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Pediatric Imaging |
1 From the Department of Radiology, MS 721, Children’s Hospital of Wisconsin, 9000 W Wisconsin Ave, Milwaukee, WI 53226 (R.G.W.); and Department of Pediatrics, MFRC, Medical College of Wisconsin, Milwaukee (P.L.H.). Received April 26, 2002; revision requested July 8; revision received October 4; accepted December 19. Address correspondence to R.G.W. (e-mail: rwells@chw.org).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: A retrospective review was performed of 71 children with parapneumonic pleural fluid accumulations who were treated with thoracostomy tube placement and intrapleural instillation of either urokinase or alteplase. The procedures were performed with urokinase between September 2, 1995, and March 27, 1998, and with alteplase between March 30, 1998, and January 2, 2002. The medical records and daily chest radiographs were reviewed by a pediatric radiologist to ascertain demographic information, signs and symptoms, laboratory results, thoracostomy tube output, treatment details, and radiographic pleural thickness and lung opacification. Multiple variables were compared for the alteplase and urokinase groups by using univariate and multivariate statistics. We defined primary treatment success as resolution of signs and symptoms at the time of discharge, without surgical intervention.
RESULTS: Primary treatment success was 98% for alteplase and 100% for urokinase, with no major complications. Greater pleural fluid drainage occurred with alteplase than urokinase during the 1st (P = .001) and 2nd (P = .002) days of fibrinolytic therapy, and for the duration of thoracostomy drainage (P < .001). Multivariate models showed greater total drainage with alteplase (P < .001), greater patient age (P < .001), larger tube size (P = .002), and greater volume of drainage during the 24 hours prior to fibrinolysis (P < .001).
CONCLUSION: Intrapleural fibrinolysis with urokinase or alteplase facilitates thoracostomy tube drainage of parapneumonic pleural fluid. With the dosing regimen used in this study, alteplase produces greater thoracostomy tube output than does urokinase.
© RSNA, 2003
Index terms: Children, respiratory system, 66.219, 66.76 • Empyema, 66.76 • Infants, respiratory system, 66.219, 66.76 • Pleura, fluid, 66.219, 66.76 • Pleura, interventional procedures • Urokinase • Thrombolysis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Tillett and Sherry (1) reported the use of a mixture of streptokinase and streptodornase for intrapleural fibrinolysis in 1949. Use of streptokinase for this purpose was limited until the availability of purified streptokinase in the 1960s resulted in an improved safety profile (2). Urokinase was introduced in 1987 and became the most frequently used agent for fibrinolysis because of concerns about the antigenicity of streptokinase. Several studies have confirmed the efficacy of urokinase for intrapleural fibrinolysis (3–6), including a few small case series that have evaluated its use in children (7–10). The recent interruption in the availability of urokinase has led to interest in the newer agent, alteplase, as an option for use in fibrinolytic therapy.
The purpose of our study was to assess the safety and efficacy of urokinase and alteplase for intrapleural fibrinolysis in children with parapneumonic pleural fluid collections.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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We used the radiographic appearance (large effusion) and the clinical course (persistent fever, enlarging effusion, or progressive hypoxemia) to determine the need for thoracostomy tube placement rather than rely on the results of pleural fluid analysis from thoracentesis. The criterion for initiating fibrinolysis was decreasing thoracostomy tube output during an 8–24-hour period, despite residual radiographic pleural thickness greater than 5 mm. We excluded patients deemed to have effusions too small to require drainage and those in whom tube thoracostomy alone was sufficient for treatment.
Review of the medical records was performed by one of the authors (R.G.W.). Our institutional review board approved the review of medical records and diagnostic imaging studies, and neither patient nor parental consent was required. We recorded the following data: age, sex, dates of hospitalization, results of pleural fluid analyses, maximum body temperature within 24 hours prior to the first fibrinolysis treatment, supplemental oxygen administration immediately prior to fibrinolysis, white blood cell count within 48 hours of initiation of fibrinolysis, time the patient was febrile prior to fibrinolysis, start and stop dates of intravenous antibiotic therapy, antibiotics used, preexisting medical conditions (eg, swallowing dysfunction or recent thoracic surgery), and performance of additional surgical interventions (eg, pleural débridement).
