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Intrapleural Fibrinolytic Therapy in Patients With Nondraining Indwelling Pleural Catheters

Vial, Macarena R. MD; Ost, David E. MD, MPH; Eapen, Georgie A. MD; Jimenez, Carlos A. MD; Morice, Rodolfo C. MD; O’Connell, Oisin MD; Grosu, Horiana B. MD

Journal of Bronchology & Interventional Pulmonology: April 2016 - Volume 23 - Issue 2 - p 98–105
doi: 10.1097/LBR.0000000000000265
Original Investigations
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Background: Tissue plasminogen activator (tPA) has been successfully used to relieve obstruction of dysfunctional devices, including vascular catheters. Intrapleural tPA is used by some centers to restore flow of nondraining indwelling pleural catheters (IPCs) in symptomatic patients with malignant pleural effusions (MPEs). Because few studies have evaluated its safety and effectiveness, we conducted a retrospective cohort study of outcomes after tPA treatment during a 10-year period at our institution.

Methods: We studied 97 patients with MPE and a nondraining IPC in the setting of persistent pleural fluid who were treated with intrapleural tPA. The primary outcome was restoration of flow after treatment. Secondary outcomes included complication rates and the need for further pleural interventions. Symptomatic relief was assessed using the Borg perceived scale.

Results: We identified 97 patients with MPE and a nondraining IPC who were treated with tPA. Flow was restored after 1 tPA dose in 83 of 97 patients (86%; 95% confidence interval, 77%-92%). Reocclusion after 1 dose was seen in 27 of 83 patients (32%), and 22 (81%) of these patients were treated with a second tPA dose. Among these 22, flow was restored in 16 (72%; 95% confidence interval, 44%-84%). Borg score improvement was only seen in patients who had restored flow (P=0.024). This finding was independent of the size of the effusion upon chest x-ray. There were 5 complications: 2 hemothoraxes and 3 infectious complications.

Conclusion: On the basis of our finding of successful flow restoration with few complications, we recommend intrapleural tPA treatment for symptomatic patients with nondraining IPCs in the setting of persistent pleural fluid.

Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

H.B.G. and M.R.V were the principal investigators and were responsible for the study design. D.E.O, G.A.E, C.A.J, and R.C.M contributed to writing of the manuscript. M.R.V and O.O. contributed to data collection and entry. H.B.G., D.E.O., R.C.M., G.A.E, and C.A.J. contributed to reviewing and editing the manuscript. H.B.G is the guarantor of the manuscript.

Disclosure: There is no conflict of interest or other disclosures.

Reprints: Horiana B. Grosu, MD, Department of Pulmonary Medicine, Unit 1462, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: hbgrosu@mdanderson.org).

Received September 28, 2015

Accepted January 25, 2016

Malignant pleural effusions (MPEs) can cause significant dyspnea, resulting in poor quality of life.1 MPEs occur in 7% to 15% of lung cancers and complicate the course of many other types of cancers.1,2 As MPE portends a poor prognosis, the primary objective is symptomatic relief. Typically, management of MPE includes repeated thoracentesis, placement of indwelling pleural catheters (IPCs), and chemical pleurodesis using sclerosing agents. IPCs have been shown to improve dyspnea in 88% to as high as 100% of patients.3,4 In a systematic review that identified 19 studies of 1370 patients with IPCs demonstrated some degree of symptomatic improvement in 95% of patients.5 Nevertheless, several complications are associated with IPCs. Loculations can develop in up to 14% of patients, with subsequent decreased IPC drainage. Also, dysfunctional and occluded IPCs have been reported in 3% to 9.1% of patients.3,5–7 Decreased drainage despite persistent evidence of pleural fluid has been attributed to clots or fibrin within the IPC or significant loculations.

The fibrinolytic agent alteplase, a tissue plasminogen activator (tPA), has been used to relieve obstruction of dysfunctional devices, especially central venous catheters and dialysis catheters.8–10 Similarly, tPA has been used by some institutions as treatment for IPC-related symptomatic loculations, with good results.11 A recent study of 37 patients with nondraining IPCs found a high success rate for restoration of flow after tPA instillation and no associated complications.12 At our institution, we follow a standardized algorithm for suspected obstructed IPCs, and it includes use of fibrinolytics, specifically tPA, if a saline flush fails to restore function. However, data on the efficacy and safety of tPA for nondraining IPCs are scarce.

