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Original Research: Pulmonary Procedures |

Intrapleural Fibrinolysis for the Treatment of Indwelling Pleural Catheter-Related Symptomatic LoculationsIndwelling Catheter-Related Symptomatic Loculation: A Multicenter Observational Study FREE TO VIEW

Rajesh Thomas, MBBS; Francesco Piccolo, MBBS; Daniel Miller, MD; Paul R. MacEachern, MD, FCCP; Alex C. Chee, MD, FCCP; Taha Huseini, MBBS; Lonny Yarmus, DO, FCCP; Rahul Bhatnagar, MBChB; Hans J. Lee, MD, FCCP; David Feller-Kopman, MD, FCCP; Nick A. Maskell, DM, FCCP; Alain Tremblay, MDCM, FCCP; Y. C. Gary Lee, PhD, FCCP
Author and Funding Information

From the Department of Respiratory Medicine (Drs Thomas, Huseini, and Y. C. G. Lee), Sir Charles Gairdner Hospital, Perth, WA, Australia; the School of Medicine and Pharmacology (Drs Thomas and Y. C. G. Lee), University of Western Australia, Perth, WA, Australia; the Lung Institute of Western Australia (Drs Thomas and Y. C. G. Lee), Perth, WA, Australia; the Department of Internal Medicine (Dr Piccolo), Swan District Hospital, Perth, WA, Australia; the Division of Respiratory Medicine and Southern Alberta Cancer Research Institute (Drs Miller, MacEachern, Chee, and Tremblay), University of Calgary, Calgary, AB, Canada; the Division of Pulmonary and Critical Care Medicine (Drs Yarmus, H. J. Lee, and Feller-Kopman), Johns Hopkins University, Baltimore, MD; and the Academic Respiratory Unit (Drs Bhatnagar and Maskell), University of Bristol, Bristol, England.

CORRESPONDENCE TO: Y. C. Gary Lee, PhD, FCCP, University of Western Australia School of Medicine & Pharmacology, 533 Harry Perkins Research Bldg, QE II Medical Centre, Perth, WA 6009, Australia; e-mail: gary.lee@uwa.edu.au


FUNDING/SUPPORT: Dr Thomas has received research scholarship support from NH&MRC, the Western Australia Cancer and Palliative Care Network (WACPCN), and LIWA, Australia. Dr Maskell has received research grant support from the National Institutes of Health Research (NIHR). Dr Y. C. G. Lee has received research grant support from the Sir Charles Gairdner Research Foundation, the Cancer Council of Western Australia, the Lung Institute of Western Australia (LIWA), Westcare, and the Dust Disease Board of New South Wales, Australia. Dr Y. C. G. Lee is a recipient of a National Health and Medical Research Council (NH&MRC) Career Development Fellowship.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(3):746-751. doi:10.1378/chest.14-2401
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BACKGROUND:  Indwelling pleural catheters (IPCs) are an effective option in the management of malignant pleural effusion. Up to 14% of patients with IPCs develop symptomatic pleural loculations causing ineffective fluid drainage and breathlessness. To our knowledge, this is the first study to describe intrapleural fibrinolytic therapy for IPC-related symptomatic loculations.

METHODS:  All patients who received intrapleural fibrinolytic therapy for symptomatic loculations between January 1, 2002, and June 30, 2014, in four established IPC centers were retrospectively included. Patient outcomes, treatment effectiveness, and adverse events were recorded.

RESULTS:  Sixty-six patients (mean age, 64.7 ± 14.2 years; 52% women) were included. Lung cancer (31.3%) and malignant pleural mesothelioma (20.3%) were the most common malignancies. Fibrinolytic instillation was performed in outpatient (61%) and inpatient settings. Tissue-plasminogen activator (n = 52), urokinase (n = 12), and streptokinase (n = 2) were used. The majority (69.7%) received only one fibrinolytic dose (range, one to six). Pleural fluid drainage increased in 93% of patients, and dyspnea improved in 83% following therapy. The median cumulative pleural fluid volume drained at 24 h posttreatment was 500 mL (interquartile range 300-1,034 mL). The area of opacity caused by pleural effusion on chest radiograph decreased from (mean, SD) 52% (14%) to 31% (21%) of the hemithorax (n = 13; P = .001). There were two cases of nonfatal pleural bleed (3%).