Technique
Informed consent for percutaneous tube thoracostomy and intrapleural fibrinolysis was obtained from the parents or legal guardian. Six pediatric radiologists (including R.G.W.) used sedation with a combination of 1–2 µg/kg intravenous fentanyl citrate (Baxter Healthcare, Deerfield, Ill) or 0.05–0.1 mg/kg (maximum, 10 mg) morphine sulfate (Abbott Laboratories, North Chicago, Ill) and 0.05–0.1 mg/kg (maximum, 10 mg) midazolam hydrochloride (Versed; Abbott Laboratories) or 3–5 mg/kg (maximum, 100 mg) pentobarbital sodium (Nembutal; Abbott Laboratories) while they performed the thoracostomy tube placements. A pediatric radiology nurse, under the direction of the radiologist performing the procedure, administered the sedation and continuously monitored the patient. Introduction of the tube was guided with fluoroscopy and ultrasonography (US). Medi-tech APD and vanSonnenberg tubes (Boston Scientific, Watertown, Mass) were used. Selection of tube size was at the discretion of the pediatric radiologist performing the procedure. The tube was connected to a water seal device and placed to 20 cm H2O suction. Tube output was recorded by the inpatient nursing service. Daily anteroposterior chest radiographs were obtained with the patient in an upright or semiupright position, as tolerated.
We instituted intrapleural fibrinolysis when thoracostomy tube output diminished, despite radiographic evidence of substantial residual pleural opacification. The fibrinolytic agent was diluted in 25–100 mL of normal saline, with the volume arbitrarily selected on the basis of patient age and size and an estimate of the volume of the pleural space to be treated. Urokinase (Abbokinase; Abbott Laboratories) was diluted in normal saline to produce a concentration of 1,000 IU/mL; therefore, treatment doses of this agent ranged from 25,000 IU to 100,000 IU (5). Alteplase (Activase; Genentech, South San Francisco, Calif) was delivered at 0.1 mg/kg, with a maximum dose of 6 mg. The selected alteplase dose corresponded to the standard used at our hospital for intravenous administration and is in the lower range of reported doses for the intravenous use of alteplase in pediatric patients (11). Urokinase was used for procedures performed between September 2, 1995, and March 27, 1998, when our hospital pharmacy interrupted the availability of urokinase. Alteplase was used for procedures performed between March 30, 1998, and January 2, 2002.
After instillation of the fibrinolytic agent, the thoracostomy tube was clamped for 1 hour, after which, standard water seal suction at 20 cm H2O was resumed. The patients were not instructed to assume special positions. Fibrinolytic treatments were continued once a day until the thoracostomy tube output decreased to less than 40 mL/d. At this point, the thoracostomy tube was removed if chest radiographs showed improvement. If pleural thickness was not improved despite output of less than 40 mL/d, imaging-guided tube manipulations and up to two more fibrinolytic treatments were carried out prior to thoracostomy tube removal. The tube manipulations consisted of redirection or replacement of the tube into pleural fluid remote to the side holes of the original tube. The loculated pleural fluid collections were detected with computed tomography or US.
Assessment of Response
We measured the therapeutic response to fibrinolysis with three variables, including pleural thickness and chest opacification on chest radiographs and thoracostomy tube output. We reviewed all available chest radiographs, including those obtained before or after fibrinolytic therapy. We measured pleural thickness at the point of maximum pleural opacity, as viewed on the initial frontal radiograph, and used that same site for measurement on the subsequent radiographs. The site for measurement was individualized for each patient. We corrected for differences in magnification by multiplying the measured pleural thickness by a correction factor equal to the transverse diameter of the chest on the first radiograph and divided this number by the transverse diameter of the chest on the current radiograph. We determined chest opacification with an estimate of the percent of ipsilateral aerated lung replacement by any combination of pleural fluid, pleural thickening, consolidated lung, and atelectatic lung.
The review of radiographs was performed retrospectively by one of the authors (R.G.W.) while blinded to the patient name, dates of fibrinolysis, and medication used for fibrinolysis. The thoracostomy tube output data were retrieved from the medical records (R.G.W.). Additional data collected include dose and volume of fibrinolytic agent instilled, number of thoracostomy tube manipulations, tube dwell time, duration of hospitalization, time after initiation of fibrinolysis until consistently afebrile (temperature < 38°C), time after initiation of fibrinolysis until oxygen supplementation was discontinued (for those patients who required supplemental oxygen), side effects and complications, and clinical findings at discharge. We defined primary treatment success as resolution of signs and symptoms of pneumonia and pleural effusion (afebrile, normal or baseline oxygenation, normal or baseline respiratory rate) at discharge, without surgical intervention. We considered major complications to include hemorrhage remote to the pleura and any side effect that required surgical or medical intervention (other than administration of analgesics).
