Tissue plasminogen activator was developed for the treatment of coronary artery thrombosis and stroke, and its use for intrapleural therapy was first documented in a case report by Walker and colleagues in 200311. Subsequent studies supported its safety and potential efficacy,13,14 but it was the MIST-2, published in 201110, that led to the general adoption of tPA and DNase for management of complex effusions. The MIST-2 was a multi-center prospective randomized trial that enrolled 210 patients and compared the combination of tPA and DNAse to placebo and to either agent alone. The primary outcome of change in pleural opacity was greatest in the tPA + DNase group. The secondary outcome of referral for surgery was lowest in the tPA + DNase group (4%), which was statistically significantly lower than in the placebo (16%, p = 0.03) and DNase alone groups (39%, p = 0.01), but was not significantly lower than in the tPA alone group (6%, p = 0.10). In attempting to replicate the protocol for tPA + DNase in our patients we encountered logistical challenges with using both agents simultaneously, and in delivering the doses every 12 hours. Furthermore, we discovered that chest tubes often were not unclamped for several hours beyond the prescribed one hour dwell time. In these patients effusion drainage was surprisingly brisk, leading us to modify our treatment regimen to the use of tPA alone with a prolonged dwell time. In reviewing that early experience we concluded that a 4 mg dose of tPA was sufficient, and that a 12 hour dwell time was most effective12. In this report we review our experience with that standardized protocol.
The findings in the current report support the initial clinical impression that our modified protocol is effective in the non-surgical management of complex pleural effusions. Some patients were discovered to have trapped lung, a condition that requires surgical decortication and that would not reasonably be expected to respond to fibrinolytic therapy. In our experience, tPA therapy led to prompt diagnosis of trapped lung and facilitated appropriate decision-making regarding the indications for and timing of decortication. Of the patients without trapped lung, for whom fibrinolytic therapy has the potential to be definitive therapy, 81% were considered to have complete drainage with no further intervention indicated, and only 6% underwent surgery to clear residual loculated effusion. Although not a prospective randomized trial, this result is nearly identical to the results reported in the tPA + DNase and tPA alone groups in MIST-2.
Bleeding is a concern with intrapleural tPA. In this series no patient experienced life-threatening hemorrhage and only one patient had treatment discontinued because of grossly bloody chest tube drainage; 5.6% of patients were given a transfusion. We calculated change in serum hemoglobin from before to after tPA treatment as a surrogate measure of blood loss and found that results resembled a normal distribution around 0. This suggests that intrapleural tPA did not consistently contribute to blood loss. Based on our earlier experience, and confirmed in this series, systemic anticoagulation is not a contraindication to intrapleural tPA, and 13 patients in this series were receiving heparin drips at the time of therapy. Even with bloody pleural effusions, especially in the setting of a malignant pleural effusion, tPA can be given without causing significant hemorrhage. Indeed, in the 95 patients for whom pleural fluid red cell count was available, higher counts were not associated with a greater drop in hemoglobin. It has been our experience that tPA for bloody, malignant effusions is often very helpful because it promotes complete drainage and pleural apposition that tamponades further bleeding.
A related concern with intrapleural tPA is the potential for systemic effects. In no patient was coagulopathic bleeding noted at sites such as intravenous lines or drains to suggest systemic effects, and the known pharmacokinetics of tPA suggests this should not be a concern. We are not aware of any data that intrapleural tPA is absorbed into the systemic circulation to any significant degree, and given that the first-pass half-life of tPA in serum is less than five minutes15–17, it reasons that any tPA absorbed across the pleura would be rapidly metabolized. It seems therefore highly unlikely that intrapleural tPA poses a significant risk of systemic hemorrhage.
Because a large proportion of our patients were treated with small, “pigtail” catheters, we were able to also evaluate the efficacy of small bore catheters. The optimal choice of tube size to facilitate effective drainage with fibrinolytics is a topic of some controversy. Intuitively a larger tube should be less likely to clog and therefore facilitate more effective drainage, yet smaller tubes are better tolerated and more easily targeted to specific areas with image guidance. In a separately published analysis of the MIST-1 data, in which tube sizes ranged from < 10 Fr to > 20 Fr, Rahman and colleagues reported that tube size had no effect on outcome18. Our results support this conclusion.