CONCLUSIONS:  Intrapleural fibrinolytic therapy can improve pleural fluid drainage and symptoms in selected patients with IPC and symptomatic loculation, but it carries a small risk of pleural bleeding. There is significant heterogeneity in its use currently, and further studies are needed to determine patient selection and optimal dosing regimen and to define its safety profile.

Figures in this Article

Malignant pleural effusion (MPE) continues to be a major cause of morbidity worldwide.1 Treatment with indwelling pleural catheter (IPC) allows ambulatory drainage of recurrent pleural fluid and is effective for the management of symptomatic MPEs.25 Serious adverse events related to IPC use are uncommon27; however, the development of fibrinous loculations within the pleural cavity can impair effective fluid evacuation via an IPC, leading to fluid accumulation and breathlessness.

IPC-related symptomatic loculations develop in up to 14% of patients.3,5 Despite its clinical significance and frequent occurrence, IPC-related symptomatic loculation has seldom been described; limited data exist on its clinical course or best management.8 Intrapleural fibrinolytic therapy has been shown to be effective and safe in the treatment of loculated MPE9,10 and, together with deoxyribonuclease (DNase), of pleural infection.1113 Extrapolating from these experiences, intrapleural instillation of fibrinolytics via the catheter has been used increasingly to treat IPC-related symptomatic pleural loculations. There is, however, no published literature on the efficacy or safety of intrapleural fibrinolytic therapy in this setting.

This multinational retrospective study combines the experience of four established IPC centers in the use of intrapleural fibrinolytic therapy for IPC-related symptomatic loculations. The data could provide a platform for future examination of intrapleural instillation of fibrinolytics in patients with IPCs.

Data were collected from four respiratory centers in four countries, namely Sir Charles Gairdner Hospital (SCGH) (Perth, Western Australia, Australia), University of Calgary (Calgary, Alberta, Canada), Southmead Hospital (SMH) (Bristol, England), and Johns Hopkins Hospital (JHH) (Baltimore, Maryland). The institutional ethics review boards of each center approved the study (Table 1). All patients who underwent IPC insertion were entered prospectively into local databases at SCGH, SMH, and JHH. Patients who received intrapleural fibrinolytic therapy for symptomatic loculation between January 1, 2002, and June 30, 2014, were captured retrospectively by interrogation of the MPE, cancer, and pharmacy electronic databases at each center. Individual centers audited different time periods depending on the availability of records and the duration of local IPC practice (Table 1). Relevant data about each case were extracted from the individual patient medical records.

Table Graphic Jump Location
TABLE 1 ]  Involved Centers, Period of Study, and Ethics Approvals

Symptomatic loculation was defined as the presence of (1) radiograph evidence of residual pleural effusion that failed to evacuate through a patent IPC; (2) breathlessness that was clinically judged to be secondary to the residual effusion; and (3) no clinical, biochemical, or microbiologic evidence of active pleural infection (eg, fever, leukocytosis, raised serum C-reactive protein, and/or pleural fluid that was purulent or cultured positive for bacteria).

All patients with an IPC who developed symptomatic loculation and received at least one dose of a fibrinolytic agent to treat the loculation were included in the study. The attending physician of individual patients determined the indication and suitability for fibrinolytic instillation according to local protocol. All patients were followed up regularly in each center until IPC removal or death.

Patient demographics, treatment details, and outcomes were captured. Clinical outcome data collected included the following:

  • 1. Treatment response following fibrinolysis:

  • • Cumulative volume of pleural fluid drainage at 24 and 72 h after the first dose of fibrinolytic instillation

  • • Subjective response in breathlessness as reported by the patient in his/her medical file

  • • Recurrence of symptomatic loculation

  • • Need for further pleural or surgical interventions, including further fibrinolytic therapy

  • 2. Other outcomes:

  • • Length of the hospital stay from the day of first dose of fibrinolytic instillation to hospital discharge or death

  • • Adverse events including significant pleural bleeding (defined as drop in hematocrit requiring blood transfusion)

Radiologic response was assessed for patients (n = 13) treated at SCGH who had had pre- and posttreatment chest radiographs (CXRs) performed (within 72 h of initiation of fibrinolytics). A posttreatment CXR was not performed routinely in other centers. Two independent investigators quantified changes on digital CXRs using a previously validated method.12 The area of pleural opacity caused by pleural effusion, expressed as a percentage of the ipsilateral hemithorax, was measured on the pretreatment and posttreatment CXRs.