Analysis
We reported the demographic, clinical, and outcome data for all patients and for patients grouped by treatment type (alteplase or urokinase). We arbitrarily created two categories for thoracostomy tube size. The tube was considered "small" if it was less than or equal to 8 F in children younger than 2 years of age or less than or equal to 10 F in patients older than 2 years of age. Otherwise, the tube was considered to be "standard". We evaluated the therapeutic response variables (change in pleural thickness, change in chest opacification, and thoracostomy tube output) by treatment type (alteplase vs urokinase) and thoracostomy tube size and measured the differences between the groups by using the Wilcoxon two-sample test. Pearson correlation was used to identify associations between continuous variables. Multivariate analyses were performed with software packages (PROC GLM; SAS Institute, Cary, NC). We created a model that used total tube output as the dependent variable, and variables that were statistically associated in the univariate analyses were modeled as independent variables. The least-squares method was used to estimate the mean thoracostomy tube output in the two treatment groups while controlling for the effects of the other associated independent variables. All analyses were performed by one of the authors (P.L.H.) with software (PC-SAS version 8.0; SAS Institute). We considered a P value less than .05 to indicate a significant difference.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Radiographs showed a decrease in pleural thickness during the course of fibrinolytic therapy in 70 (99%) of the 71 patients and a decrease in lung opacification in 65 (92%) (Figure). Univariate analysis showed significantly greater therapeutic response in patients treated with alteplase when compared with patients treated with urokinase for decrease in pleural thickness (P = .004), decrease in pleural thickness after the first treatment (P = .04), decrease in lung opacification (P = .04), thoracostomy tube output after the first treatment (P = .007), thoracostomy tube output after the second treatment (P < .001), and total thoracostomy tube output (P < .001) (Table 3). The end point of pleural thickness after the last day of fibrinolysis was similar for the two groups; the mean was 0.8 cm ± 0.4 for the patients treated with alteplase and 0.7 cm ± 0.4 for the patients treated with urokinase. Follow-up chest radiographs obtained more than 1 month after discharge showed complete or almost complete resolution of parenchymal consolidation and pleural opacification in all 27 patients for whom the studies were available.
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Multivariate analysis incorporating all variables that showed statistically significant associations with total thoracostomy tube output in the univariate analysis demonstrated that only treatment group, age, tube size, and tube output during the 24 hours prior to fibrinolysis were associated with total tube output (Table 4). Analysis of the univariate correlations suggested that collinearity was not a significant factor in this model. While controlling for the effects of other variables by using the least-squares method, the mean total thoracostomy tube output was 956 mL for patients treated with alteplase versus 746 mL for patients treated with urokinase and 984 mL for patients treated with standard thoracostomy tubes versus 718 mL for patients treated with small thoracostomy tubes. Unidentified confounding variables may be responsible for some of these observed associations; therefore, these data should be interpreted cautiously.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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During the time that patients were treated with urokinase, this agent was approved by the U.S. Food and Drug Administration (FDA) for the treatment of pulmonary embolism and coronary artery thrombosis in adults and for catheter clearance in patients of all ages. The FDA halted distribution of urokinase in 1999 because of concerns about the safety of the manufacturing process. The FDA approved alteplase in 1987 for the treatment of acute myocardial infarction, pulmonary embolism, and acute ischemic stroke in adults, and in 2001 for catheter clearance in patients of all ages (13). Neither agent has FDA approval for intrapleural fibrinolysis.