In this study, we evaluated the effectiveness and safety of intrapleural tPA in restoring flow of nondraining IPCs in symptomatic patients with MPE.

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PATIENTS AND METHODS

Patient Population

We performed a retrospective review of all patients with nondraining IPCs treated with tPA from January 2005 to January 2015 at our institution. Institutional review board (IRB) approval was obtained from MD Anderson Cancer Center’s IRB4 committee (protocol PA15-0257). We identified cases using billing procedure codes for intrapleural fibrinolysis (CPT codes 32561 and 32562). We included patients aged 18 years or older with nondraining IPCs treated with tPA. We excluded patients with documented empyema. The indication for the procedure needed to be clearly documented in the patient’s chart as nondraining IPC or a sudden decrease in IPC drainage with persistent significant pleural effusion confirmed by chest x-ray and/or ultrasound.

We hypothesized that tPA given intrapleurally would lead to restoration of IPC patency with increased fluid flow.

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Procedure

After IPC placement, patients were seen in follow-up at 10 to 14 days followed by monthly clinic visits. All patients were managed using a standardized algorithm following IPC placement (Fig. 1). Most patients with functioning IPCs were switched from daily drainage to every-other-day drainage as IPC output decreased and were evaluated for elective removal. Patients who developed decreased IPC drainage with persistent pleural effusions were evaluated for suspected IPC occlusion using a second standardized algorithm (Fig. 2).

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

Patients who had suspected IPC dysfunction had a chest x-ray and were seen in the clinic. The IPC was first flushed with 20 mL of saline. The IPC was then drained after the flush. If >150 mL of pleural fluid was obtained, the saline flush was considered a success, and the patient resumed standard drainage procedures as outlined in Figure 1. If <150 mL of pleural fluid was drained, the saline flush was considered a failure. At that point, 4 mg tPA was instilled through the IPC using sterile technique, followed by a 20-mL sterile saline flush. The tPA dwell time was 1 hour, at which point the IPC was drained again. If >150 mL of pleural fluid was drained, the tPA treatment was considered successful, and the patient resumed standard drainage procedures as outlined in Figure 1. If <150 mL of pleural fluid was obtained, the tPA treatment was considered to have failed. In the latter case, the patient was instructed to return to the clinic within 2 days for a repeat procedure. The tPA instillation is generally performed on an outpatient basis.

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Definitions and Outcomes

Restoration of IPC flow was defined as the ability to withdraw ≥150 mL after a dysfunction was documented.

A small pleural effusion was defined as occupying at least 20% and up to 25% of the affected hemithorax upon chest x-ray, a moderate pleural effusion was defined as occupying >25% and up to 50% of the affected hemithorax, and a large effusion was defined as occupying >50% of the affected hemithorax. If the pleural effusion occupied <20% of the hemithorax, the patient was evaluated for elective removal. Loculations were defined as evidence of septations on imaging (ultrasonography, CT, or PET-CT of the chest). Improvement of pleural effusion on the chest x-ray was defined as a decrease in pleural effusion size by ≥50% when compared with preintervention chest x-rays.

Borg scores recorded before and after tPA treatment were compared. Improvement was defined as an increase of at least 1 point in the Borg score; this threshold was based on a consensus statement on chronic breathlessness that has suggested a 1-point improvement as the minimally clinically important difference for breathlessness.13

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Statistical Analysis

For demographic and clinical characteristics, we used mean and SD to describe continuous normally distributed variables. We used medians and interquartile ranges (IQRs) (25% to 75%) for non-normally distributed data. We used frequencies for categorical data. Patient and clinical characteristics in the 2 groups were tabulated and compared using the χ2 test or Fisher exact test for categorical variables and a 2-sample t test for continuous variables. To explore and adjust for confounding, we used stratified analysis using the Mantel-Haenszel method. For continuous non-normally distributed data, we used the Wilcoxon rank-sum (Mann-Whitney) test.

