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Adjunctive Intrapleural Tissue Plasminogen Activator Administered via Chest Tubes Placed with Imaging Guidance: Effectiveness and Risk for Hemorrhage¹

¹ From the Department of Radiology, Division of Abdominal Imaging and Intervention, Massachusetts General Hospital, 55 Fruit St, White 270, Boston, MA 02114. Received February 2, 2007; revision requested April 11; revision received May 18; accepted June 13; final version accepted August 1. Address correspondence to D.A.G. (e-mail: dgervais{at}partners.org).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE... References

 
Purpose: To retrospectively determine the effectiveness of and risk for hemorrhage with intrapleural adjunctive tissue plasminogen activator (tPA) administered via chest tubes placed with imaging guidance.

Materials and Methods: This HIPAA-compliant study was approved by the institutional review board of Massachusetts General Hospital, with informed consent waived. A retrospective review of 66 patients (age range, 1–95 years; mean age, 55 years; 44 male, 22 female) who received intrapleural tPA between 2000 and 2006 was performed. Overall effectiveness of tPA was defined as successful drainage without need for additional decortication or video-assisted thoracoscopic surgery. Primary and secondary effectiveness were defined as effectiveness after one and two cycles of tPA, respectively. Imaging findings and complications were recorded. Hemorrhagic complications were noted, and the Fisher exact test was used to show whether concurrent systemic anticoagulation increased bleeding risk.

Results: Fifty-seven (86%) of 66 patients underwent complete drainage with tPA without further surgical procedures. Primary effectiveness was seen in 52 (87%) of 60 patients and secondary effectiveness was seen in five (83%) of six. Loculation of fluid was the most common finding in this selected cohort. Number of fluid pockets, pleural heterogeneity, and pleural thickness were not predictors of effectiveness. There were five major pleural hemorrhages in four patients across five tPA cycles. Hemorrhages occurred only in patients receiving therapeutic anticoagulation (four of 12) and in none of the other patients (P < .001). No hemorrhages occurred in the 38 patients receiving prophylactic anticoagulation.

Conclusion: Intrapleural tPA is effective in improving drainage of loculated effusions not drained with catheters alone; prophylactic systemic anticoagulation does not increase bleeding risk with intrapleural tPA, but therapeutic anticoagulation is associated with a significantly increased risk of pleural hemorrhage.

© RSNA, 2008

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE... References

 
Adjunctive intrapleural fibrinolytic therapy improves drainage of complex pleural collections not responsive to simple catheter drainage (1). Early reports about streptokinase motivated intrapleural fibrinolytic use, including streptokinase and urokinase, in chest tubes placed by interventional radiologists and surgeons in the 1980s and 1990s (1–11). Although streptokinase has been widely available and less expensive than other fibrinolytics, urokinase became more popular in the United States because of potential streptokinase antigenicity. Since the U.S. Food and Drug Administration removed urokinase from the U.S. market in 1999, interventional radiologists have turned to alternative fibrinolytics for intrapleural use. One such alternative is the tissue plasminogen activator (tPA) alteplase.

Little has been reported about the results of intrapleural tPA use for collections that are not amenable to simple catheter drainage with small catheters (8–16 F) placed by interventional radiologists (12–14). The largest adult series, reported by Skeete et al (12), consisted of primarily large-bore surgically placed chest tubes.

The purpose of our study was to retrospectively determine the effectiveness of and risk for hemorrhage with intrapleural adjunctive tPA administered via chest tubes placed with imaging guidance.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE... References

 
Study Design and Data Collection
This study was compliant with the Health Insurance Portability and Accountability Act and was approved by the institutional review board of Massachusetts General Hospital (Boston, Mass) with informed consent waived. Our database of interventional procedures was searched (P.F.H.) for all patients who received tPA through chest tubes placed with imaging guidance. From January 2000 to February 2006, 2241 chest catheters were placed with imaging guidance in 2089 patients in a tertiary care center including adult (18 years) and pediatric (<18 years) patients. The tPA was instilled in 66 patients (63 adults, three nonadults; age range, 1–95 years; mean age, 55 years; 44 male, 22 female).

Medical records (D.A.L., D.A.G.) and images (D.A.G., P.R.M.) in these 66 patients were reviewed by investigators with 1 (D.A.L.), 15 (D.A.G.), and 30 (P.R.M.) years of experience using intrapleural fibrinolytics. Imaging characteristics of the effusion, number of tPA cycles, treatment results, additional treatment required for failed catheter drainage, complications and their outcomes, and presence of concurrent anticoagulation or antiplatelet agents were recorded.

