Effectiveness and Risks Associated With Intrapleural Alteplase by Means of Tube Thoracostomy

Transcription

1 Effectiveness and Risks Associated With Intrapleural Alteplase by Means of Tube Thoracostomy Sharon Ben-Or, MD, Richard H. Feins, MD, Nirmal K. Veeramachaneni, MD, and Benjamin E. Haithcock, MD Division of Cardiothoracic Surgery, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Background. The use of fibrinolytics has been described for the treatment of complex pleural processes. This has evolved from streptokinase to urokinase to alteplase. Intrapleural fibrinolysis has added an alternative to surgical intervention in patients with complex pleural processes. This study describes the use of alteplase as an alternative to surgical intervention for these processes. Methods. From December 2004 to March 2009, 118 patients required alteplase for complex pleural processes. The type of tube thoracostomy, pleural process, antithrombotic type, international normalized ratio, prothrombin time, partial thromboplastin time, platelets, doses, and outcomes were reviewed for each patient. Complications and the need for additional interventions were evaluated. Results. Patients received one to eight doses of intrapleural alteplase through a tube thoracostomy. Indications for intrapleural alteplase were empyema (n 32; 27.1%), loculated pleural effusion (n 44; 37.3%), hemothorax (n 13; 11.0%), parapneumonic effusion (n 25; 21.2%), and malignant effusion (n 6; 5.1%). The success rate was 86.4% (102 of 118 patients). The incidence of bleeding was 8.5% (n 10). Binary analysis did not demonstrate an increase in bleeding with abnormal coagulation variables. Of the patients with a bleeding complication, 7 required operative interventions. Twenty (16.9%) required a second tube thoracostomy for incomplete evacuation of the pleural process. Nine (7.6%) required an operative intervention for incomplete evacuation of the pleural process. Conclusions. Intrapleural alteplase appears to be effective in treating complex parapneumonic processes. Systemic anticoagulation, prothrombin time, partial thromboplastin time, international normalized ratio, and platelet count do not appear to be risk factors for bleeding complications. One or two doses of alteplase appear most successful. (Ann Thorac Surg 2011;91:860 4) 2011 by The Society of Thoracic Surgeons The management of complex pleural processes is both difficult and controversial. Etiologies include hemothorax, empyema, loculated pleural effusion, malignant effusion, and parapneumonic effusion. Treatment for this disease process has traditionally been surgical to avoid the complication of fibrothorax resulting in pulmonary compromise. The advent of video-assisted thoracoscopic surgery (VATS) in the 1990s has provided a less morbid approach to open evacuation of complex pleural processes. Yet, the risk of conversion to an open procedure carries significant morbidity and mortality. The morbidity of open surgical decortication versus VATS decortication has been reported as 25% and 18%, respectively [1]. The use of fibrinolytics in the treatment of complex pleural processes was initially described 60 years ago by Accepted for publication Oct 29, Presented at the Fifty-sixth Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 4 7, Address correspondence to Dr Haithcock, Division of Cardiothoracic Surgery, University of North Carolina School of Medicine, 3040 Burnett- Womack Bldg, CB #7065, Chapel Hill, NC ; benjamin_haithcock@med.unc.edu. Tillett and colleagues [2] with the introduction of streptokinase. Since then, fibrinolysis by means of streptokinase has been challenging as a result of the development of antibodies as well as the development of delayed hypersensitivity reaction. It has been challenged by a large, randomized, double-blind study demonstrating no improvement in mortality, length of stay, or need for further intervention among individuals with pleural infections. However, the authors stated that there was a role for fibrinolytics in certain patients [3]. Urokinase was introduced to alleviate those issues seen with streptokinase, but it was taken off the market by the US Food and Drug Administration because of the risk of viral transmission [4]. This evolved into the development of alteplase [5]. The use of intrapleural alteplase has been documented in the adult [6 12] and pediatric [13 17] literature. These studies consist of a small sample of patients with no consensus on dosing regimen. Although complications have been described, no formal analysis has been reported on risk factors for complication as well as the need for further intervention. This study aims to describe the 2011 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg BEN-OR ET AL 2011;91:860 4 INTRAPLEURAL ALTEPLASE 861 Table 1. Successful Treatment for Each Dose Patients No. of Doses Bleeding use of