A 2-tailed P-value of <0.05 was considered statistically significant for all analyses. We used Intercooled Stata 13 software (College Station, TX) for the analyses.

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RESULTS

We reviewed 97 consecutive cases of nondraining IPCs treated with tPA from January 2005 to January 2015. All 97 patients underwent a chest x-ray before instillation of the first dose of tPA, and 58 (60%) of them had moderate or large effusions. Most patients had some degree of loculations, with only 18 patients (18%) having free-flowing effusions. Patient characteristics are summarized in Table 1.

TABLE 1

TABLE 1

All 97 patients had failed to respond to saline flushes and were treated with intrapleural tPA, and their IPCs were drained 1 hour later. All patients had documented follow-up clinic visits or telephone follow-up within 24 to 48 hours of treatment with tPA.

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Restoration of Flow

Figure 3 shows the patient outcomes based on restoration of flow. Median time to occlusion after IPC placement was 27.5 days (IQR, 15 to 35 d). Time to occlusion had no effect on restoration of flow (P=0.975).

FIGURE 3

FIGURE 3

Restoration of flow in patients treated with 1 dose of tPA was seen in 83 of 97 patients (86%; 95% confidence interval, 77%-92%). No reocclusion after 1 dose of tPA was seen in 56 of 83 patients (67.5%) [median follow-up of 78 d (IQR, 26 to 305 d)]. In 35 of the 56 patients (63%), the IPC was eventually removed electively because of decreased drainage and absence of significant pleural fluid [median time to catheter removal of 189 d (IQR, 81.5 to 424.5 d)]; 15 of 56 patients (27%) died with the IPC in place; and 6 of 56 (10%) were alive with the IPC in place at the time of last follow-up. Two of the patients whose IPC was removed electively because of decreased drainage developed pleural fluid reaccumulation that required thoracentesis.

Reocclusion after 1 dose of tPA was seen in 27 of 83 patients (32.5%). Of these, only 22 (81%) were treated for a second time with tPA; 5 (19%) were not. Restoration of flow with a second dose of tPA occurred in 16 of the 22 patients (72%; 95% confidence interval, 49%-89%). Two of the 16 patients (12.5%) developed a third reocclusion, and the IPC was removed; however, both of those patients needed repeat intervention. In the remaining 14 patients (87.5%), there was no reocclusion after the second treatment with tPA, and the IPC was ultimately removed electively because of decreased drainage without significant pleural fluid in 9 of these 14 patients (64%). Three of the 14 patients (21%) died with the IPC in place, and 2 of the 14 (14%) were still alive with the IPC in place at the time of last follow-up.

Six of 22 patients (27%) did not have restoration of flow after a second treatment with tPA. Among these 6 patients, the IPC was ultimately removed due to nondrainage in 4 patients, 1 patient died with the IPC in place, and 1 patient was transitioned to comfort care with the IPC in place at the time of last follow-up. One of 4 patients who had the IPC removed required thoracentesis.

Five of 27 patients (18%) who developed reocclusion after the first dose of tPA and were not treated with tPA a second time had their IPCs removed. Among these 5 patients, 2 required repeat pleural intervention. The interventions were thoracentesis in 1 patient and placement of another IPC in the other patient.

Fourteen of 97 patients (14%) did not have restoration of function after the first dose of tPA. Two of these patients were treated with a second dose of tPA within 2 days of the first dose, with no restoration of flow. The IPC was removed in 11 patients, and 3 patients died with the IPC in place. Of the 11 patients who had their IPCs removed because of nondrainage, 4 (36.3%) required thoracentesis (Table 2).

TABLE 2

TABLE 2

Overall, at the end of our study out of 97 patients, 44 (46%) had their IPC removed electively, 22 (23%) had their IPC removed for nondrainage, 9 (9%) patients were alive with IPC in place, and 22 (23%) were dead with IPC in place.

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Chest X-Ray, Restoration of Flow, and Borg Scores

Pretreatment and posttreatment chest x-rays were available in 91 patients. Of these, 77 (84%) had restoration of flow, and 14 (15%) did not. The chest x-ray improved more in those who had restoration of flow (37 of 77, 48%) than in those who did not (1 of 14, 7%) (P=0.006) (Table 3).