Catheter Placement
All chest catheters were placed by a resident or fellow supervised by a staff interventional radiologist, including investigators with 4 (R.N.U.), 5 (R.S.A.), 15 (D.A.G.), 22 (P.F.H.), and 30 (P.R.M.) years of experience. Because of the rotating nature of interventional radiology coverage, tubes were placed by 10 other staff members with experience ranging from 5 to 25 years. Catheter type and size, imaging guidance modality, placement technique, and approach were determined by the attending radiologist on the basis of the nature of the fluid and size of intercostal access. All catheters were inserted by using a trocar technique with ultrasonographic (US) or computed tomographic (CT) guidance (65 patients) or by using a Seldinger technique with fluoroscopic guidance (one patient). Catheter size ranged from 8.5 to 16 F, with the most common catheter being a 16-F pigtail catheter (Cook, Bloomington, Ind) chosen for stiffness and kink resistance. For small collections or for unusually small intercostal windows, the smaller catheters were chosen. For both CT and US guidance, real-time visualization was not used. Instead, imaging was used to determine an appropriate puncture site to achieve optimal drainage and to avoid major organs. Imaging was also used to measure the depth of catheter insertion. For patients receiving anticoagulants, anticoagulation was stopped before catheter placement by discontinuing intravenous heparin when the patient was called to the radiology department and resuming the infusion 2–4 hours later. Patients receiving warfarin received heparin instead for catheter placement. Warfarin was resumed after catheter placement. Antiplatelet agents were withheld 1–5 days before the procedure.

After catheter insertion, a three-way stopcock was placed on the catheter and connected to drainage. By using the stopcock, manual aspiration of the contents was performed until return ceased, and the catheter was placed on suction. Immediate postdrainage CT or US was then performed. Catheters underwent continuous suction (20 cm water).

In these 66 patients, 64 had placement of a single catheter, one had two catheters, and one had three catheters. One patient had an initial catheter replaced with a larger catheter to improve drainage. Pleural effusions were characterized as empyema (n = 27), parapneumonic effusion (n = 26), hemothorax (n = 8), postoperative effusion (n = 4), and malignant effusion (n = 1). Empyemas were distinguished from other complicated parapneumonic effusions by presence of pus or positive culture or Gram stain results.

Imaging and Image Findings
All but one patient, in whom fluoroscopic guidance was used, underwent chest CT before or at the time of chest tube placement; the one patient without preprocedural CT underwent CT after chest tube placement. All patients underwent postdrainage CT either at the time of drainage or as a separate diagnostic procedure 1–14 days after drainage (Lightspeed, GE Healthcare, Piscataway, NJ; four to 16 sections; transverse section thickness, 2.5–5 mm; 120–140 kV; 220–300 mA). Image findings were recorded before and after catheter placement. Findings assessed were fluid loculation and formation of fluid pockets. A loculated effusion was defined at CT as one that did not freely layer dependently with normal concave meniscus formation and that could have a single fluid pocket or multiple fluid pockets not freely layering. A pocket of fluid at CT was defined as an area that was separated from others by either (a) a space with no intervening pleural fluid or (b) a waist of continuous fluid that was no more than one-third the maximum thickness of the fluid. The number of pockets was recorded for each patient. Images were interpreted by means of consensus of two radiologists (D.A.G., P.R.M.) with 15 and 30 years of experience in placing and managing chest tubes.

Because other investigators have suggested that pleural thickness may help predict effectiveness of intrapleural fibrinolytics, pleural thickness was measured with electronic cursors on a picture archiving and communication system monitor from CT before drainage. The pleura was noted as either homogeneous or heterogeneous, depending on whether its thickness was uniform or not (2).

tPA Administration
The tPA was instilled on the basis of (a) extremely viscous contents yielding little to no drainage at immediate postdrainage imaging or (b) a large residual collection at follow-up imaging. In 51 patients, tPA administration was initiated on the basis of incomplete drainage documented at interval CT (n = 39) or chest radiography (n = 12) performed between chest tube placement and tPA initiation. In the remaining 15 patients, tPA was started immediately after chest tube insertion in 11 patients and within 24–48 hours in four patients without interval imaging. Time to initiation of tPA after chest tube placement ranged from 0 to 19 days (median, 3.8 days).

