Management of Malignant Pleural Effusions an Ofﬁcial ATS/STS/STR Clinical Practice Guideline David J

AMERICAN THORACIC SOCIETY DOCUMENTS

Management of Malignant Pleural Effusions An Ofﬁcial ATS/STS/STR Clinical Practice Guideline David J. Feller-Kopman*, Chakravarthy B. Reddy*, Malcolm M. DeCamp, Rebecca L. Diekemper, Michael K. Gould, Travis Henry, Narayan P. Iyer, Y. C. Gary Lee, Sandra Z. Lewis, Nick A. Maskell, Najib M. Rahman, Daniel H. Sterman, Momen M. Wahidi, and Alex A. Balekian; on behalf of the American Thoracic Society, Society of Thoracic Surgeons, and Society of Thoracic Radiology

THIS OFFICIAL CLINICAL PRACTICE GUIDELINE WAS APPROVED BY THE AMERICAN THORACIC SOCIETY OCTOBER 2018, THE SOCIETY OF THORACIC SURGEONS JUNE 2018, AND THE SOCIETY OF THORACIC RADIOLOGY JULY 2018

Background: This Guideline, a collaborative effort from the MPE; 3) using either an indwelling pleural catheter (IPC) or American Thoracic Society, Society of Thoracic Surgeons, and chemical pleurodesis in symptomatic patients with MPE and Society of Thoracic Radiology, aims to provide evidence-based suspected expandable lung; 4) performing large-volume recommendations to guide contemporary management of patients thoracentesis to assess symptomatic response and lung expansion; with a malignant pleural effusion (MPE). 5) using either talc poudrage or talc slurry for chemical pleurodesis; 6) using IPC instead of chemical pleurodesis in patients with Methods: A multidisciplinary panel developed seven questions nonexpandable lung or failed pleurodesis; and 7) treating using the PICO (Population, Intervention, Comparator, and IPC-associated infections with antibiotics and not removing the Outcomes) format. The GRADE (Grading of Recommendations, catheter. Assessment, Development and Evaluation) approach and the Evidence to Decision framework was applied to each question. Recommendations Conclusions: These recommendations, based on the best available were formulated, discussed, and approved by the entire panel. evidence, can guide management of patients with MPE and improve patient outcomes. Results: The panel made weak recommendations in favor of: 1) using ultrasound to guide pleural interventions; 2)not Keywords: pleural effusion; malignant; palliation; pleurodesis; performing pleural interventions in asymptomatic patients with pleural catheter

Contents PICO 2: In Patients with Known PICO 4: In Patients with Methods or Suspected MPE Who Are Symptomatic MPE with Recommendations for Specific Asymptomatic, Should Pleural Known or Suspected Treatment Questions Drainage Be Performed? Expandable Lung and No PICO 1: In Patients with Known PICO 3: Should the Management Prior Definitive Therapy, or Suspected MPE, Should of Patients with Symptomatic Should IPCs or Chemical Thoracic Ultrasound Be Known or Suspected MPE Be Pleurodesis Be Used as Used to Guide Pleural Guided by Large-Volume First-Line Definitive Pleural Interventions? Thoracentesis and Pleural Intervention for Management Manometry? of Dyspnea?

*Co–ﬁrst authors.

ORCID IDs: 0000-0002-9008-3617 (D.J.F.-K.); 0000-0003-3589-0018 (N.P.I.); 0000-0002-0036-511X (Y.C.G.L.); 0000-0003-3934-4452 (S.Z.L.); 0000-0002-1276-6500 (N.A.M.); 0000-0003-1195-1680 (N.M.R.); 0000-0003-1249-0804 (D.H.S.). Correspondence and requests for reprints should be addressed to David J. Feller-Kopman, M.D., Section of Interventional Pulmonology, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, 1800 Orleans Street, Suite 7-125, Baltimore, MD 21287. E-mail: [email protected]. This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org. Am J Respir Crit Care Med Vol 198, Iss 7, pp 839–849, Oct 1, 2018 Copyright © 2018 by the American Thoracic Society DOI: 10.1164/rccm.201807-1415ST Internet address: www.atsjournals.org

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PICO 5: In Patients with Nonexpandable Lung, Failed Tunnel Infection, or Pleural Symptomatic MPE Undergoing Pleurodesis, or Loculated Infection), Should Medical Talc Pleurodesis, Should Talc Effusion, Should an IPC or Therapy Alone or Medical Poudrage or Talc Slurry Be Chemical Pleurodesis Be Therapy and Catheter Removal Used? Used? Be Used? PICO 6: In Patients with PICO 7: In Patients with IPC- Discussion Symptomatic MPE with associated Infection (Cellulitis,