Statistical analyses were performed using computer software (SigmaPlot 11.0; Systat Software). The data were tested for normality using the Shapiro-Wilk test. Results were expressed as mean (SD) if normally distributed and as median (interquartile range [IQR]) if not. The Mann-Whitney rank sum test was used to compare pleural fluid drainage before and after fibrinolytic treatment. The CXR effusion size before and after treatment was compared using a paired t test. Statistical significance was defined as P < .05.

Demographics

One hundred sixty-five patients at SCGH, 105 at SMH, 220 at JHH, and an estimated 1,200 patients at the University of Calgary underwent IPC insertion for the management of recurrent pleural effusions during the study period. A total of 66 patients (52% women) with a mean age of 64.7 (14.2) years fulfilled the inclusion criteria. Most patients (n = 64) had an MPE: 13 (20.3%) from malignant pleural mesothelioma, 20 (31%) from lung carcinoma, and the remainder from pleural metastases of extrathoracic malignancies. Most patients (79%) had received prior chemotherapy, and 37% had radiotherapy. Nonexpandable lung was present on prior chest imaging in 32 of the 62 patients (52%). Of the 51 patients who had previous pleural fluid cultures performed, nine (18%) had bacterial colonization (eight grew coagulase-negative Staphylococcus); none had clinical evidence of active pleural infection.

Setting of Intervention

The median time from IPC insertion to first fibrinolytic treatment dose was 58 days (IQR, 28-100 days; range, 0-600 days). A fibrinolytic agent was administered in 40 patients (61%) in an outpatient setting at two centers (SMH and Calgary). These patients received a single instillation of the fibrinolytic agent via IPC in the outpatient clinic and were discharged home after a brief period of observation. Subsequent IPC drainage was performed either in clinic or in the community. Fibrinolysis was performed solely as inpatient therapy in the remaining centers (SCGH and JHH). In the inpatient group, the median time of hospitalization from day of first fibrinolytic dose to discharge was 2 days (IQR, 1-4 days; range 0-11 days).

Fibrinolytic Agent Used

There was significant variability, both within and among individual centers, in the selection of fibrinolytic agents and the dose regimen used. The agents used included tissue-plasminogen activator (tPA) at empirical doses ranging from 4 to 10 mg (n = 52), urokinase 100,000 International Units (n = 12), and streptokinase 250,000 International Units (n = 2). The majority of cases (69.7%) received only a single dose of the fibrinolytic agent (range, one to six doses).

Treatment Outcomes
Drainage:

Intrapleural instillation of fibrinolytics increased the volume of pleural fluid drained in most patients (56 of 60; 93.3%). The cumulative pleural fluid volume drained increased from a median of 0 mL (IQR, 0-50 mL) at baseline to 500 mL (300-1,034 mL) at 24 h (n = 56) (P < .001) and to 900 mL (600-1,825 mL) at 72 h (n = 44) (Fig 1).

Figure Jump LinkFigure 1 –  Pleural fluid drained after fibrinolytic therapy. IQR = interquartile range.Grahic Jump Location
Symptomatic Improvement:

Of the 48 patients with a recorded symptomatic response, 40 (83%) had improvement in breathlessness following therapy. No patient reported worsening of breathlessness following therapy.

Radiographic Change:

In patients with available pre- and postfibrinolytic therapy CXRs (n = 13), the area of pleural opacity caused by effusion (expressed as a percentage of the hemithorax) improved significantly from a mean 52% (SD, 14) at baseline to 31% (SD, 21) within 72 h (P = .001) (Fig 2).

Figure Jump LinkFigure 2 –  Change in effusion size on chest radiograph.Grahic Jump Location
Adverse Events:

There were no episodes of extrathoracic bleeding or other systemic reactions. There were two cases (3%) of significant, but nonfatal, pleural bleeding. Neither patient appeared to have medical comorbidities or was receiving drugs that could have increased their bleeding risks; they had normal coagulation profiles and platelet levels. Case 1 patient had solid pleural metastases from renal cell carcinoma and developed a symptomatic hemoglobin drop (of 48 g/L) 2 days after fibrinolytic treatment. Case 2 patient had metastatic breast carcinoma and developed a significant fall in hemoglobin (of 60 g/L) 3 days after therapy. Both remained hemodynamically stable and responded to supportive management and packed RBC transfusions (6 units over 4 days for case 1 patient; 4 units for case 2 patient). Neither case required invasive radiologic or surgical interventions.