The dose of tPA was 4–6 mg diluted in an appropriate volume of 0.9% saline administered twice a day via the chest tube with a 30-minute dwell time, during which the tube was clamped with a three-way stopcock and following which suction was resumed. Volume was generally 50 mL of 0.9% saline but was reduced for small collections on the basis of initial cavity volume. For smaller collections, volume ranged from 10 to 30 mL and was generally set at 30%–50% of cavity volume to avoid overdistending the cavity, thereby minimizing risk of bacteremia and/or systemic tPA dissemination. Two of the three pediatric patients received 1 mg tPA, and the third patient received 4 mg tPA, with the protocol otherwise identical to that used in adults.

A cycle of tPA was defined as a total of 3 days at this dose. For patients with multiple catheters, tPA was divided equally among them. At the end of each cycle, CT of the chest was performed within 24 hours to assess for residual fluid. Inadequate drainage was determined by means of imaging findings that showed persistent fluid collection combined with little to no output from the catheter. Surgical consultants determined whether and when to proceed to decortication.

Effectiveness of Adjunctive Intrapleural tPA
Overall effectiveness was defined as complete drainage at CT while avoiding subsequent surgical procedures to achieve complete drainage. If patients required subsequent surgical decortication or surgical drainage at video-assisted thoracoscopic surgery (VATS) intrapleural tPA treatment was deemed a failure. Primary effectiveness was effectiveness after one tPA cycle. Secondary effectiveness was effectiveness after two tPA cycles.

Complications
In addition to recording complications, we focused on risk factors for hemorrhage, searching for evidence of local or systemic hemorrhage and recording details such as presence or absence of concurrent systemic anticoagulation, anticoagulation agent, and dose. tPA-related bleeding was diagnosed if either (a) a new hemothorax appeared on CT scans after tPA administration or (b) the chest catheter drainage became hemorrhagic after tPA administration with concurrent hematocrit decrease.

Complications were categorized according to the Society of Interventional Radiology reporting guidelines. Major complications were those requiring treatment with another procedure, transfusion, prolonged hospitalization, or intensive care unit admission. Thus, major bleeding was defined as a hematocrit decrease requiring transfusion in the setting of bleeding into the collection chamber and/or imaging evidence of new hemothorax. Minor complications were defined as those requiring minimal treatment exclusive of additional procedures, transfusion, intensive care unit admission, or prolonged hospitalization.

Statistical Analysis
A t test was used to compare differences in mean pleural thickness between the group that underwent successful drainage with tPA and the group that required subsequent thoracoscopic procedures. A Fisher exact test was used to compare hemorrhagic complication rates, as well as pleural homogeneity versus heterogeneity, between these groups. P .05 was considered to indicate a significant difference. Statistical tests were performed by using software (SAS version 9.1; SAS, Cary, NC).

	RESULTS

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Overall, Primary, and Secondary Effectiveness
The overall tPA effectiveness in achieving pleural drainage of complex collections not drainable by means of percutaneous catheters alone was 57 (86%) of 66 (Fig 1). Further analysis revealed that 60 patients underwent a single tPA cycle. Of these 60 patients, seven required decortication for complete drainage, one patient died without the effusion clearing, and 52 complex effusions cleared without surgery, for a primary effectiveness rate of 87%. Six of the 66 patients underwent two tPA cycles. One of these six patients required VATS with debridement and surgical chest tube placement, and the effusion cleared in the other five patients, yielding an 83% secondary effectiveness rate.

View larger version (129K): [in this window] [in a new window] [Download PPT slide]   Figure 1a: Transverse chest CT images of successful tPA-assisted drainage of complex effusion in a 92-year-old woman. (a) Unenhanced image at the level of the innominate vein shows loculated pleural effusion on the right side, with the superior chest tube (arrows) in place. Anterior portion of the tube (top arrow) is seen as it courses through this plane just before it enters the pleura and reverses course to reenter the transverse plane (bottom arrow). (b) Unenhanced image at the level of the left atrium shows more inferior component of the right effusion situated posteriorly but not layering freely. (c) Unenhanced image at the level of the posterior costophrenic sulcus shows additional fluid on the right and a chest tube (arrow) coursing through the pleural space to reach fluid more superiorly. (d) Contrast material–enhanced image, at the same level as a, obtained within 24 hours after tPA administration shows complete drainage. (e) Contrast-enhanced image, at a similar level as b, obtained within 24 hours after tPA administration shows minimal fluid remaining, a satisfactory result.

