kinase) have been reported to be a safe and effec-tive means of treating parapneumonic effusions andempyemas [4–10]. Because of concerns about aller-gic reactions with streptokinase in the pediatricpopulation and the recent unavailability of uroki-

From the Departments of Child Health and Anesthesiology, Divi- nase (see below), the only available agent for usesion of Pediatric Critical Care/Pediatric Anesthesiology, Univer- in children is tissue plasminogen activator (TPA).sity of Missouri, Columbia, MO.

The only previous report of the use of TPA as aReceived Mar 22, 2001, and in revised form Apr 24, 2001. Ac- adjunct to closed tube drainage of a parapneumoniccepted for publication May 1, 2001.

process was printed as an abstract from the 1999Address correspondence to Dr Tobias, University of Missouri,

meeting (8th Interventional Radiology and En-Department of Anesthesiology, 3W40H, One Hospital Drive,Columbia, MO 65212, or e-mail: Tobiasj@health.missouri.edu. dovascular Therapy Seminar) of the Midwest Insti-

Copyright q 2001 Blackwell Science, Inc. 287

288 Journal of Intensive Care Medicine Vol 16 No 6 November/December 2001

tute for Interventional Therapy (Peoria, IL). It is sistent opacification of the left hemithorax. TPA wasmixed, 5 mg in 50 ml, and two doses were instilledavailable at http://www.miit.com/percutaneous_

drainage.htm, but has not been published in the into the pigtail catheter at an 8-hour interval. Eachwas left in the pleural space with the chest tubepeer-reviewed medical literature [11]. We report the

use of TPA as an adjunct to closed tube drainage clamped for 1 hour. Over the 24 hours followingthe instillation of TPA into the pigtail catheter, theof a parapneumonic effusion in a 6-year-old boy.output from the thorax was 960 ml.

The following morning, repeat chest X-rayshowed clearing of the opacification of the left hem-Case Reportithorax (Fig 2). The patient remained afebrile anddenied pain on the left side. The pigtail catheterA 6-year-old, 19.9 kg boy was referred to our institu-was removed and he was discharged to the inpa-tion for treatment of a large left-sided pleural effu-tient ward. The following day he was dischargedsion. Past history was positive for pneumococcalhome. Follow-up chest X-ray at 4 weeks after dis-pneumonia diagnosed 10 days prior to admissioncharge from the hospital showed no residual opaci-with a blood culture positive for a penicillin-sensi-fication of the left hemithorax.tive Streptococcus pneumoniae. Treatment had in-

cluded a combination of intravenous ceftriaxoneand oral amoxicillin. Although there was an initialresolution of his fever, 48 hours prior to admission Discussionhe developed a fever and left-sided chest pain.Chest X-ray revealed opacification of the left hemi- Streptokinase and urokinase have both been usedthorax. The patient was admitted to the pediatric in the management of parapneumonic effusionsintensive care unit (ICU), blood cultures were ob- with a similar reported efficacy of 38–100% andtained, and antibiotic therapy initiated with ceftriax- 63–100%, respectively [4–10]. Because of the possi-one. Following sedation and the application of local bility of allergic reactions related to the presenceanesthesia with 1% lidocaine, an 8.5 French pigtail of antistreptococcal antibodies, which are morecatheter was placed into the left hemithorax using prevalent in pediatric patients, there is limited usethe Seldinger technique. Immediately following of streptokinase in children. Although there are noplacement, 330 ml of turbid fluid was removed. reports of adverse effects such as fever, bleeding,

Gram stain revealed numerous white blood cells, or allergic reactions with urokinase [9,10], potentialbut no organisms. The culture was subsequently safety issues have been raised [12]. The U.S. Foodnegative at 72 hours. The cell count (18,000 WBC/ and Drug Administration (FDA) identified potentialmm3), protein (1.8 g/dl), and glucose (20 mg/dl) deviations from the current good manufacturingwere compatible with an exudate. Over the next practice regulations regarding urokinase. Uroki-24 hours, 240 ml of additional fluid drained. The nase is derived from the culture of renal cells har-patient continued to spike temperatures to vested postmortem from human fetuses.38.57–397C. Repeat chest X-ray (Fig 1) revealed per- Concerns were raised concerning potential defi-

Fig 2. Chest X-ray obtained after instillation of two dosesFig 1. Chest X-ray obtained 24 hours after placement ofthe pigtail catheter. There is still marked opacification of of tissue plasminogen activator through the pigtail cathe-

ter.the left hemithorax.