Recurrence of Symptomatic Loculations:

Symptomatic loculations recurred in 27 patients (40.9%) at a median of 13 days (range, 2-69 days) following therapy. Of these, 10 received repeat fibrinolytic therapy and three had a second IPC inserted. Only one patient had a sustained improvement in drainage and symptoms following the second dose of fibrinolytic therapy.

Mortality:

Mortality at 30 and 90 days after fibrinolytic therapy was 20% and 54.5%, respectively. All deaths were attributed to progression of underlying malignancy. No death was attributed directly to fibrinolytic therapy.

Symptomatic pleural loculation is increasingly recognized as a relatively frequent complication of IPC use.3,5 Fibrinolytic agents have been used in many centers to break down pleural loculations in the hope of reestablishing IPC fluid drainage, without the support of quality evidence or clear guidelines. To our knowledge, this multicenter observational study from four established IPC centers is the first to describe the clinical outcome of intrapleural fibrinolytics for IPC-related symptomatic loculations. It confirms significant heterogeneity in current practice (eg, choice of agent, timing, and dose), reveals potential benefits and harm, and highlights the need for quality research on the use of intrapleural fibrinolytics for this indication.

The increased use of IPCs worldwide has enabled the assessment of long-term safety and potential complications, with recent studies focusing on IPC-associated pleural infection14 and catheter tract metastases.6 Symptomatic loculation, another well-recognized complication,3,5 may develop as a result of the increased procoagulant and decreased fibrinolytic activity in malignant pleural diseases that leads to excessive fibrin formation and pleural septations.15 Repetitive pleural irritation by the indwelling catheter may also act as a local trigger for fibrin deposition. One of the largest published series, by Tremblay and Michaud,5 reported an incidence of 8.4% (n = 21) in 250 patients with IPCs, whereas a smaller series reported an incidence of 13.5% (n = 5) in 34 patients with IPCs.3

When symptomatic loculations develop despite a patent IPC, the primary aim of palliating breathlessness becomes difficult. Often, these patients have limited options. Many have to undergo further invasive procedures (pleural aspirations or removal of the ineffective IPC and/or replacement by another IPC or chest drain) or are restricted to pharmacologic palliation of their breathlessness. The related hospitalizations, as well as the increased risks and costs of additional procedures, could be reduced if pleural drainage via the IPC could be reestablished successfully by breaking down the pleural loculations.

Fibrinolytic agents have been used to break down pleural loculations primarily in the setting of pleural infection.911,16 However, several small series (involving six to 24 cases)13,1720 have also described the use of intrapleural fibrinolysis for the management of loculated malignant effusions (although not in the setting of IPCs). Most of these studies reported that fibrinolytics increased fluid drainage and improved radiologic appearance. Intrapleural fibrinolytics have, therefore, been used empirically to treat IPC-related loculations. Intrapleural DNase, when combined with tPA, has been shown to provide additional benefits in pleural infection.12 The role of combination intrapleural tPA-DNase instilled through small-bore chest drains for patients with loculated MPEs is the subject of an upcoming clinical trial.21

The various study sites involved in this series used different fibrinolytic agents, at different dosages, with variable instillation frequency, in both inpatient and outpatient settings, and without consistent predefined patient selection criteria. This heterogeneity reflects the lack of data, paucity of experience, and absence of specific guidelines regarding the use of fibrinolytics for this particular indication.

Data from our series suggested that fibrinolytics may play a role in IPC-related symptomatic loculations. It provided subjective improvement in symptoms, paralleled by an objective increase in the pleural fluid drainage and significant reductions in the radiographic pleural opacity in the majority of patients. However, the duration of benefits varied; in 40% of patients, fibrinolytics provided only short-term relief before the loculations recurred. The reasons for early failure in some patients remain unclear but may be related to host factors (eg, malignancy type), IPC (eg, inflammatory reaction to IPC material), or therapy (eg, dose or frequency of fibrinolytic instillation). It is currently unknown if the presence of a trapped lung predisposes to the development of loculations.