Malignant pleural effusions (MPEs) are beyond the scope of a single document, of pneumothorax after thoracentesis for the second leading cause (next to this panel opted to narrow the focus of any/all causes of pleural effusions has been parapneumonic effusions) of exudative the guidelines to key issues that are reported to be as high as 39% (12), although effusions, accounting for greater than of the most relevance to clinicians and more recent and larger studies have shown 125,000 hospital admissions per year in the patients/caregivers. substantially lower rates of pneumothorax United States and estimated inpatient in all cases, but especially when ultrasound charges of greater than $5 billion per year guidance is used (13, 14). The use of (1). Though some patients are initially Methods ultrasound guidance for thoracentesis has asymptomatic, the majority will eventually also been shown to reduce the rates of develop dyspnea at rest. Likewise, as MPE is We used the GRADE (Grading of “dry taps” and less common complications, associated with an average survival of 4–7 Recommendations, Assessment, such as solid organ puncture or hemothorax months (2), treatment should aim to relieve Development, and Evaluation) approach (12, 15). dyspnea in a minimally invasive manner, (10, 11) to formulate clinical questions in Although the largest studies in and ideally minimize repeated procedures PICO (Patient, Intervention, Comparator, the literature have assessed the use of and interaction with the healthcare system and Outcome) format, summarize relevant ultrasound for thoracentesis in all types of (i.e., to provide a definitive pleural evidence, and develop recommendations pleural effusions, this question appraised the for clinical practice. To identify the best intervention) (3). With increasing focus on fi evidence for whether ultrasound is superior patient-centered outcomes, many of these available evidence, we identi ed existing for guiding pleural interventions specifically techniques, including thoracoscopy and systematic reviews and performed for MPE. placement of indwelling pleural catheters additional systematic reviews, including Summary of the evidence. The search (IPCs), can be performed in the outpatient a systematic review for PICO4 that will strategy for this question obtained one setting (4–6). The American Thoracic be published separately. Full methodologic retrospective observational study that Society published the first guidelines for details and tables supporting the specifically assessed complication rates management of MPE in 2000 (7), followed recommendations here can be found in for thoracentesis in MPE with or by the British Thoracic Society guidelines, theonlinesupplement. without ultrasound guidance (16). Three published in 2010 (8). Both were based on retrospective observational studies assessed the consensus of a group of international safety and efficacy for ultrasound guidance experts in the field who reviewed the Recommendations for of pleural effusions, including, but not available literature at that time. However, Specific Treatment limited to, MPE were also included in recent data suggest that these guidelines Questions the initial review (17–19). In addition, are followed less than 50% of the time two studies comprised of larger patient (9). Since publication of the British PICO 1: In Patients with Known or populations, including a meta-analysis Thoracic Society guidelines, there Suspected MPE, Should Thoracic (13) and large retrospective cohort (14) have been several large, multicenter, Ultrasound Be Used to Guide Pleural that reviewed complication rates after randomized trials, as well as other well- Interventions? thoracentesis for all causes of pleural conducted studies that have substantially effusion were included to help formulate impacted the way patients with MPE Background. Pleural interventions (e.g., the recommendation. are evaluated and treated. A recent thoracentesis, pleural drainage catheter The outcomes of pneumothorax, and survey by the European Society of insertion) are frequently performed for pneumothorax requiring chest tube Thoracic Surgeons found a majority of diagnostic or therapeutic purposes in placement, were considered critical. No respondents who were aware of existing patients with MPE. These procedures may studies assessed other complication rates guidelines suggested that they are in be performed with or without imaging (i.e., hemothorax, pain at site) or procedural need of updating/revisions (9). guidance, in both inpatient and outpatient success specifically for malignant effusions. This document aims to provide settings. The use of ultrasound guidance practicing clinicians with the synthesis of Iatrogenic pneumothorax is the most reduced the risk of pneumothorax after latest evidence along with recommendations common complication of thoracentesis, thoracentesis for malignant effusions (1.0% to improve patient centered outcomes. and, in a minority of cases, requires chest vs. 8.9%, relative risk [RR] = 0.10, 95% Because the clinical questions surrounding tube placement, which can necessitate or confidence interval [CI] = 0.03–0.37) (16). the management of MPEs can be broad and lengthen hospital stay. Historically, the rate There were no chest tubes placed in the

840 American Journal of Respiratory and Critical Care Medicine Volume 198 Number 7 | October 1 2018 AMERICAN THORACIC SOCIETY DOCUMENTS ultrasound guidance group compared The decision to use ultrasound to patients with lung cancer, and the with three (2.2%) chest tubes in the guidance for pleural interventions in follow-up period was relatively short. group without image guidance (95% CI patients with malignant effusions will Porcel and colleagues (2) published a not estimable) (16). The other three depend on local expertise, availability, and retrospective study of 556 patients with observational studies (17–19) assessed access to ultrasound machines. newly diagnosed lung cancer. They found safety and success of ultrasound guidance Research priorities. Future studies that 40% of patients with lung cancer in pleural effusions of all causes, and did should further investigate the use of developed a pleural effusion during the not report complication rates specifically ultrasound in expanded roles for pleural course of their disease, half of which for malignant effusions. interventions in patients with malignant were too small for any sampling or Two larger studies assessed the risk of effusions. For example, ultrasound can be intervention. Of these 112 (20%) cases pneumothorax after thoracentesis with or used to identify intercostal vessels, with the with small/minimal pleural effusions, none without ultrasound guidance for all causes goal of decreasing the small, but real, risk required an interventional procedure 6 6 of pleural effusion. A meta-analysis of 24 of hemorrhagic complications associated during follow up (mean SD = 10 11 studies and 6,605 thoracenteses published in with pleural procedures (20). In addition, mo). Although these small effusions did not 2010 found that the overall pneumothorax ultrasound can be used to evaluate for go on to become symptomatic, they did risk after thoracentesis was 6.0%, and that nonexpandable lung before thoracentesis, confer a survival disadvantage compared fi ultrasound guidance was associated with a which may aid in guiding de nitive with those without a pleural effusion management (21), or to determine if (median survival, 7.5 vs. 12.7 mo; P , lower risk of pneumothorax (4.0% vs. 9.3%; fi odds ratio = 0.3, 95% CI = 0.2–0.7) (13). pleurodesis was successful. 0.001). This nding was mirrored in a Moreover, 34.1% of pneumothoraces in larger Korean series (7.7 mo vs. 17.7 mo; PICO 2: In Patients with Known P , this meta-analysis required chest tube 0.001) (23). or Suspected MPE Who Are Recommendation. In patients with placement (13). Asymptomatic, Should Pleural known or suspected MPE who are A more recent, large, retrospective Drainage Be Performed? asymptomatic, we suggest that therapeutic cohort study published in 2013 that pleural interventions not be performed reviewed 62,261 thoracenteses for pleural Background. Asymptomatic MPEs are a (conditional recommendation, very low effusions of all causes reported an overall commonly encountered scenario for confidence in estimate of effects; Tables E4B risk of pneumothorax of 2.7% and found clinicians. All invasive pleural procedures and E5B). that ultrasound guidance reduced the risk of carry a small risk of complications, and, Justification. Data are insufficient to pneumothorax by 19% (odds ratio = 0.81, – therefore, any intervention must have recommend sampling or draining these 95% CI = 0.74 0.90) (14). The frequency benefits that outweigh these risks. One asymptomatic effusions. Unless there are of chest tube placement was not reported potential benefit of early intervention that clinical indications, such as obtaining fluid for this study, but pneumothorax was fi fi has been regularly proposed is the possible to de ne clinical stage/obtain molecular associated with a signi cantly longer length reduced risk of developing a nonexpandable markers, the drainage of asymptomatic of hospital stay and total patient lung at a later stage in the disease process. effusions would only subject the patient to hospitalization cost (14). Despite the lack of Summary of the evidence. The search the risks of the procedure (albeit a small a randomized trial comparing thoracentesis revealed two studies pertinent to the clinical risk) without providing clinical benefit. fi with and without ultrasound speci cally in question. Improvement in quality of life, Clearly, if pleural fluid is required for patients with MPE, the panel agrees that breathlessness, and other symptoms (e.g., diagnostic purposes, fluid and/or tissue ultrasound guidance, which has no pain), future need of interventions, and days sampling would be appropriate. significant harms associated with its usage, spent in hospital during the patient’s Research priorities. Published has an important benefit of reducing remaining lifespan were considered critical literature on this topic has focused pneumothorax rates. outcomes, and healthcare costs for fluid exclusively on MPE in the lung cancer Recommendation. In patients with management in remaining lifespan and setting. A large prospective study of all known or suspected MPE, we suggest walking distance or other exertional MPEs is needed with longer follow up of that ultrasound imaging be used to guide activities were considered important subjects. A prospective study evaluating pleural interventions (conditional outcomes. Tremblay and colleagues (22) whether delay in draining asymptomatic recommendation, very low confidence in undertook a retrospective review of 113 pleural effusions increases the risk of estimate of effects; see Tables E4A and E5A patients presenting to a lung cancer clinic subsequent nonexpandable lung should in the online supplement). over a 3-month period in Canada with a also be investigated. Likewise, as pleural Justification and implementation pleural effusion on chest radiography or palliation can still be achieved in patients considerations. This recommendation is computed tomography (CT) thorax. A total who develop symptoms even with based not only on the limited observational of 14 of these were asymptomatic or did not nonexpandable lung, trials defining the evidence for ultrasound guidance for require intervention; 13 patients were then optimal way to palliate effusions from a management of malignant effusions, but followed up for a median time of 98 days, patient and cost perspective are essential. also on the stronger evidence from larger and none required intervention during It is also vital for us to improve our studies in the management of pleural this period. The study’s conclusions were understanding of what biological role an effusions of all types described previously limited by the small number of patients and MPE may play in disease progression and here. its retrospective design. It was also limited why survival is significantly worsened by the