alteplase at a tertiary referral center and to describe the complications associated with this treatment. Patients and Methods A search of the pharmacy database from the University of North Carolina at Chapel Hill for dispensed alteplase from December 2004 until March 2009 was performed, and a retrospective review of the medical records was conducted. All patients who received intrapleural alteplase were included in this study. Approval for this study was obtained by the University of North Carolina at Chapel Hill s institutional review board, and individual patient consent was waived. Complications were defined as the need for further intervention or bleeding. Bleeding was defined by hemoptysis, a decrease in hematocrit, need for blood transfusion after administration of alteplase, or increased sanguinous output from the tube thoracostomy. Success was defined as improvement in chest radiographs. Data are presented as frequency, median with range, or mean standard deviation as deemed appropriate. Categorical variables between groups were analyzed by Pearson s 2 test, one-tail test, or logistic regression. A probability value less than 0.05 was considered statistically significant. All data analysis was performed using SAS version 9.2 software (SAS Institute, Cary, NC). Results Between December 2004 and March 2009, 118 patients received intrapleural alteplase to treat a variety of pleural processes. These patients received between one and eight doses of 25 mg of alteplase in 120 ml of normal saline solution through a tube thoracostomy placed either at the bedside or under image guidance. After administration of alteplase, the tube was clamped for 2 hours while the patient was moved from the supine to right and left lateral decubitus positions. Seventy-eight (66.1%) patients were male, with an average age of years (range, 2 to 88 years). Indications for treatment were determined by chest radiographs and, when necessary, thoracentesis. The indications for intrapleural alteplase included empyema (n 32; 27.1%), complex pleural effusion (n 42; 35.6%), hemothorax (n 13; 11.0%), parapneumonic effusion (n 25; 23.7%), and malignant effusion (n 6; 5.1%). Alteplase was administered through a chest tube (n 88; 74.6%), a pigtail catheter placed by interventional radiology (n 24; 20.3%), or an indwelling pleural catheter (n 6; 5.1%). Of the 118 patients, 83 (69.5%) were successfully treated with alteplase with self-limiting bleeding occurring in 3 of these patients (Table 1). Thirty-five patients were unsuccessfully treated with alteplase. Seven of these patients experienced bleeding, all of whom required operative intervention: 3 required VATS and 4 required a thoracotomy. One patient was found to have diffuse areas of bleeding secondary to coagulopathy, with the remainder having discrete sources of bleeding including tumor bed, abscess cavity, chest tube site, and lung injury from the chest tube. Twenty-nine patients had residual pleural processes, with 19 requiring additional tube thoracostomy and 9 requiring surgical intervention. Of these 9 patients, 4 underwent VATS and 5 underwent a thoracotomy and were found to have retained hemothorax, development of thick fibrous peel resulting in lung entrapment, and multiloculated effusion. Risk factors for bleeding were analyzed and summarized in Table 2. Patients received an average of doses (Fig 1). Binary analysis did not demonstrate increased bleeding in patients with abnormal international normalized ratio, prothrombin time, partial thromboplastin time, or platelets or an increased risk of bleeding with systemic anticoagulation. Similarly, univariate logistic regression analysis did not demonstrate a relationship between the number of doses with bleeding risk, with an odds ratio of 0.20 (p 0.34). Intrapleural alteplase was successful in 78.1% (25 of 32 patients) of patients with empyemas, 61.5% (8 of 13 patients) of patients with hemothoraces, 100% (8 of 8 patients) of patients with malignancy as a cause to the pleural process, 71.4% (30 of 42 patients) of complex pleural effusions, and 48% (12 of 25 patients) of parapneumonic effusions. Of the patients who experienced a bleeding complication, this occurred in 6.3% (2 of 32 patients) of patients with an empyema, 12.5% (1 of 8 patients) of patients with malignancy as a cause to the pleural process, 4.8% (2 of 32 patients) of patients with a complex Table 2. Risk Factors for Bleeding INR ( ) PT ( ) PTT ( ) Platelets ( ) Antithrombotics None 50 (42.4%) Subcutaneous heparin 30 (25.4%) Aspirin 7 (5.9%) Enoxaparin 6 (5.1%) Unknown 5 (4.2%) Aspirin/clopidogrel 4 (3.4%) Heparin infusion 4 (3.4%) Other 11 (9.3%) INR international normalized ratio; PTT partial thromboplastin time. PT prothrombin time;