Despite recurrence of loculations in some patients, the short-term benefits from fibrinolytics may be considered worthwhile in the setting of advanced cancers and short expected survival, because palliation of symptoms is the primary aim. Fibrinolytic therapy can also be repeated for recurrent symptomatic loculation; however, the efficacy of this approach needs further evaluation.

Avoiding recurrent or prolonged hospitalizations is an important outcome in patients with malignancy and is considered one of the major benefits of an IPC.3 In this study, the majority of patients (61%) received therapy as outpatients. Even those who were treated as inpatients mostly required only brief admissions (median, 2 days).

Previous studies have attempted to assess the risk of bleeding following intrapleural fibrinolytic instillation. Intrapleural streptokinase has been shown not to activate systemic fibrinolysis in patients with empyema.22 Large clinical studies of fibrinolytic therapy for pleural infection have shown a low incidence of major bleeding. In the Multi-Center Intra-pleural Sepsis Trial (MIST)-1 study,11 seven of 208 patients who were given intrapleural streptokinase developed systemic or pleural bleeding, whereas in the MIST-2 study,12 tPA, when used in combination with DNase, caused bleeding in three of 52 cases. The risk of systemic absorption of fibrinolytics may be further reduced in patients with a pleural malignancy because of their abnormal pleural surfaces and reduced lymphatic drainage.20

Pleural bleeding requiring blood transfusions occurred in two patients in our study. No additional invasive intervention was required in either case, and both made a full recovery. Nonetheless, there are no easily identifiable features to predict pleural bleeding; hence, caution is needed until the risk factors of hemorrhage, and its best management, are defined.

This study has provided useful information to add to the literature. However, it must be interpreted with its many limitations. In our series, fibrinolytic therapy was performed in approximately 4% of all patients with IPCs (66 of a total estimated 1,690 IPC cases), much less than the reported incidence of IPC-related symptomatic loculation (up to 14%). This could reflect underreporting of true cases because of the retrospective nature of the study, selection bias from the likely exclusion of patients with contraindications to intrapleural fibrinolytics, or both. The risks of development of symptomatic loculation and factors that predict response to fibrinolytic therapy could also not be evaluated. The four centers have significant experience in pleural medicine, including IPC management. Whether the finding can be extrapolated to other centers requires validation. Nevertheless, we believe this study remains the first to describe the use of and response to intrapleural fibrinolysis in IPC-related symptomatic loculation.

Intrapleural fibrinolytic therapy can improve pleural drainage and symptoms in selected patients with IPC and symptomatic loculation but it carries a small risk of pleural bleeding. There is significant heterogeneity in how intrapleural fibrinolytics are currently used for IPC-related symptomatic loculation. This therapeutic option needs to be explored further to aid patient selection, determine the optimal dosing regimen, and define its safety profile.

Author contributions: Y. C. G. L. is the guarantor of this manuscript. R. T. and Y. C. G. L. contributed to the conception and design of the study; R. T., F. P., and T. H. contributed to the imaging analyses; R. T., F. P., and Y. C. G. L. contributed to the statistical analyses; and R. T., F. P., D. M., P. R. M., A. C. C., T. H., L. Y., R. B., H. J. L., D. F.-K., N. A. M., A. T., and Y. C. G. L. contributed to the pleural data collection and manuscript drafting, revision, and final approval.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Yarmus has received research grant support from Rocket Medical. Dr Feller-Kopman has served on the advisory board of CareFusion. Drs Maskell and Y. C. G. Lee were coinvestigators of the TIME-2 trial for which Rocket Medical plc provided the indwelling catheters and supplies without charge. They have served on the advisory board of CareFusion and Sequana Medical. Dr Maskell has received unrestricted research grants from CareFusion to run the IPC-Plus and Reduce trials. Dr Tremblay holds intellectual property concerning the treatment of malignant pleural diseases, which has been licensed to CareFusion. He serves as a consultant to CareFusion. Drs Thomas, Piccolo, Miller, MacEachern, Chee, Huseini, Bhatnagar, and H. J. Lee have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