American Thoracic Society Documents 841 AMERICAN THORACIC SOCIETY DOCUMENTS development of asymptomatic pleural require another procedure within 9 days additional procedure (therapeutic effusion in patients with known lung cancer. after initial drainage (3). thoracentesis), may not be required. Summary of the evidence. Studies of Research priorities. Research is needed PICO 3: Should the Management of drainage/manometry are limited by to establish better means to predict Patients with Symptomatic Known variation in how manometry was symptomatic response from MPE drainage, or Suspected MPE Be Guided by performed, cut-off values selected, exact and also to predict lung expansion to guide Large-Volume Thoracentesis and parameter(s) captured, heterogeneity of individualized treatment. Future studies Pleural Manometry? patient populations enrolled, and lack of of manometry should first focus on long-term follow up. Only one study has standardizing measurement parameters, and Background. Performing a therapeutic examined the use of manometry in then applying it to the algorithm of MPE drainage before a definitive pleural predicting “longer-term” outcomes. Lan management to assess its role (if any) on long- intervention in patients with MPE can serve and colleagues (32) reported results of term clinical outcomes. In addition, prospective two purposes: confirming symptomatic 55 patients with MPE who underwent studies investigating the utility of performing a improvement after fluid drainage and bleomycin pleurodesis. An elastance of less therapeutic thoracentesis before definitive identifying the presence of nonexpandable than 19 cm H2O measured after draining therapy, especially focusing on patient-centered lung (also referred to as “unexpandable 500 ml of fluid predicted a 98% chance of outcomes, are needed. Advanced ultrasound lung” or “lung entrapment” in the success, defined as pleural fluid control at methods are also being investigated to identify literature) (24). Nonexpandable lung occurs 1 month. All 11 patients with an elastance nonexpandablelungbeforethoracentesis(21). in at least 30% of patients with MPEs, and of 19 cm H2O or greater did not achieve may be a contraindication for pleurodesis pleurodesis. The small cohort size, lack of a PICO 4: In Patients with Symptomatic (8, 25–27). The absence of lung expansion validation group, and longer-term follow- MPE with Known or Suspected after fluid evacuation should ideally steer up preclude a more definitive conclusion. Expandable Lung and No Prior the clinician to avoid futile attempts at Likewise, there are no studies that demonstrate Definitive Therapy, Should IPCs or pleurodesis and use IPCs as the treatment the benefits of a therapeutic thoracentesis to Chemical Pleurodesis Be Used of choice in these patients. guide definitive pleural intervention. Despite as First-Line Definitive Pleural Measurement of pleural pressures or the sparse evidence, the panel agreed that Intervention for Management of elastance (change in pressure over volume the potential benefits of large-volume Dyspnea? drained) is one of the most studied thoracentesis, including identification of lung approaches to predict if the lung will expand entrapment and nonresolution of dyspnea, Background. Historically, the treatment after drainage. Studies to date generally outweighed the harms. of choice for patients with MPE has included both malignant and benign Recommendation. In patients with been pleurodesis, with talc being the effusions, and the majority investigated symptomatic MPE, we suggest large-volume recommended agent of choice (8, 33). the “safety” limit of how much fluid thoracentesis if it is uncertain whether the To achieve pleurodesis, it is necessary to can be removed, and prediction of patient’s symptoms are related to the have the visceral and parietal pleura in nonexpandable lungs was based on the effusion and/or if the lung is expandable apposition. Given that at least 30% of changes in pressure curves, rather than a (the latter if pleurodesis is contemplated) patients with MPE have nonexpandable post-drainage chest CT (26, 28, 29). Lung to assess lung expansion (conditional lung (25), and the fact that dyspnea in expansion can be assessed with positive- recommendation, very low confidence in patients with pleural effusion relates more pressure ventilation if the patient estimate of effects; Tables E4C and E5C). to diaphragmatic inefficiency than lung undergoes thoracoscopy performed under Justification. There is limited evidence expansion (34), IPCs have become the general anesthesia (30). Post-procedure defining the benefits on clinical outcomes in treatment of choice for patients with known imaging after draining all/most-all of the patients with MPEs to support the routine nonexpandable lung (8). There are currently pleural fluid can also assess lung use of pleural pressure measurements or no recommendations as to whether IPCs expansion. Another benefitofalarge- therapeutic thoracentesis to guide definitive or pleurodesis should be used in patients volume drainage procedure lies in pleural palliation. Despite the sparse with known or suspected expandable confirming that the patient’sdyspnea evidence, the panel agreed that the potential lung. is due to the effusion. This may not be benefits of large-volume thoracentesis, Summary of the evidence. The search apparent if only a small-volume diagnostic including identification of nonexpandable strategy for this question yielded 10 studies, thoracentesis is performed (31). If the lung entrapment and nonresolution of including 1,279 participants. Studies patient does not receive benefitfromthe dyspnea, outweighed the harms. It is also included pleurodesis via surgical or medical thoracentesis, the clinician needs to noteworthy (see the subsequent PICOs) that thoracoscopy with talc poudrage, chest tube investigate other causes of dyspnea IPC is an option suitable for both patients with with talc slurry, repeat thoracentesis, (i.e., pulmonary embolism, pericardial expandable and nonexpandable lung, and is or no treatment. Of the studies included, effusion,etc.),andfurtherattemptsat now considered an adequate alternative to five were randomized controlled trials pleural palliation are not required. Likewise, pleurodesis in patients who have expandable (Putnam and colleagues [35], NVALT [Dutch a large-volume thoracentesis may offer lung. As such, if the plan is to manage the Society of Pulmonologists]-14 [36], TIME further insight into the speed of pleural MPE with an IPC, a large-volume [Therapeutic Intervention in Malignant fluid reaccumulation after drainage. Recent thoracentesis to assess lung expansion, Effusion]-2 [37], CALGB [Cancer data suggest that up to 60% of patients will regardless of whether the lung expands an and Leukemia Group B] 30102 [38], and