Stevens and Tobias: Tissue Plasminogen Activator 289

ciencies in the mechanisms used to prevent the TPA. Larger clinical trials are needed to further eval-uate the role of TPA in this disease process.transmission of infectious agents. Although there

have been no documented cases of infectious dis-ease transmission, the process involved in changing Referencespolicies and procedures by the company resultedin the unavailability of urokinase for many months. 1. Taryl D, Potts D, Sahn S. The incidence and clinical correlatesBecause of such issues, urokinase is still not avail- of parapneumonic effusions in pneumococcal pneumonia.

Chest 1978;74:170–173able on our hospital pharmacy formulary.2. Light RW, Girard WM, Jenkinson SG, et al. ParapneumonicTPA has been used in children for the treatment

effusions. Am J Med 1980;69:507–512of various thromboembolic states [13], but we found 3. Moulton J. Image-guided management of complicated pleu-only one report concerning TPA treatment of locu- ral fluid collections. Radiol Clin N Am 2000;38):345–374lated or complex pleural effusions [11]. Castaneda 4. Doski J, Lou D, Hicks B, et al. Management of parapneu-

monic collections in infants and children. J Pediatr Surg[11] reported his experience with thrombolytic2000;35:265–270agents in 30 patients ranging in age from 2 to 84

5. Muers M. Streptokinase for empyema. Lancet 1997;349:years (mean age 41.5 years) with empyema. Three 1491–1492of the patients were treated with TPA. Therapy with 6. Bouros D, Schiza S, Tzanakis N, et al. Intrapleural urokinaseTPA involved instilling 5 mg of TPA in 20–30 ml of versus normal saline in the treatment of complicated parap-

neumonic effusions and empyema. A randomized doublesaline into the chest tube and leaving it in the pleu-blind study. Am J Respir Care Crit Care Med 1999;159:37–42ral space for 2 hours. Thrombolytic therapy was

7. Bouros D, Schiza S, Siafakas N. Utility of fibrinolytic agentssuccessful in 29 of 30 patients, including complete for draining intrapleural infections. Semin Respir Infect 1999;drainage of the pleural fluid or reduction of the 14:39–47pleural fluid with resolution of clinical signs. Pleural 8. Barletta J. Streptokinase and urokinase for the treatment of

pleural effusions and empyemas. Ann Pharmacother 1999;drains were in place for a mean of 4.9 days prior33:495–498to and 2.7 days after thrombolytic therapy. Mean

9. Kornecki A, Sivan Y. Treatment of loculated pleural effusionfluid drainage was 616 ml prior to the thrombolytic with intrapleural urokinase in children. J Pediatr Surg 1997;agent and 993 ml after the thrombolytic agent. 32:1473–1475

10. Krishnan S, Amin N, Dozor AJ, et al. Urokinase in the man-Previous studies have demonstrated the potentialagement of complicated parapneumonic effusions in chil-role for thrombolytic therapy as adjunctive treat-dren. Chest 1997;112:1579–1583ment of parapneumonic effusions and empyemas.

11. Castaneda F. Percutaneous drainage and fibrinolytic therapyDue to the current limited availability of urokinase, for the treatment of loculated or complex pleural effusionsalternative thrombolytic agents are needed. Consid- [abstract]. Paper presented at the 8th Interventional Radiol-

ogy and Endovascular Therapy Seminar. <http://www.miit.-ering the potential for allergic reactions with strep-com/percutaneous_drainage.htm>tokinase, it is our opinion that TPA is the most

12. Nightingale SL. From the Food and Drug Administration.appropriate alternative. Our anecdotal experienceJAMA 1999;281:786

in this initial patient and the data from the three 13. Johnson TR, Tobias JD. Initial experience with tissue plas-patients in the report of Castaneda [11] provide minogen activator in two pediatric oncology patients. J In-

tensive Care Med 2000;15:53–58preliminary evidence suggesting the efficacy of