CXR

chest radiograph

DNase

deoxyribonuclease

IPC

indwelling pleural catheter

IQR

interquartile range

JHH

Johns Hopkins Hospital

MPE

malignant pleural effusion

SCGH

Sir Charles Gairdner Hospital

SMH

Southmead Hospital

tPA

tissue-plasminogen activator

Lee YC, Light RW. Management of malignant pleural effusions. Respirology. 2004;9(2):148-156. [CrossRef] [PubMed]
 
Davies HE, Mishra EK, Kahan BC, et al. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA. 2012;307(22):2383-2389. [CrossRef] [PubMed]
 
Fysh ET, Waterer GW, Kendall PA, et al. Indwelling pleural catheters reduce inpatient days over pleurodesis for malignant pleural effusion. Chest. 2012;142(2):394-400. [CrossRef] [PubMed]
 
Putnam JB Jr, Light RW, Rodriguez RM, et al. A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions. Cancer. 1999;86(10):1992-1999. [CrossRef] [PubMed]
 
Tremblay A, Michaud G. Single-center experience with 250 tunnelled pleural catheter insertions for malignant pleural effusion. Chest. 2006;129(2):362-368. [CrossRef] [PubMed]
 
Thomas R, Budgeon CA, Kuok YJ, et al. Catheter tract metastasis associated with indwelling pleural catheters. Chest. 2014;146(3):557-562. [CrossRef] [PubMed]
 
Van Meter ME, McKee KY, Kohlwes RJ. Efficacy and safety of tunneled pleural catheters in adults with malignant pleural effusions: a systematic review. J Gen Intern Med. 2011;26(1):70-76. [CrossRef] [PubMed]
 
Chee A, Tremblay A. The use of tunneled pleural catheters in the treatment of pleural effusions. Curr Opin Pulm Med. 2011;17(4):237-241. [CrossRef] [PubMed]
 
Bouros D, Schiza S, Patsourakis G, Chalkiadakis G, Panagou P, Siafakas NM. Intrapleural streptokinase versus urokinase in the treatment of complicated parapneumonic effusions: a prospective, double-blind study. Am J Respir Crit Care Med. 1997;155(1):291-295. [CrossRef] [PubMed]
 
Bouros D, Schiza S, Tzanakis N, Chalkiadakis G, Drositis J, Siafakas N. Intrapleural urokinase versus normal saline in the treatment of complicated parapneumonic effusions and empyema. A randomized, double-blind study. Am J Respir Crit Care Med. 1999;159(1):37-42. [CrossRef] [PubMed]
 
Maskell NA, Davies CW, Nunn AJ, et al; First Multicenter Intrapleural Sepsis Trial (MIST1) Group. UK Controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med. 2005;352(9):865-874. [CrossRef] [PubMed]
 
Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011;365(6):518-526. [CrossRef] [PubMed]
 
Thommi G, Nair CK, Aronow WS, Shehan C, Meyers P, McLeay M. Efficacy and safety of intrapleural instillation of alteplase in the management of complicated pleural effusion or empyema. Am J Ther. 2007;14(4):341-345. [CrossRef] [PubMed]
 
Fysh ET, Tremblay A, Feller-Kopman D, et al. Clinical outcomes of indwelling pleural catheter-related pleural infections: an international multicenter study. Chest. 2013;144(5):1597-1602. [CrossRef] [PubMed]
 
Idell S, Girard W, Koenig KB, McLarty J, Fair DS. Abnormalities of pathways of fibrin turnover in the human pleural space. Am Rev Respir Dis. 1991;144(1):187-194. [CrossRef] [PubMed]
 
Thommi G, Shehan JC, Robison KL, Christensen M, Backemeyer LA, McLeay MT. A double blind randomized cross over trial comparing rate of decortication and efficacy of intrapleural instillation of alteplase vs placebo in patients with empyemas and complicated parapneumonic effusions. Respir Med. 2012;106(5):716-723. [CrossRef] [PubMed]
 
Hsu LH, Soong TC, Feng AC, Liu MC. Intrapleural urokinase for the treatment of loculated malignant pleural effusions and trapped lungs in medically inoperable cancer patients. J Thorac Oncol. 2006;1(5):460-467. [CrossRef] [PubMed]
 