View larger version (131K): [in this window] [in a new window] [Download PPT slide]   Figure 1b: Transverse chest CT images of successful tPA-assisted drainage of complex effusion in a 92-year-old woman. (a) Unenhanced image at the level of the innominate vein shows loculated pleural effusion on the right side, with the superior chest tube (arrows) in place. Anterior portion of the tube (top arrow) is seen as it courses through this plane just before it enters the pleura and reverses course to reenter the transverse plane (bottom arrow). (b) Unenhanced image at the level of the left atrium shows more inferior component of the right effusion situated posteriorly but not layering freely. (c) Unenhanced image at the level of the posterior costophrenic sulcus shows additional fluid on the right and a chest tube (arrow) coursing through the pleural space to reach fluid more superiorly. (d) Contrast material–enhanced image, at the same level as a, obtained within 24 hours after tPA administration shows complete drainage. (e) Contrast-enhanced image, at a similar level as b, obtained within 24 hours after tPA administration shows minimal fluid remaining, a satisfactory result.

View larger version (150K): [in this window] [in a new window] [Download PPT slide]   Figure 1c: Transverse chest CT images of successful tPA-assisted drainage of complex effusion in a 92-year-old woman. (a) Unenhanced image at the level of the innominate vein shows loculated pleural effusion on the right side, with the superior chest tube (arrows) in place. Anterior portion of the tube (top arrow) is seen as it courses through this plane just before it enters the pleura and reverses course to reenter the transverse plane (bottom arrow). (b) Unenhanced image at the level of the left atrium shows more inferior component of the right effusion situated posteriorly but not layering freely. (c) Unenhanced image at the level of the posterior costophrenic sulcus shows additional fluid on the right and a chest tube (arrow) coursing through the pleural space to reach fluid more superiorly. (d) Contrast material–enhanced image, at the same level as a, obtained within 24 hours after tPA administration shows complete drainage. (e) Contrast-enhanced image, at a similar level as b, obtained within 24 hours after tPA administration shows minimal fluid remaining, a satisfactory result.

View larger version (105K): [in this window] [in a new window] [Download PPT slide]   Figure 1d: Transverse chest CT images of successful tPA-assisted drainage of complex effusion in a 92-year-old woman. (a) Unenhanced image at the level of the innominate vein shows loculated pleural effusion on the right side, with the superior chest tube (arrows) in place. Anterior portion of the tube (top arrow) is seen as it courses through this plane just before it enters the pleura and reverses course to reenter the transverse plane (bottom arrow). (b) Unenhanced image at the level of the left atrium shows more inferior component of the right effusion situated posteriorly but not layering freely. (c) Unenhanced image at the level of the posterior costophrenic sulcus shows additional fluid on the right and a chest tube (arrow) coursing through the pleural space to reach fluid more superiorly. (d) Contrast material–enhanced image, at the same level as a, obtained within 24 hours after tPA administration shows complete drainage. (e) Contrast-enhanced image, at a similar level as b, obtained within 24 hours after tPA administration shows minimal fluid remaining, a satisfactory result.

View larger version (143K): [in this window] [in a new window] [Download PPT slide]   Figure 1e: Transverse chest CT images of successful tPA-assisted drainage of complex effusion in a 92-year-old woman. (a) Unenhanced image at the level of the innominate vein shows loculated pleural effusion on the right side, with the superior chest tube (arrows) in place. Anterior portion of the tube (top arrow) is seen as it courses through this plane just before it enters the pleura and reverses course to reenter the transverse plane (bottom arrow). (b) Unenhanced image at the level of the left atrium shows more inferior component of the right effusion situated posteriorly but not layering freely. (c) Unenhanced image at the level of the posterior costophrenic sulcus shows additional fluid on the right and a chest tube (arrow) coursing through the pleural space to reach fluid more superiorly. (d) Contrast material–enhanced image, at the same level as a, obtained within 24 hours after tPA administration shows complete drainage. (e) Contrast-enhanced image, at a similar level as b, obtained within 24 hours after tPA administration shows minimal fluid remaining, a satisfactory result.