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AMPLE [Australian Malignant Pleural Recommendation. In patients with combining IPCs with chemical Effusion] [39]), four were retrospective MPE with known (or likely) suspected pleurodesis are being conducted, and observational studies (40–43), and one was expandable lung and no prior definitive the results from these trials may provide a prospective observational study (44). The therapy, and whose symptoms are additional options that can be beneficial to critical outcomes included improvement in attributable to the effusion, we the patients. dyspnea, survival, mortality, hospital length suggest that either IPCs or chemical of stay (LOS), and treatment failure, as pleurodesis be used as first-line definitive PICO 5: In Patients with Symptomatic measured by the need for additional intervention for management of dyspnea MPE Undergoing Talc Pleurodesis, interventions. Empyema, bleeding (conditional recommendation, low Should Talc Poudrage or Talc Slurry requiring intervention, and cellulitis were confidenceinestimateofeffects; Be Used? considered important. Tables E4D and E5D). Both interventions resulted in Justification. The available data Background. More than 50% of malignant improved dyspnea scores from baseline, favored IPCs in terms of fewer days spent in effusions will reaccumulate after initial but no differences were found between the hospital in patients’ remaining life and drainage (3), and therefore definitive interventions at 30 days (39, 42) or 42 days less risk of treatment failure. On the other pleural intervention (i.e., an intervention (36, 37). In the TIME-2 trial, the hand, data were in favor of chemical to prevent recurrent presentation improvement in the Visual Analog pleurodesis with respect to the risk of with breathlessness and minimize Score between the groups at 6 months cellulitis. We prioritized hospital days and symptoms/repeated procedures) is a favored IPCs (mean difference of 214.0 mm, treatment failure as critical, patient- priority. Guidelines recommend the use 95% CI = 225.2 to 22.8; P = 0.01) (37). centered outcomes; cellulitis, although of a “definitive” pleural procedure after There was no significant difference in ranked below the critical outcomes, was so recurrence of pleural fluid after an initial survival between the two interventions, strongly associated with IPCs as to result in thoracentesis; however, a recent large although no study examined survival as a a neutral recommendation for either option retrospective study of 23,431 patients primary outcome. Two studies reporting for relief of dyspnea. Clearly, when with MPE demonstrated that only 24% 3-month mortality showed no difference performed as an inpatient, chemical underwent a definitive pleural procedure between IPC and pleurodesis (RR = 1.25, pleurodesis will have an increased initial (as opposed to repeat thoracentesis) after 95% CI = 0.45–3.45) (25, 37). hospital stay compared with an outpatient rapid reaccumulation of fluid (3). Those For hospital LOS, IPCs were favored in IPC placement. When choosing one option undergoing definitive pleural procedures all studies that reported this outcome. In the over the other, care providers should factor experienced fewer additional pleural AMPLE study, the difference in median LOS in the specific patient’s values and procedures, fewer procedures performed in was 2.92 days (95% CI = 0.43–5.84) (30). preferences by taking into consideration the emergency department, and fewer NVALT-14 also reported fewer median thatIPCsreducetimeinhospital,butare complications than those undergoing hospital days for patients who underwent associated with an increased risk of repeat thoracentesis, underlining the IPC compared with chemical pleurodesis cellulitis. A recently published RCT, the importance of definitive pleural (2 d vs. 7 d, respectively; P , 0.001) (27), IPC-Plus study (6), showed that the intervention at the appropriate time in whereas the TIME-2 reported a median combination of IPC and talc slurry the treatment process. of 3.5 fewer hospital days (95% CI = 24.8 resulted in higher pleurodesis rates and Pleurodesis involves the administration to 21.5) (36, 37). improved quality of life in the IPC-talc of a drug or material in the pleural space to For treatment failure as assessed by the group as compared with the IPC-saline cause adhesions between the parietal and need for additional ipsilateral interventions, group. Our recommendation is an visceral pleura, and prevention of fluid pooled results from four studies favored important advance in the management reaccumulation. Talc is the most widely IPCs over chemical pleurodesis (RR = 0.32, of MPE, as previous guidelines had used pleurodesis agent, and has been shown 95% CI = 0.18–0.55) (36, 37, 39, 42). recommended IPCs as a treatment option in previous meta-analysis (33) and a head- Infectious complications were reported onlyforpatientswithnonexpandable to-head RCT (45) to be the most effective more frequently with IPCs. Pooled results lungs, and some physicians had refrained pleurodesis agent. There are two delivery from four randomized controlled trials fromplacingIPCsinpatientswith methods: talc poudrage (also known as (RCTs) showed a fivefold-increased risk of expandable lungs. insufflation), which is conducted during cellulitis with IPCs when compared with Research priorities. Additional studies either surgical or medical thoracoscopy, chemical pleurodesis (RR = 5.83, 95% CI = should be conducted to validate the findings when talc is blown in as a dry powder; or 1.56–21.87) (36, 37, 39, 42); there was a of the aforementioned studies and further talc slurry, when talc mixed with sterile similar trend for increased rates of pleural assess whether IPCs may be superior to fluid is injected through a chest tube at the infection with IPCs (RR = 3.32, 95% CI = pleurodesis for outcomes, such as total bedside. 0.82–13.44). days spent in the hospital, patient-reported Summary of the evidence. The search No RCTs reported bleeding quality of life, and other patient-centered strategy for this question found three complications requiring intervention. measures. Other factors that should be randomized trials (25, 46, 47), two Pooled results from 174 patients in two addressed in future studies include prospective observational studies (48, 49), retrospective studies showed no difference patients’ preference, cost implications, four meta-analyses (50–53), and a network between treatment arms (IPC 2.2% vs. and variation in practice and resources in meta-analysis (33). Studies included both chemical pleurodesis 3.7%) (41, 43). different regions of the world. Studies general anesthetic and local anesthetic