3 862 BEN-OR ET AL Ann Thorac Surg INTRAPLEURAL ALTEPLASE 2011;91:860 4 Fig 1. Distribution of total number of doses. pleural effusion, and 8.0% (2 of 25 patients) of patients with a parapneumonic effusion. Complications occurred in 32.0% (8 of 25 patients) of parapneumonic effusions, 16.7% (7 of 32 patients) of empyemas, 16.7% (7 of 42 patients) of complex pleural effusions, 16.7% (1 of 6 patients) of malignancies, and 0% of hemothoraces. Operative intervention occurred in 20.0% (5 of 25 patients) of parapneumonic effusions, 12.5% (4 of 32 patients) of empyemas, 7.1% (3 of 42 patients) of complex pleural effusions, 0% of malignancies, and 30.8% (4 of 13 patients) of hemothoraces. Pearson s 2 analysis was performed on diagnosis and incidence of complications as well as on diagnosis and incidence of operative intervention, and these relationships were not statistically significant. Comment The management of complex pleural processes has traditionally been surgical. With the advent of fibrinolytic agents, treatment has evolved away from surgery. The use of streptokinase was challenged by a large, doubleblind, randomized trial showing no change in morbidity and mortality among individuals with pleural infections. However, the authors recognized a role for intrapleural fibrinolysis in select patients [5]. Furthermore, the use of streptokinase lost popularity with the observation of delayed hypersensitivity reactions in patients as well as antibody formation, leading to the use of urokinase, which evolved into the use of alteplase. Comparison of intrapleural alteplase with tube thoracostomy alone for complex pleural processes has been demonstrated to be more efficacious with improvement in chest radiograph results, white blood cell count, and C-reactive protein [6, 7]. Moreover, tube thoracostomy duration has been shown to be shorter when comparing alteplase with tube thoracostomy alone [17]. Only one randomized controlled trial exists to date comparing VATS with tube thoracostomy with alteplase infusion. This study by St. Peter and associates [18] was composed of only 36 pediatric patients. Results revealed no difference in length of stay, oxygen requirement, days until afebrile, and analgesic requirements. They did demonstrate a significantly higher procedural charge in the surgical arm [18]. The current study is the largest study to date to evaluate the effectiveness and risk factors for complications with the administration of intrapleural alteplase. The risk of bleeding has been documented in the literature, with it mainly being anecdotal or as a reported complication [8, 9]. A study from Massachusetts General Hospital noted a statistically significant increased risk of bleeding in fully anticoagulated patients [10]. Our study, however, shows that anticoagulants, international normalized ratio, prothrombin time, partial thromboplastin time, platelet number, and dosages had no influence on bleeding risk. In summary, a total of 102 of 118 patients were completely treated alone or with a second tube thoracostomy. Seven of the 10 patients who experienced bleeding required an operative intervention. The overall effectiveness of alteplase was 86.4%, with the greatest success rate at one and two doses. Patients who had more than two doses were more likely to have residual disease, which suggests that after two doses, operative intervention should be considered. Our study has several limitations. The initial diagnosis and success was determined through chest radiograph. There was not a uniform process of determining which patient required what intervention; it was based on the clinicians interpretation of the data. The sample size is small, and fewer patients received higher doses. This is also a retrospective observational study lacking a control group. Although this study demonstrated that international normalized ratio, prothrombin time, partial thromboplastin time, platelets, dosing, and anticoagulants had no relationship with bleeding complications, analysis of hepatic function and of fully anticoagulated patients was not performed. This study relies on documentation of anticoagulants, complications, and indications for administration of alteplase. Furthermore, no standardized imaging variables were performed to ascertain the patients response to treatment. Finally, surgical intervention was at the discretion of the surgeon, allowing for a selection bias. The optimal management of various pleural processes remains controversial, with treatment ranging from tube thoracostomy alone to infusion of intrapleural alteplase to surgical intervention. This retrospective study suggests that intrapleural alteplase is safe to use regardless of bleeding risk factors that exist. A multicenter randomized study to further elicit a safety and efficacy profile as well as optimal timing of infusion is warranted to facilitate the treatment of this common clinical quandary. We thank Chris Wiesen, PhD, for his assistance in the statistical analysis of the data for this manuscript.