View larger version (148K): [in this window] [in a new window] [Download PPT slide]   Figure 2a: Transverse contrast-enhanced chest CT images of tPA failure in a 35-year-old man with a loculated empyema. (a) Image shows incomplete drainage despite chest tube (arrow). (b) Image obtained at a slightly superior level shows additional loculated fluid. (c) Image obtained after 3 days of tPA administration shows slight increase in fluid. (d) Image after 3 days of tPA administration, obtained at the superior level (same as in b), shows little change.

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   Figure 2b: Transverse contrast-enhanced chest CT images of tPA failure in a 35-year-old man with a loculated empyema. (a) Image shows incomplete drainage despite chest tube (arrow). (b) Image obtained at a slightly superior level shows additional loculated fluid. (c) Image obtained after 3 days of tPA administration shows slight increase in fluid. (d) Image after 3 days of tPA administration, obtained at the superior level (same as in b), shows little change.

View larger version (150K): [in this window] [in a new window] [Download PPT slide]   Figure 2c: Transverse contrast-enhanced chest CT images of tPA failure in a 35-year-old man with a loculated empyema. (a) Image shows incomplete drainage despite chest tube (arrow). (b) Image obtained at a slightly superior level shows additional loculated fluid. (c) Image obtained after 3 days of tPA administration shows slight increase in fluid. (d) Image after 3 days of tPA administration, obtained at the superior level (same as in b), shows little change.

View larger version (118K): [in this window] [in a new window] [Download PPT slide]   Figure 2d: Transverse contrast-enhanced chest CT images of tPA failure in a 35-year-old man with a loculated empyema. (a) Image shows incomplete drainage despite chest tube (arrow). (b) Image obtained at a slightly superior level shows additional loculated fluid. (c) Image obtained after 3 days of tPA administration shows slight increase in fluid. (d) Image after 3 days of tPA administration, obtained at the superior level (same as in b), shows little change.

Maximum pleural thickness ranged from 1 to 15 mm (mean, 3.4 mm). In patients successfully treated with tPA, pleural thickness ranged from 1 to 13.5 mm. For patients in whom tPA failed, pleural thickness ranged from 1 to 15 mm. Mean pleural thickness did not differ significantly between these two groups (P = .68). The pleura was homogeneous in 58 patients and heterogeneous in eight. Pleural heterogeneity did not significantly predict tPA failure (P = .71).

Complications
There were no complications at the time of catheter placement. Five major pleural hemorrhages were associated with five tPA cycles in four adults (parapneumonic effusion in three, empyema in one). Of the four patients who bled, three received 4 mg of tPA, and one received 6 mg. Hemorrhage occurred 1–2 days after tPA initiation. The CT findings in the patients with pleural bleeding included moderate new hemothorax in one patient (Fig 3), whereas the other three patients demonstrated only small new foci of high-attenuation hemorrhage adjacent to the chest tube. In these latter three patients, the indicator of hemorrhage was blood in the collection chamber with an associated hematocrit decrease.

View larger version (145K): [in this window] [in a new window] [Download PPT slide]   Figure 3a: Transverse contrast-enhanced chest CT images of tPA-associated hemothorax in a 75-year-old man with a parapneumonic effusion who was receiving therapeutic systemic anticoagulation. (a) Image shows persistent loculated fluid despite intrapleural catheter (arrow); tPA administration was initiated. (b) Image obtained within 24 hours after tPA administration shows new high-attenuation material (arrows) indicating development of new hemothorax.

View larger version (140K): [in this window] [in a new window] [Download PPT slide]   Figure 3b: Transverse contrast-enhanced chest CT images of tPA-associated hemothorax in a 75-year-old man with a parapneumonic effusion who was receiving therapeutic systemic anticoagulation. (a) Image shows persistent loculated fluid despite intrapleural catheter (arrow); tPA administration was initiated. (b) Image obtained within 24 hours after tPA administration shows new high-attenuation material (arrows) indicating development of new hemothorax.

All hemorrhagic complications required blood transfusion and were considered major. Effusions in the four patients who bled eventually drained via catheters in three patients but required VATS in one patient. Thus, tPA was successful in clearing a pleural effusion even in the setting of new hemorrhage in 75% (three of four) of patients. All patients who bled survived.