American Thoracic Society Documents 843 AMERICAN THORACIC SOCIETY DOCUMENTS thoracoscopic talc poudrage under either the observational studies (RR = 0.74, research areas that require further evidence. general or local anesthesia, and poudrage 95% CI = 0.51–1.06). These should focus on patient-centered conducted either by pulmnologists or Therewerenosignificant differences outcome measures of breathlessness/ surgeons. Data from the published meta- in complications between poudrage and quality of life, if patients undergoing talc analyses were not used for evidence slurry (see evidence table), with the pleurodesis (via either poudrage or synthesis, as they were outdated, included exception of an increase in pneumonia slurry) require hospital admission and if unpublished data, or reported outcomes favoring talc slurry, but this was aggressive pleural drainage schedules can that were poorly defined. For example, imprecisely estimated (RR = 2.18, 95% lead to lower total catheter days in patients Mummadi and colleagues (52) pooled CI = 1.02–4.64). treated with both IPC and talc than the all respiratory complications as one In a post hoc subgroup analysis, the more conservative schedule used in the outcome, whereas Tan and colleagues (51) largest study to date (25) reported results IPC-plus study (6). did not define the outcome of effusion that favored poudrage compared with recurrence. In our review, the outcomes slurry in patients with expandable lung, and PICO 6: In Patients with Symptomatic of mortality, respiratory failure, and MPE due to either lung cancer or breast MPE with Nonexpandable Lung, treatment success (defined as no further cancer (82% vs. 67% pleurodesis success at Failed Pleurodesis, or Loculated ipsilateral pleural intervention) were 1 mo in those alive to be assessed; P = Effusion, Should an IPC or Chemical considered critical, and the outcomes 0.022). However, care should be taken in Pleurodesis Be Used? of complications (empyema, bleeding, interpretation of this finding in isolation pneumonia) were considered important. and as a post hoc subgroup analysis. Background. At least 30% of patients with Other complications (cellulitis and fever) There were no extractable data for MPE will have nonexpandable lung (25). were considered not important for this important outcomes, such as breathlessness Likewise, pleurodesis is unsuccessful in up outcome. and time in hospital. to 30% of patients (25), and as many as 14% Of the randomized trials, the largest A published network meta-analysis of patients with MPE develop symptomatic one compared surgical thoracoscopic talc (33) assessed optimal management for loculations after prior treatment (8, 44). poudrage to talc slurry pleurodesis in prevention of malignant effusion The use of an IPC in these patient groups 482 patients, assessing only those with recurrence, and included 62 randomized may enable further drainage of fluid, greater than 90% expansion of the lung studies of all pleurodesis agents, including alleviation of symptoms, and avoidance on chest radiograph (25). No difference talc and IPCs. This analysis rated talc of admission and multiple subsequent was found between pleurodesis success at pleurodesis as highly effective for procedures. 1 month (78% for poudrage vs. 72% prevention of fluid recurrence. Both talc Summary of the evidence. The search for slurry). Yim and colleagues (46) poudrage and slurry were ranked highly, strategy for this question yielded five randomized 57 patients with expandable but one method was not significantly better noncomparative case series (55–59) lung and good performance status to talc than the other, consistent with our findings and a single prospective, comparative poudrage or slurry pleurodesis, with no described previously here. observational study (60). The outcomes of difference between groups in terms of Recommendation. In patients with mortality and reduced hospital stay (LOS of pleurodesis success or hospital stay. Terra symptomatic MPE and expandable lung 2 d or less) were considered critical, and the and colleagues (47) randomized 60 patients undergoing talc pleurodesis, we suggest the outcomes of complications (i.e., empyema) to surgical poudrage or talc slurry use of either talc poudrage or talc slurry were considered important. pleurodesis and demonstrated a higher rate (conditional recommendation, low No difference was demonstrated in of immediate lung expansion (.90% on confidence in estimate of effects; Tables E4E mortality in the single comparative study CT) in the surgical group, but no difference and E5E). (60). There appeared to be a large effect in any other outcome over 6 months. Justification and implementation of reduced hospital stay using IPCs in Collating all the evidence, there were considerations. Given the low confidence the single comparative study, with 19 inconclusive findings for mortality in estimates for critical outcomes, the panel of 34 patients with IPC (56%) staying in the randomized trials (RR = 0.70, 95% could not recommend one approach over the hospital less than 2 days compared CI = 0.33–1.12). There was a larger and the other. The decision to use poudrage or with 0 of 7 patients receiving talc statistically significant effect seen in the slurry should depend on several factors, pleurodesis (60). observational studies (RR = 0.22, 95% CI = including local expertise (i.e., availability There were no comparative data on 0.06–0.80) favoring talc poudrage, but it is of thoracoscopy), whether additional tissue complications, but the pooled risk of likely that selection bias seriously affects is needed for molecular-marker analysis complications across case series for IPCs this result (as fitter patients will be (would favor thoracoscopy), as well as used in patients with nonexpandable lung selected for talc poudrage over slurry in patient-related factors (i.e., if a chest tube is or failed pleurodesis was relatively low for observational studies). already in place). both empyema (2.4%) and cellulitis (3.8%) Findings were also inconclusive, Research priorities. A prospective, (55, 56, 58, 59). with no significant differences between randomized study of patients with No studies reported breathlessness or treatment arms for respiratory failure expandable lung comparing talc poudrage treatment failure as an outcome. (RR = 1.74, 95% CI = 0.81–3.74) or for via medical thoracoscopy and slurry via Recommendation. In patients with treatment failure in either the randomized “small bore” (,14F) chest tubes is ongoing symptomatic MPEs with nonexpandable trials (RR = 1.02, 95% CI = 0.31–3.31) or (54). There are a number of important lung, failed pleurodesis, or loculated