4 Ann Thorac Surg BEN-OR ET AL 2011;91:860 4 INTRAPLEURAL ALTEPLASE 863 References 1. Cardillo G, Carleo F, Carbone L, et al. Chronic postpneumonic pleural empyema: comparative merits of thoracoscopic versus open decortication. Eur J Cardiothorac Surg 2009;36: Tillett WS, Sherry S. The effect in patients of streptococcal fibrinolysin (streptokinase) and streptococcal desoxyribonuclease on fibrinous, purulent, and sanguinous pleural exudations. J Clin Invest 1949;28: Maskell NA, Davies CW, Nunn AJ, et al. U.K. controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med 2005;352: Moulton JS, Benkert RE, Weisiger K, Chambers JA. Treatment of complicated pleural fluid collections with imageguided drainage and intracavitary urokinase. Chest 1995; 108: Thommi G, Shehan C, Bell A, Coughlin N, Mcleay M. Intrapleural instillation of TPA in the management of complicated pleural effusions [Abstract]. Chest 2000;118(Suppl 4): S Skeete DA, Rutherford EJ, Schlidt SA, Abrams JE, Parker LA, Rich PB. Intrapleural tissue plasminogen activator for complicated pleural effusions. J Trauma 2004;57: Froudarakis ME, Kouliatsis G, Steiropoulos P, et al. Recombinant tissue plasminogen activator in the treatment of pleural infections in adults. Respir Med 2008;102: Walker CA, Shirk MB, Tschampel MM, Visconti JA. Intrapleural alteplase in a patient with complicated pleural effusion. Ann Pharmacother 2003;37: 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: Gervais DA, Levis DA, Hahn PF, Uppot RN, Arellano RS, Mueller PR. Adjunctive intrapleural tissue plasminogen activator administered via chest tubes placed with imaging guidance: effectiveness and risk for hemorrhage. Radiology 2008;246: Levinson GM, Pennington DW. Intrapleural fibrinolytics combined with image-guided chest tube drainage for pleural infection. Mayo Clin Proc 2007;82: Ruiz A, Porcel JM, Madroñero AB, Galindo C. Hemothorax following administration of intrapleural alteplase. Respiration 2006;73: Ray TL, Berkenbosch JW, Russo P, Tobias JD. Tissue plasminogen activator as an adjuvant therapy for pleural empyema in pediatric patients. J Intensive Care Med 2004;19: Bishop NB, Pon S, Ushay HM, Greenwald BM. Alteplase in the treatment of complicated parapneumonic effusion: a case report. Pediatrics 2003;111:E Wells RG, Havens PL. Intrapleural fibrinolysis for parapneumonic effusion and empyema in children. Radiology 2003; 228: Feola GP, Shaw CA, Coburn L. Management of complicated parapneumonic effusions in children. Tech Vasc Interv Radiol 2003;6: Weinstein M, Restrepo R, Chait PG, Connolly B, Temple M, Macarthur C. Effectiveness and safety of tissue plasminogen activator in the management of complicated parapneumonic effusions. Pediatrics 2004;113:e St Peter SD, Tsao K, Spilde TL, et al. Thoracoscopic decortication vs tube thoracostomy with fibrinolysis for empyema in children: a prospective, randomized trial. J Pediatr Surg 2009;44: DISCUSSION DR CHRISTINE LAU (Charlottesville, VA): I would first like to congratulate Dr Ben-Or and her colleagues at the University of North Carolina at Chapel Hill for an excellent presentation, and I would like to thank you for kindly providing me a copy of your manuscript in advance. Your paper is a case series of 118 patients who underwent alteplase via various types of tubes for complex pleural processes. As you noted, the study is limited because there were not inclusion criteria for the decision to give alteplase and it was based on surgeon choice. Almost 70% of your patients were successfully treated with alteplase, and 30% required additional treatment procedures, although only 16 patients in your series eventually required any type of operation; 7 of these were for bleeding after alteplase and 9 for their initial disease. You state bleeding from alteplase was not increased in patients at higher risk, such as those with increased INR (international normalized ratio), increased PT (prothrombin time), or systematically anticoagulated. I think it would be nice if you could add additional data such as length of stay, morbidity, mortality, cost of alteplase, type of chest tube use that was successful, as well as CT (computed tomographic) scan suggestive of which type preoperatively would be successful, and also how do you follow them postoperatively? But today I have two questions. In general, were the patients that you treated successfully partial or were these complete responses? In other words, with the partial responses, were you able to get them through because they were nonoperative candidates or were they complete responses and how did you follow that? And the second question is, your numbers with systemic anticoagulation were quite small, and it is not entirely clear to me what you are trying to say here. Could you clarify that and could you give me a take-home message? Would you feel comfortable using alteplase in somebody who is anticoagulated with