No other complications occurred. No systemic hemorrhage was documented in any patient.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE... References

 
Our series of patients with complex pleural effusions, the majority of which were empyemas or parapneumonic effusions, treated with tPA is among the largest cohort reported to date, to our knowledge. The finding of an overall effectiveness rate of 86% is comparable with results with urokinase and streptokinase in prior reports, which indicate an 80%–92% rate of avoiding decortication (1–11). These results are especially encouraging given the small-bore 8.5–16-F catheters used in our study. For example, in the series by Skeete et al (12) in which larger surgical chest tubes were predominant, 78% of the 41 patients with 42 effusions treated with intrapleural tPA avoided decortication. Wells and Havens (13) reported a 98% effectiveness rate in 45 children; however, inclusion criteria were based on chest radiographs showing a persistent 5-mm pleural thickness at 8–24 hours after catheter placement, a finding that might not always predict failure of drainage by chest tubes alone.

Our results with two cycles of fibrinolytics are worthy of further discussion. Although only six patients underwent a second tPA cycle, complete drainage in five of these patients is noteworthy. This secondary effectiveness rate suggests that patients whose effusions initially are not completely drained with a 3-day tPA cycle may still avoid additional procedures if another tPA cycle is performed. This finding provides an area of further study of the optimal tPA duration to maximize effectiveness and minimize decortication.

The major limitation of our study was its retrospective nature. However, the focus on imaging findings in general and CT findings in particular may provide guidance for the design of future prospective studies. Currently, the largest prospective randomized study, to our knowledge, by Maskell et al (15) failed to show a benefit of intrapleural fibrinolytics in avoiding further surgical procedures such as decortication. However, these investigators failed to triage based on imaging findings. Maskell et al (15) randomly assigned patients with empyema to chest tube drainage with placebo or streptokinase regardless of the presence or absence of imaging findings that would suggest the need for fibrinolytics. Because most effusions, including empyemas, can be drained without adjunctive fibrinolytics, such a study design obscures the potential benefit of finbrinolytic therapy in a selected patient cohort.

In our series, the most common CT finding prior to tPA administration was loculation. The most common CT finding after chest tube placement was inadequate resolution of the effusion despite satisfactory tube position within the effusion. Thus, the appropriate cohort of patients most likely to benefit from tPA are those who show CT evidence of inadequate drainage of a loculated effusion via one or more chest tubes. If prospective randomized studies are to be performed, this is the cohort that should form the study population.

Other imaging findings have been promoted as predicting successful drainage. Park et al (2) found in 31 patients that pleural thickness of 5 mm or more was associated with failure of urokinase to effect complete drainage. Unlike Park et al, we did not find pleural thickness a significant predictor of successful drainage because we were able to avoid decortication in patients whose pleura were as large as 13.5 mm. Thus, abnormal pleural thickness should not contravene a trial of tPA.

To our knowledge, we are the first to report the association of tPA-related pleural hemorrhage and full-dose systemic anticoagulation. For patients who are not simultaneously undergoing full-dose systemic anticoagulation treatment, our cohort provides an encouraging safety record for intrapleural tPA. Notably, prophylactic anticoagulation did not increase bleeding risk. Because most of the patients in our study were undergoing prophylactic anticoagulation, our results suggest a reasonable safety profile in these patients. Given the expanding indications for prophylactic anticoagulation, demonstrating safety in these patients is important.

However, for patients simultaneously undergoing full-dose systemic anticoagulation, our rate of major hemorrhage of 33% raises important questions of whether tPA should be recommended for these patients. Undoubtedly, some would argue that intrapleural tPA should be avoided in these patients, but we believe that the decision must be made on an individual basis. Despite the bleeding risk, effectiveness was not severely compromised in the group that bled. Thus, the clinical decision as to whether to administer intrapleural tPA in an individual patient in the setting of full systemic anticoagulation will require consideration of several factors, including possible interruption of anticoagulation and risks and benefits of alternative procedures such as decortication versus no additional treatment. Further study is needed to determine whether lower tPA doses (2 mg) can be used to achieve similar effectiveness with lower bleeding risk in patients with therapeutic-dose anticoagulation.

Lahorra et al (16) confirmed lack of a systemic effect on coagulation parameters with intracavitary urokinase in abscesses. Likewise, Davies et al (17) showed lack of systemic effect with intrapleural streptokinase. However, these findings were in the absence of systemic anticoagulation. Because we did not observe an increased risk of systemic hemorrhagic complications during intrapleural tPA administration, we speculate that pleural bleeding is caused by a local effect on the pleura magnified by systemic anticoagulation.