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effusion, we suggest the use of IPCs over associated with IPCs, as well as abundant who either had prior unsuccessful attempts chemical pleurodesis (conditional clinical experience that chemical pleurodesis at pleurodesis or developed symptomatic recommendation, very low conﬁdence in is rarely effective in the setting of loculations after either pleurodesis or IPC estimate of effects; Tables E4F and E5F). nonexpandable lung. None of the studies placement. Justiﬁcation. This recommendation is examined the success rate (resolution of Research priorities. Given the paucity based primarily on the reduced LOS and low symptoms or need for additional pleural of robust clinical data, there is a clear need observed incidence of complications procedures) of talc pleurodesis in patients for studies to directly compare IPC and

Pleural intervention not needed Known or suspected MPE Asymptomatic (unless for diagnostic purposes)

Symptomatic

Ultrasound guided therapeutic thoracentesis (i.e. large-volume tap*)

Improvement in Dyspnea

No Yes

Investigate for other Lung re-expansion causes of dyspnea

No Yes 4C/FPO

Discussion of relative risks / benefits of Talc poudrage or talc slurry Predicted very short survival** IPC vs pleurodesis vs combination +/- IPC approaches

Yes No

Palliate dyspnea with: Consider placement of IPC (IPC should also be repeat thoracentesis if needed, considered in patients with failed pleurodesis Evidence of IPC-related infection oxygen, morphine or symptomatic loculated effusion)

Lung re-expansion

No Yes

Initiation of oral antibiotics based on Consider drainage as guided Consider daily drainage local sensitivities. Attempt to keep by symptoms or local protocol and/or talc slurry catheter in place***

Figure 1. Management of patients with known or suspected malignant pleural effusion (MPE). *With goals of assessing lung expansion and relief of dyspnea. This step may not be necessary if the patient’s dyspnea is known to be attributable to the MPE. **Physicians are not great predictors of prognosis. As such, the recommendation of “Predicted very short survival” should be used as a rough guideline and individualized on a case-by-case basis. ***Note: there is a low likelihood (2–4%) of indwelling pleural catheter (IPC)–related infection. Escalation of care (intravenous antibiotics, hospital admission, removal of catheter) should be made on a case-by-case basis, and is recommended if there are any signs/symptoms of worsening infection.