Our study is a retrospective case series and suffers from a lack of randomization of patients treated with alteplase and those treated with urokinase. Comparison of various objective measures of illness type and severity at the time of fibrinolysis, such as pleural fluid analysis, maximum body temperature, oxygen requirement, blood leukocyte count, and predisposing medical conditions, however, failed to demonstrate a significant difference between the groups (Table 1). The single exception was that patients who received alteplase began fibrinolytic therapy with radiographic evidence of greater pleural opacity than patients who received urokinase (mean pleural thickness, 2.2 vs 1.6 cm; P = .004). Patients treated with alteplase were slightly older than patients treated with urokinase (6.5 vs 4.6 years), but this difference was not statistically significant. The thoracostomy tube size and the volume used for instillation of the fibrinolytic agent were arbitrary; however, we identified no significant differences in prefibrinolysis thoracostomy tube dwell time or number of fibrinolysis treatments. The length and type of antibiotic therapy were similar for both groups. When the effect of identified confounding factors was controlled for in multivariate models, the total thoracostomy tube output was greater in patients treated with alteplase than in those treated with urokinase (Table 4); however, that benefit did not result in detectable differences in the clinical response (Table 3).
In addition to greater total thoracostomy tube output, we found a significantly greater response to pleural fibrinolysis in patients treated with alteplase with respect to fluid drained 24 hours after the first and second fibrinolysis treatments, a decrease in pleural thickness after fibrinolysis, and a decrease in radiographic chest opacification. Radiographs indicated that patients treated with alteplase began therapy with greater pleural opacification than patients treated with urokinase; therefore, drainage of more fluid with alteplase may be, at least in part, related to a greater pretherapy pleural abnormality. This variable, however, was not associated with total fluid output in the multivariate analysis. No significant differences between patients treated with alteplase and patients treated with urokinase were identified for the clinically important end-point variables of chest opacification after fibrinolysis and pleural thickness 1 month after therapy. We found that total volume of thoracostomy tube output and volume of fluid drained after the first fibrinolytic treatment were functions of thoracostomy tube size, although this correlation was not present on the 2nd day of treatment. Tube size did not appreciably affect other relevant end points, such as overall change in pleural thickness, change in pleural thickness after the first treatment, and overall change in chest opacification.
The lack of randomization between the two groups mandates that the results of our study be interpreted with caution. In addition to intrinsic differences in the two medications used, other factors that could account for the observed differences in therapeutic response between the two groups include variation in the virulence and antibiotic susceptibility of the infecting organisms, variation in the stage of the illness when treatment was started, experience of the radiologists performing the tube placements and fibrinolysis, variations in patient care, and lack of dose equivalency for the concentrations of alteplase and urokinase.
Our patients were treated with 0.1 mg/kg of alteplase. The urokinase dose varied according to the instilled volumes and averaged 3,100 IU/kg; therefore, 1 mg of alteplase was approximately equivalent to 31,000 IU urokinase in our dosing regimen. The specific activity of alteplase is 580,000 IU/mg (1 mg of alteplase = 580,000 IU of urokinase) (manufacturer’s recommendation, Genentech, South San Francisco, Calif); therefore, in terms of specific activity, the patients treated with urokinase received disproportionately lower doses of medication. The specific activity, however, is determined with an in vitro clot lysis assay and is of questionable usefulness in determining the in vivo thrombolytic activity (13). The FDA-approved preparations for catheter clearance are 2 mg of alteplase (manufacturer’s recommendation, Genentech) and 5,000 IU of urokinase (manufacturer’s recommendation, Abbott Laboratories) (1 mg of alteplase = 2,500 IU of urokinase). The approved treatment of pulmonary embolism with alteplase in a 70-kg adult is 100 mg administered intravenously in a graded fashion over 2 hours (manufacturer’s recommendation, Genentech), while the recommended dose for urokinase during the first 2 hours of therapy is 256,667 IU (manufacturer’s recommendation, Abbott Laboratories) (1 mg of alteplase = 2,567 IU of urokinase). By these standards, our patients received disproportionately high doses of urokinase. Clinical studies comparing alteplase and urokinase for treatment of myocardial infarction, stroke, deep venous thrombosis, and dialysis fistula thrombosis have used wide ranges of doses of both medications.
Larger thoracostomy tubes, fewer tube manipulations, and smaller medication irrigation volumes were used in the patients treated with alteplase than in the patients treated with urokinase. Other measured treatment variables failed to show significant differences between the treatment groups with univariate analysis. The procedural experience of the radiologists and the assisting personnel was unavoidably different between the two patient groups in this retrospective study. This may, in part, account for the selection of slightly larger thoracostomy tubes and the performance of fewer tube manipulations in patients treated with alteplase; however, the same basic technique was used for thoracostomy tube placement, and the criteria for fibrinolysis were the same throughout the study period.