The literature provides some reports of hemorrhage after administration of intrapleural fibrinolytics. Blom et al (18) reported a life-threatening hemothorax in an 8-month-old boy who had not undergone anticoagulation. A massive hemothorax ensued after urokinase administration. However, imaging was limited to chest radiography, and no CT was performed to confirm chest tube position in the pleural space (18). Therefore, it is unknown whether some urokinase entered the lung parenchyma thereby predisposing the boy to severe bleeding. Godley and Bell (19) reported major hemorrhage after a single 500 000 IU dose of streptokinase, with hemorrhage from the chest tube as well as from the endotracheal and nasogastric tubes. These investigators speculated that a bronchopleural fistula and possible vascular erosion may have predisposed the patient to systemic absorption of streptokinase (19). Skeete et al (12) reported on 41 patients, with a single case of new hematuria in a patient undergoing dialysis, and they speculated that concurrent anticoagulation should be avoided. These investigators also emphasized the safety of tPA in seven patients with recent trauma, including penetrating chest trauma. In contrast, Temes et al (11) reported one major hemorrhage in a patient with fractured ribs among 26 patients treated with intrapleural fibrinolytic therapy. In their study, Temes et al excluded patients who had undergone systemic anticoagulation. More recently, Wells and Havens (13) reported minor bleeding, but no major bleeding, in pleural fluid drained in four of 45 patients after tPA administration.

In our study, only one of four patients with major pleural hemorrhage developed a large hemothorax. The rapid hematocrit decrease, coupled with the clear presence of blood in the drainage chamber, provided the first clue to diagnosis in all patients. However, hemorrhagic fluid by itself is expected output of hemothorax and some empyemas or parapneumonic effusions. In these settings, hemorrhagic drainage in the absence of a hematocrit decrease is not an indication to discontinue tPA.

Limitations in our study result from its retrospective nature. In the absence of a prospective protocol, the timing to initiation of tPA treatment was not standardized nor was the timing of an additional cycle. Delays in initiating tPA administration in properly selected patients may result in inadequate drainage. Likewise, the decision for patients to undergo decortication rather than additional tPA administration was made by the surgical service and not on the basis of a standard research protocol. Inconsistencies across the course of the study may have influenced the failure rate.

In conclusion, tPA is associated with effectiveness comparable to historic results with streptokinase and urokinase in patients in whom initial chest tube placement fails to achieve complete drainage as demonstrated at CT. In our cohort, intrapleural tPA had an 86% effectiveness rate and was safe in patients receiving concurrent prophylactic doses of systemic anticoagulation; however, patients receiving intrapleural tPA and a concurrent therapeutic dose of systemic anticoagulation are at significantly higher risk of pleural hemorrhage.

	ADVANCES IN KNOWLEDGE

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE... References

 

• Use of adjunctive intrapleural tissue plasminogen activator (tPA) has an 86% success rate in draining complex pleural effusions not completely treated by means of catheter drainage alone.
  
• Adjunctive intrapleural tPA is safe in patients simultaneously receiving prophylactic levels of systemic anticoagulation.
  
• Adjunctive intrapleural tPA is associated with a statistically increased risk (P < .001) of intrapleural hemorrhage in patients simultaneously receiving therapeutic levels of systemic anticoagulation.
  

	IMPLICATIONS FOR PATIENT CARE

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE... References

 

• Adjunctive intrapleural tPA can be used to treat patients whose effusions do not drain with catheters alone.
  
• Given the effectiveness of intrapleural tPA in draining complex pleural collections, the increasing number of patients undergoing prophylactic anticoagulation can be treated with tPA, with most avoiding decortication.
  
• For patients undergoing systemic anticoagulation, awareness of the increased bleeding risk with concurrent intrapleural tPA may help to individualize decision making for patient care.
  

	ACKNOWLEDGMENTS

 
The authors acknowledge advice from Elkan Halpern, PhD, for statistical analysis of data in this article.

	FOOTNOTES

 

Abbreviations: tPA = tissue plasminogen activator • VATS = video-assisted thoracoscopic surgery

Author contributions: Guarantors of integrity of entire study, all authors; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, D.A.G.; clinical studies, D.A.G., R.S.A.; statistical analysis, D.A.G., D.A.L., P.F.H., R.N.U., P.R.M.; and manuscript editing, all authors.

Authors stated no financial relationship to disclose.

	References

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE... References

 

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