American Thoracic Society Documents 845 AMERICAN THORACIC SOCIETY DOCUMENTS pleurodesis for alleviating breathlessness patients. One case series comprising nearly IPC-related pleural infection, including in patients with partially expandable half of the pooled patient population did not the need for catheter removal, the initial lung, loculated effusion, and failed talc comment on whether infected IPCs were use of oral versus intravenous antibiotics, pleurodesis. Thomas and colleagues (61) removed (67). In the remaining case series, inpatient versus outpatient therapy, have shown significant increases in pleural 41 of 57 patients (72%) were managed andtheuseofrTPA-DNasethrough drainage and improvement in symptoms without removing the infected IPC (44, 64, the IPC. Outcomes should include in selected patients with IPC-related 68–70). Although no comparative data were mortality, resource utilization, and need symptomatic loculations with the use of reported between the two groups, the pooled for escalation of care. Confounders in fibrinolytics; however, there was a small mortality attributed to the IPC infection future studies include colonization versus (3%) risk of nonfatal hemorrhagic among these 57 patients was 12.3%. When true infection, as well as distinguishing complications. A recent RCT, however, examining all case series with 107 patients, cellulitis versus tunnel infection versus suggested no benefit of intrapleural the pooled mortality attributed to IPC empyema. urokinase (given via a chest tube) in infection was 9.3%. patients with loculated MPE (62). There are no data suggesting that Additional prospective studies are catheter removal is superior or inferior to Discussion required to definetherolethat keeping the catheter in place. fibrinolytics have in the treatment of Recommendation. In patients with These recommendations (Figure 1) focus symptomatic loculations, including dose, IPC-associated infections, treating through on patient-centered outcomes, such as dwell time, and clinical setting (inpatient the infection without catheter removal is dyspnea, and the need for recurrent vs. outpatient). It should also be noted usually adequate. We suggest catheter procedures and hospitalizations. Clearly, that “loculated effusion” can represent a removal if the infection fails to improve as with the PICO 3 recommendations that very heterogenous group, and that patients (conditional recommendation, very low IPCs or chemical pleurodesis can be used with a few loculations may still benefit confidence in estimate of effects; Tables E4G for patients with MPE and expandable from pleurodesis. Likewise, in a patient and E5G). lung, the specificrisksandbenefits of with a good performance status and low Justification. Given the lack of strong each procedure should be discussed in LENT (pleural fluid lactate dehydrogenase, data supporting one method of treatment detail with the patient/caregiver, and Eastern Cooperative Oncology Group over another, clinical experience suggests decisions should be made on an performance score, neutrophil-to- that patients can be treated in a variety individual basis. Factors influencing lymphocyte ratio, and tumor type) score (a of ways, including oral or intravenous this specific decision can include the marker of expected relatively good survival antibiotics, as well as keeping the catheter availability of a support network to help in MPE) (63), it may not be unreasonable in place, or removing the catheter. with IPC drainage, and the patient’s to offer minimally invasive (video-assisted Treatment decisions should be made on an desire to avoid hospitalization. Likewise, thoracoscopic surgery or robotic assisted) individual basis. Considerations should be small studies have suggested that we may decortication. made based on the clinical status of the be able to achieve the “best of both patient, including signs/symptoms of worlds” in the future, with approaches PICO 7: In Patients with IPC-associated pleural sepsis (i.e., fever, leukocytosis, combining IPCs with pleurodesis agents Infection (Cellulitis, Tunnel Infection, failure to thrive), as well as the type (6, 71). or Pleural Infection), Should Medical of infection (pleural space vs. tunnel As our understanding of the Therapy Alone or Medical Therapy and infection vs. cellulitis) and the risks of molecular mechanisms of pleural fluid Catheter Removal Be Used? symptomatic fluid reaccumulation should formation/resorption and pleurodesis the catheter be removed. Considerations evolve (72, 73), future trials can focus on Background. IPCs have become the as to resources available to provide “turning off” production, increasing treatment of choice for many patients with home intravenous antibiotic therapy, resorption, or creating pleurodesis with MPE (8, 38, 40, 64–66). Though the the proximity of the patient to the care minimally invasive techniques. In incidence of IPC-related infection is low, team,aswellasthepatient’s local support addition, the role of gene therapy and catheter-related infection remains a network should be taken into account. immunotherapy may significantly alter concern, as well as a potential barrier to Patients with IPC-related pleural infection our approach to these patients (74). their use. Aggregated data from three RCTs require close monitoring to assure clinical Patient-reported outcome measures show IPC-related rates of cellulitis and improvement with the implemented should be prioritized over secondary pleural space infection of 7.3% and 4.6%, treatment plan. Should there be any endpoints, such as radiographic respectively (35, 37, 44). Unfortunately, worsening of the patient’s clinical status improvement (31). Given the “critical there are few data regarding the (i.e., development of pleural sepsis), it mass” of interested researchers and management of IPC-related infection. would be appropriate to escalate collaboration between the traditionally Summary of the evidence. The search intervention (i.e., switch from oral to siloed disciplines of surgery, medicine, strategy for this question yielded six intravenous antibiotics, consider catheter and radiology, we anticipate significant noncomparative observational studies (44, removal, rediscuss the patient’scourse progress in the field of MPE in the 64, 67–70) and one nested case series within with a multidisciplinary team). forthcoming years and the need to an RCT (37) that reported clinical outcomes Research priorities. Future studies re-evaluate our practice on a regular of IPC-associated infection among 107 should investigate the best treatment for basis. n

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This ofﬁcial guideline was developed by an ad hoc subcommittee of the ATS, STS, and STR.