TABLE 3

TABLE 3

Baseline Borg scores were available in 83 patients and were not associated with the size of the effusion on chest x-ray (P=0.241). Pretreatment and posttreatment Borg scores were available in 65 patients. Of these, only 51 had a baseline Borg score of ≥1 and hence could show an improvement after the intervention. Among these 51 patients, 45 had restoration of flow. Borg score improvement was only seen in those who had restoration of flow (24 of 45, 53%) versus 0 of 6 in those who had no restoration of flow (P=0.024). This finding was independent of the size of the effusion upon chest x-ray (Mantel-Haenszel method, P=1.00).

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Complications

A total of 121 doses of tPA were given to 97 patients. Complications occurred in 5 patients (4%). Two of these patients developed hemothorax within 24 hours of tPA instillation. On review of fluid characteristics before the tPA instillation, none of the patients had hemorrhagic fluid and none had been on anticoagulation medication. Both patients were treated conservatively with daily drainage of the IPC; 1 required blood transfusions. Two patients developed empyema 3 days after tPA instillation. One was treated conservatively with IPC on continuous suction and antibiotics. The other patient required chest tube placement and removal of the IPC. One patient developed tunnel site infection 2 days after tPA installation and was treated with antibiotics.

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DISCUSSION

This is the largest study to date assessing the effectiveness and safety of tPA in restoring flow of nondraining IPCs. Our findings demonstrate restoration of flow after 1 dose of tPA in 86% of patients with documented dyspnea improvement in 53% of patients in whom the flow was restored. Complications occurred only in 5 patients, 2 of whom developed hemothorax within 24 hours of tPA instillation.

The management of nondraining IPCs is poorly described in the literature to date. A recent study by Wilshire et al12 found successful restoration of flow in all 37 patients with nondraining IPCs after tPA instillation. Our success rate of 86% is slightly lower; however, the definitions used were significantly different. In their study, success was defined as any increase in fluid drainage through the IPC, without a specific cut point. With the ≥150-mL definition for success that we used in our study, the restoration of flow in their study after 1 dose of tPA would have been 29 of 37 (78%), similar to our findings.

In addition to confirming prior data on efficacy of tPA in restoring flow, we also assessed the relationship of dyspnea improvement and restoration of flow. As expected, dyspnea improved only when flow was restored. In addition, we also report a 1.6% rate of hemothorax as a complication to the use of tPA for nondraining IPCs. Thomas et al11 found a 3% incidence of hemothorax for the treatment of loculated pleural effusions with fibrinolytics; however, it is not specified whether hemothorax was present in patients receiving tPA or other fibrinolytic agent. Rahman et al14 found a 3.8% incidence of hemothorax with the use of tPA and DNase combined for the treatment of empyema. Both reports mention doses of up to 10 mg tPA, which could explain the higher incidence of hemorrhagic complications. Whether higher doses could improve efficacy is unknown and could be the subject of future studies, but it may be associated with increased risk of hemorrhagic complications.

There are some limitations to our study. First, due to the retrospective design of the study, some data on dyspnea were not available for all patients. In addition, in our cohort, the majority of patients had some degree of loculations; hence, the effectiveness of tPA might vary in other populations. Last, we do not know whether the effectiveness of tPA was due to reestablishing IPC patency or due to dissolution of septations present in loculated effusions. We found no difference in effectiveness when comparing patients with and without loculations, but we recognize the study was likely underpowered to detect such a difference.

In summary, we conclude that tPA is effective and relatively safe for restoring function of IPCs. If reocclusion occurs after restoring flow, a second treatment with tPA may still be effective. If tPA fails to restore flow, then consideration of other drainage procedures is warranted. We propose the algorithm for management shown in Figure 4. Further studies are needed to identify risk factors that may lead to occlusion, and modalities to prevent such occlusions are needed.

FIGURE 4

FIGURE 4

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ACKNOWLEDGMENT

The authors thank Sunita Patterson (Department of Scientific Publications, MD Anderson Cancer Center) for editorial assistance.

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Keywords:

malignant pleural effusion; indwelling pleural catheter; fibrinolytic agents

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