A concern with embarking on a course of fibrinolytic therapy rather than proceeding immediately to surgery is that it can prolong hospitalization. In our experience, half of patients completed therapy within six days. Because a handful of patients had extremely prolonged chest tube drainage, mean duration of chest tube drainage in our study was 8.5 days. The MIST-2 did not report duration of chest tube drainage, but mean length of hospitalization in the tPA + DNAase group, which was statistically significantly shorter than for all other groups, was 11.8 ± 9.4 days when prolonged-stay outliers were discarded. This suggests that our protocol compares favorably to the standardized MIST-2 regimen. Furthermore, we believe this number can be reduced with consistent implementation of a care-algorithm such that length-of-stay can be similar to, and perhaps even shorter than surgery.
Objective assessment of outcome is a significant challenge in evaluating the effectiveness of various strategies for managing complex pleural effusions. Existing studies of fibrinolytic therapy have used a variety of outcome metrics, including length of hospital stay, all-cause mortality, need for surgery, or radiographic improvement. All of these metrics have a significant subjective component. The MIST-2 used reduction in pleural opacity (on chest x-ray) as a primary endpoint, and referral for surgery as a secondary endpoint. Although imaging algorithms can provide objectivity to the radiographic analysis of chest x-ray findings, they may not be able to accurately distinguish between pleural fluid, atelectasis and consolidation as the cause of radiographic opacity. Furthermore, although reduction in radiographic opacity may reflect efficacy of therapy, ultimately the outcome that matters is the volume of residual effusion, not how much smaller it is from where it started. The need for surgery is a highly subjective assessment by the treating team, and therefore has its limitations as an objective outcome measure as well. In our study, we used the combination of radiographic assessment and the decision for surgery as an outcome measure. While this should provide some degree of comparability to results of other studies, its highly subjective nature makes firm conclusions suspect and direct comparison to alternative strategies difficult. High-resolution imaging with chest CT, especially when done with intravenous contrast, is ideally suited for distinguishing pleural fluid from adjacent atelectasis and consolidation, and software algorithms can be constructed to automatically calculate volumes. However, frequent and repeated use of chest CT to evaluate therapeutic progress with pleural effusions can expose the patient to potentially high levels of radiation. Development of a high-resolution volumetric measure that minimizes radiation exposure would be very helpful for objective assessment of fibrinolytic efficacy.
The half-life of tPA in the blood is minutes, but there is no information on its half-life in pleural fluid. tPA is a naturally occurring protein in the pleural space and so it is reasonable that the half-life is prolonged. Furthermore, in a study of tPA in cerebrospinal fluid Kramer and colleagues19 found that concentrations remained elevated for six and, in a few patients, even 12 hours after a single dose. In our experience with a 12-hour dwell time occasionally patients would complain of increasing chest pressure beginning about six hours after the administration of the tPA. This experience, and the observation that a dwell time of up to 12 hours can be highly effective, suggest that the half-life of tPA in the pleural space may be several hours.
There are several limitations to this study. As a retrospective chart review the results are subject to selection bias and there may have been bias in clinical decision-making that subsequently affected the determination of outcome measures. However it is a consecutive series of patients and the study population is large, so that although the results may not be directly comparable to results from other studies because of these biases, the primary conclusion remains provocative. Another limitation is that we have not included longer-term follow-up to confirm that effusions considered effectively treated did not recur. Our use of change in serum hemoglobin to evaluate bleeding incidence is questionable because of multiple uncontrolled and confounding variables.
There are two significant advantages to our regimen compared to MIST-2. First, our protocol is significantly easier to implement. In an environment where rules prohibit nurses from administering medication through chest tubes, and where 24-hour physician coverage is limited, it is much easier to adhere to a single dose daily than to a dose every 12 hours. And secondly, because we used a lower dose of tPA and did not use DNase, the regimen is less costly. According to our pharmacy, the Wholesale Acquisition Cost for Pulmozyme® (DNAse) is $111.47 per 1 mg, and for Activase® (tPA) is $148.47 per 2 mg. Therefore the drug costs alone for one day of the MIST-2 regimen (Pulmozyme® 5 mg and Activase® 10 mg twice daily) is $2,599.40 compared to $296.84 for one day of our regimen.
The natural history of pleural fibrosis suggests that symptom duration, and perhaps other clinical features should predict the efficacy of intrapleural fibrinolytic therapy. However symptom duration is a highly subjective and unreliable metric, and proved essentially useless as a predictor of outcome in our series. Pleural fluid characteristics also had no predictive value. As a result it is our practice to give tPA if imaging shows incomplete pleural drainage regardless of effusion etiology or duration. Minimal drainage (< 100 mL) or imaging showing a trapped lung indicates that further tPA therapy is futile, while a high volume of drainage suggests that further therapy may be successful. This protocol facilitates rapid clinical decision-making and is safe.