Coumadin, for example? DR BEN-OR: Thank you, Dr Lau, for your comments. With respect to how the patients did in terms of complete responses versus partial responses, we continued the treatment until they had a complete response and we were able to assess that with a CAT (computed axial tomographic) scan before discontinuation of the tube. If anyone did not have a complete response, they either received a pigtail or they went to the operating room, and that was determined on how discrete the collection was and how thick it appeared on CAT scan. With respect to systemic anticoagulation, you are correct that we did have a small population of patients who received systemic anticoagulation. My take-home message from looking at all the data is some of the patients were actually burn patients who were on Xigris, and they did not have an increased risk of bleeding, and that is what I did not expect. And we looked at patients who had platelets greater than 50 and less than 50, and actually the patients who were thrombocytopenic had no incidence of bleeding. So my take-home message from that is that it is safe for patients who are systemically anticoagulated. DR RODNEY LANDRENEAU (Pittsburgh, PA): One thing, I know we reviewed a paper from your institution authored, I believe, from the pulmonary/critical care physicians from your institution from a year or so ago, and those investigators in their paper said it was almost a 100% success rate with this therapy. They had a wide variance in the doses of agent used, and I am

5 864 BEN-OR ET AL Ann Thorac Surg INTRAPLEURAL ALTEPLASE 2011;91:860 4 just wondering, is this report an extension of the same group of patients or is this the surgical team s efforts you report here? DR BEN-OR: These probably include the same group of patients as well as the surgical team s efforts. DR LANDRENEAU: We were very surprised when we reviewed this at our journal club that they had such tremendous success with it. I don t know, Rick, what are you all doing? DR RICHARD H. FEINS (Chapel Hill, NC): Well, we don t have a 100% success rate. I think one of the messages that really didn t come through as strongly as it should but I think is important is when I was in Rochester this rarely worked, and I came to UNC with that bias. However it has worked at UNC, and it works well. I think it works because it is under the management of the surgeons, and we know when to stop, and we know what a satisfactory result is and what isn t. Plus, we have something we can do about it if it doesn t work. DR LANDRENEAU: This was from your institution. DR FEINS: Which one? Before me. DR LANDRENEAU: You weren t there. DR FEINS: Right. But I am just saying that the success of this, in my opinion, is dependent upon surgeons controlling it. DR DAVID TOM COOKE (Sacramento, CA): Doctor Ben-Or, that was a very good presentation. I have just two questions. One is, did you look at the quality of the patients either ASA or Zubrod score in terms of which patients were actually operative candidates to begin with and what patients weren t, and would that information bias your approach in terms of who gets tpa (tissue plasminogen activator) or who goes to the OR (operating room) for a VATS (video-assisted thoracoscopic surgery) evacuation of their empyema? And the second question is, did all patients get the same size tubes, and if not, did you do a subset analysis of chest tubes, ie, a 24F or a 28F chest tube, versus a 9F pigtail catheter or something like that to see if the chest tube diameter affected the outcomes or the success rate of your patients? DR BEN-OR: I did not look at the quality of our patients; however, at UNC we typically will start with a tube thoracostomy and alteplase in a good majority of our patients before going directly to VATS. There are only a few in my limited time there that we have gone directly to VATS and that is if they seemed overtly septic at the time. As for the tube size, we did not look at the chest tube size. We did look at chest tube versus pigtail, and what was surprising to find, and I excluded this slide because of the fear of incurring the wrath of the audience, was that the patients who had pigtails actually did a lot better than the patients who had chest tubes. DR JOHN A. HOWINGTON (Evanston, IL): How did you come up with the dose of 25 mg? In my former institution at the University of Cincinnati, we had similar results, about a 70% to 80% success rate, but we used 6 mg in 50 of them. We didn t see the double-digit local bleeding problems that you saw. So it may be dose-related. So how did you come up with that dose would be a question? I would collaborate with you on doing a trial, but I would want to do it with a lower dose. Thank you. DR BEN-OR: Thank you. Our pharmacy just dispenses a 25-mg standard for everyone. We have not done anyone with 6 mg. We just had the pharmacy look up alteplase and had 25 mg for everyone.