Our study design did not allow direct demonstration that fibrinolytic therapy is superior to other treatment approaches or that the patients would not have recovered without thoracostomy tube placement or fibrinolysis; however, comparison of our findings to published data provides some indication of the efficacy of this technique. In our patients, the primary treatment success was 99%, the mean thoracostomy tube dwell time was 5.7 days ± 3.3, and the mean hospitalization time was 11.2 days ± 5.5. The treatment of patients who have pediatric empyema by using thoracostomy tube drainage alone is reported to have a primary treatment success rate (resolution without thoracotomy) of 32%–89% (14–18). Reported average lengths of hospitalization range from 20 to 23 days (14,15, 17,18). Average thoracostomy tube dwell times between 7 and 16 days have been reported (16,18). In a review of 47 children with empyema, Chan et al (14) found that 82% of fibropurulent empyemas resolved with antibiotics and tube thoracostomy alone (average hospitalization, 23 days), but conservative treatment failed and surgical decortication was performed in the remaining 18% of patients (average hospitalization, 40 days).
Treatment of fibropurulent empyema in children with thoracoscopy is reported to be associated with average hospitalizations of 7–25 days, average thoracostomy tube dwell times of 3–21 days, and treatment success rates of 89%–100% (15,19–22). Doski et al (21) reported a 100% primary treatment success rate, a median thoracostomy tube dwell time of 3 days, and a median hospitalization of 7 days for 41 children in whom video-assisted thoracoscopy was used as the initial method for treatment of parapneumonic effusion. The median thoracostomy tube dwell time for our patients was 5 days and the median hospitalization was 10 days.
Our results compare favorably with those of other investigators who have evaluated intrapleural fibrinolysis in pediatric patients by using streptokinase and urokinase. Rosen et al (23) found a 100% treatment success and an average hospitalization of 19 days in five children treated with streptokinase. Reports of the use of urokinase for pleural fibrinolysis in children indicate treatment success of 86%–100%, mean hospitalizations of 14–16 days, and average thoracostomy tube dwell times of 6–17 days (7–10,24). The largest pediatric urokinase series of which we are aware is by Krishnan et al (10), in which nine children with parapneumonic effusions were treated with 20,000 IU of urokinase three times a day for 3 days. The treatment success rate was 100% (four of the children were treated with thoracoscopy prior to fibrinolysis), and the mean hospital stay was 15.5 days ± 1.4.
Observed and potential risks of intrapleural fibrinolysis include systemic toxicity, promotion of a bronchopleural fistula, hemorrhage, and allergy. Fever, malaise, headache, nausea, arthralgias, and leukocytosis occurred in up to 75% of patients who received the early versions of streptokinase (25,26). In a report by Rosen et al (23) of pediatric patients treated with purified streptokinase, transient fever and chest wall discomfort occurred in an unspecified number of patients, but no serious complications were identified. Evaluation of data from four case series of pleural fibrinolysis with urokinase in children identified two complications or side effects (transient chest pain) in 24 patients, although differing standards of reporting were likely used in these studies (7–10). A study of 102 adult patients treated with intrapleural urokinase found complications in 13 (12.7%), including nine with hydropneumothorax, three with infection at the thoracostomy tube site, and one with an unspecified "adverse reaction" (4). No serious complications occurred in our patients; however, minor complications or side effects occurred in 18% of the patients treated with urokinase and in 15% of the patients treated with alteplase.
We conclude that urokinase and alteplase improve thoracostomy tube drainage of parapneumonic pleural fluid and that intrapleural fibrinolysis with urokinase or alteplase is a safe and effective method for treating children with parapneumonic effusion or empyema. Our data suggest that at the doses used, alteplase produces greater thoracostomy tube output than does urokinase.
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, R.G.W.; study concepts and design, R.G.W., P.L.H.; literature research, R.G.W.; clinical studies, R.G.W., P.L.H.; data acquisition, R.G.W.,; data analysis/interpretation, R.G.W., P.L.H.; statistical analysis, R.G.W., P.L.H.; manuscript preparation, definition of intellectual content, editing, revision/review, and final version approval, R.G.W., P.L.H.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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