Ben-Or S, Feins RH, Veeramachaneni NK, Haithcock BE. Effectiveness and risks associated with intrapleural alteplase by means of tube thoracostomy. Ann Thorac Surg. 2011;91(3):860-863. [CrossRef] [PubMed]
 
Okur E, Baysungur V, Tezel C, Ergene G, Okur HK, Halezeroglu S. Streptokinase for malignant pleural effusions: a randomized controlled study. Asian Cardiovasc Thorac Ann. 2011;19(3-4):238-243. [CrossRef] [PubMed]
 
Davies CW, Traill ZC, Gleeson FV, Davies RJ. Intrapleural streptokinase in the management of malignant multiloculated pleural effusions. Chest. 1999;115(3):729-733. [CrossRef] [PubMed]
 
Standiford SB. Combination tissue plasminogen activator (tPA) and dornase alfa (DNase) administration through intrapleural catheters for the treatment of loculated or non-draining malignant pleural effusions. NCT02135588. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2014. https://clinicaltrials.gov/ct2/show/NCT02135588. Updated May 26, 2015.
 
Davies CW, Lok S, Davies RJ. The systemic fibrinolytic activity of intrapleural streptokinase. Am J Respir Crit Care Med. 1998;157(1):328-330. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Pleural fluid drained after fibrinolytic therapy. IQR = interquartile range.Grahic Jump Location
Figure Jump LinkFigure 2 –  Change in effusion size on chest radiograph.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Involved Centers, Period of Study, and Ethics Approvals

References

Lee YC, Light RW. Management of malignant pleural effusions. Respirology. 2004;9(2):148-156. [CrossRef] [PubMed]
 
Davies HE, Mishra EK, Kahan BC, et al. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA. 2012;307(22):2383-2389. [CrossRef] [PubMed]
 
Fysh ET, Waterer GW, Kendall PA, et al. Indwelling pleural catheters reduce inpatient days over pleurodesis for malignant pleural effusion. Chest. 2012;142(2):394-400. [CrossRef] [PubMed]
 
Putnam JB Jr, Light RW, Rodriguez RM, et al. A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions. Cancer. 1999;86(10):1992-1999. [CrossRef] [PubMed]
 
Tremblay A, Michaud G. Single-center experience with 250 tunnelled pleural catheter insertions for malignant pleural effusion. Chest. 2006;129(2):362-368. [CrossRef] [PubMed]
 
Thomas R, Budgeon CA, Kuok YJ, et al. Catheter tract metastasis associated with indwelling pleural catheters. Chest. 2014;146(3):557-562. [CrossRef] [PubMed]
 
Van Meter ME, McKee KY, Kohlwes RJ. Efficacy and safety of tunneled pleural catheters in adults with malignant pleural effusions: a systematic review. J Gen Intern Med. 2011;26(1):70-76. [CrossRef] [PubMed]
 
Chee A, Tremblay A. The use of tunneled pleural catheters in the treatment of pleural effusions. Curr Opin Pulm Med. 2011;17(4):237-241. [CrossRef] [PubMed]
 
Bouros D, Schiza S, Patsourakis G, Chalkiadakis G, Panagou P, Siafakas NM. Intrapleural streptokinase versus urokinase in the treatment of complicated parapneumonic effusions: a prospective, double-blind study. Am J Respir Crit Care Med. 1997;155(1):291-295. [CrossRef] [PubMed]
 
Bouros D, Schiza S, Tzanakis N, Chalkiadakis G, Drositis J, Siafakas N. Intrapleural urokinase versus normal saline in the treatment of complicated parapneumonic effusions and empyema. A randomized, double-blind study. Am J Respir Crit Care Med. 1999;159(1):37-42. [CrossRef] [PubMed]
 
Maskell NA, Davies CW, Nunn AJ, et al; First Multicenter Intrapleural Sepsis Trial (MIST1) Group. UK Controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med. 2005;352(9):865-874. [CrossRef] [PubMed]
 
Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011;365(6):518-526. [CrossRef] [PubMed]
 
Thommi G, Nair CK, Aronow WS, Shehan C, Meyers P, McLeay M. Efficacy and safety of intrapleural instillation of alteplase in the management of complicated pleural effusion or empyema. Am J Ther. 2007;14(4):341-345. [CrossRef] [PubMed]
 
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