Members of the subcommittee are as Imaging, University of California San Francisco, Dickinson and Lung Therapeutics; and follows: San Francisco, California; 8Children’s Hospital received research support from AstraZeneca and Rocket Medical. N.A.M. Co-Chair 1 Los Angeles, Keck School of Medicine at DAVID J. FELLER-KOPMAN, M.D. ( ) University of Southern California, Los served on an advisory committee and 2 CHAKRAVARTHY B. REDDY, M.D. (Co-Chair) Angeles, California; 9Institute for received research support from 3 MICHAEL K. GOULD, M.D., M.S. (Co-Chair) * Respiratory Health, University of CareFusion/Becton Dickinson. N.M.R. 4 served as a consultant and received ALEX A. BALEKIAN, M.D. * Western Australia, Perth, Australia; 5‡ 10School of Clinical Sciences, University research support from Rocket Medical. MALCOLM M. DECAMP, M.D. D.H.S. served as a consultant for Broncus 6 of Bristol, Bristol, United Kingdom; REBECCA L. DIEKEMPER, M.P.H. * 11 Technologies, CSA Medical, Ethicon Endo- 7‡ Department of Medicine, University of TRAVIS HENRY, M.D. Surgery, FKD Therapies, Olympus, 8 Oxford, Oxford, United Kingdom; Pinnacle Biologics, and Spiration; received NARAYAN P. IYER, M.D. * 12Department of Medicine, New York 9‡ research support from Advantagene; and Y. C. GARY LEE, M.B. CH.B., PH.D. University School of Medicine, New York, served on a data and safety monitoring 6 13 SANDRA Z. LEWIS,PH.D. * New York; and Department of board for Spiration. M.M.W. served as a 10‡ NICK A. MASKELL, D.M. Medicine, Duke University School of consultant for Boston Scientiﬁc, CSA 11‡ Medicine, Durham, North Carolina. NAJIB M. RAHMAN, M.B. CH.B., D.PHIL. Medical, Merit Medical, Olympus, and 12‡ Veran Medical Technologies; served on an DANIEL H. STERMAN, M.D. *Methodology team. 13‡ advisory committee for Holaira; and served MOMEN M. WAHIDI, M.D. ‡ as a consultant and on an advisory Guideline panelists. committee for CareFusion/Becton 1Department of Medicine, Johns Hopkins Dickinson. C.B.R., M.M.D., R.L.D., T.H., University, Baltimore, Maryland; 2Huntsman N.P.I., and S.Z.L. reported no relationships Cancer Institute, University of Utah, Salt Lake Author Disclosures: D.J.F.-K. served as a with relevant commercial interests. consultant for Holaira, Merit Endotek, and City, Utah; 3Department of Research and Veran Medical Technologies; and served Evaluation, Kaiser Permanente Southern 4 on a data and safety monitoring board for Acknowledgment: The committee is grateful California, Pasadena, California; Department CSA Medical. M.K.G. received research to all of their patients with malignant pleural of Medicine, Keck School of Medicine at support from Medial EarlySign; and effusions for allowing them to participate in University of Southern California, Los Angeles, 5 received royalties from UpToDate for their care with the goals of improving their California; Department of Surgery, University authoring chapters on lung cancer quality of life. They are especially grateful to of Wisconsin School of Medicine and Public diagnosis and staging. A.A.B. provided N.S. and S.S. for their input into patients’ and 6 Health, Madison, Wisconsin; Doctor expert testimony for the Ford Motor caregivers’ values that helped them prioritize Evidence, Santa Monica, California; Company. Y.C.G.L. served on an advisory outcomes, and to S.S. for her review of this 7Department of Radiology and Biomedical committee for CareFusion/Becton manuscript.

References effusions: a survey among members of the European Society of Thoracic Surgeons. Interact Cardiovasc Thorac Surg 2017;24: – 1. Taghizadeh N, Fortin M, Tremblay A. US hospitalizations for malignant 414 417. pleural effusions: data from the 2012 National Inpatient Sample. Chest 10. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE 2017;151:845–854. guidelines: 1. Introduction—GRADE evidence profiles and summary 2. Porcel JM, Gasol A, Bielsa S, Civit C, Light RW, Salud A. Clinical features of findings tables. J Clin Epidemiol 2011;64:383–394. and survival of lung cancer patients with pleural effusions. Respirology 11. GRADE handbook for grading quality of evidence and strength 2015;20:654–659. of recommendations. Schunemann ¨ HJ, Brożek J, Guyatt G, 3. Ost DE, Niu J, Zhao H, Grosu HB, Giordano SH. Quality gaps and Oxman AD, editors. The GRADE Working Group; 2013 [accessed comparative effectiveness of management strategies for recurrent 2018 Jun 6]. Available from: http://guidelinedevelopment.org/ malignant pleural effusions. Chest 2018;153:438–452. handbook. 4. DePew ZS, Wigle D, Mullon JJ, Nichols FC, Deschamps C, Maldonado 12. Grogan DR, Irwin RS, Channick R, Raptopoulos V, Curley FJ, Bartter T, F. Feasibility and safety of outpatient medical thoracoscopy at a large et al. Complications associated with thoracentesis: a prospective, tertiary medical center: a collaborative medical-surgical initiative. randomized study comparing three different methods. Arch Intern Chest 2014;146:398–405. Med 1990;150:873–877. 5. Wahidi MM, Reddy C, Yarmus L, Feller-Kopman D, Musani A, Shepherd 13. Gordon CE, Feller-Kopman D, Balk EM, Smetana GW. Pneumothorax RW, et al. Randomized trial of pleural fluid drainage frequency in following thoracentesis: a systematic review and meta-analysis. Arch patients with malignant pleural effusions: the ASAP Trial. Am J Respir Intern Med 2010;170:332–339. Crit Care Med 2017;195:1050–1057. 14. Mercaldi CJ, Lanes SF. Ultrasound guidance decreases complications 6. Bhatnagar R, Keenan EK, Morley AJ, Kahan BC, Stanton AE, Haris M, and improves the cost of care among patients undergoing et al. Outpatient talc administration by indwelling pleural catheter for thoracentesis and paracentesis. Chest 2013;143:532–538. malignant effusion. N Engl J Med 2018;378:1313–1322. 15. Diacon AH, Brutsche MH, Soler ` M. Accuracy of pleural puncture sites: 7. American Thoracic Society. Management of malignant pleural effusions. a prospective comparison of clinical examination with ultrasound. Am J Respir Crit Care Med 2000;162:1987–2001. Chest 2003;123:436–441. 8. Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ; BTS Pleural 16.CavannaL,MordentiP,Bertè R, Palladino MA, Biasini C, Anselmi E, et al. Disease Guideline Group. Management of a malignant pleural Ultrasound guidance reduces pneumothorax rate and improves safety effusion: British Thoracic Society pleural disease guideline 2010. of thoracentesis in malignant pleural effusion: report on 445 consecutive Thorax 2010;65:ii32–ii40. patients with advanced cancer. World J Surg Oncol 2014;12:139. 9. Scarci M, Caruana E, Bertolaccini L, Bedetti B, Brunelli A, Varela G, 17. Kiranantawat N, Sungsiri J, Geater SL. Outcome of ultrasound-guided et al.; ESTS Malignant Pleural Effusion Working Group. small-bore catheter drainage in exudative pleural effusions. JMed Current practices in the management of malignant pleural Assoc Thai 2014;97:548–553.

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18. Liu YH, Lin YC, Liang SJ, Tu CY, Chen CH, Chen HJ, et al. Ultrasound- 38. Demmy TL, Gu L, Burkhalter JE, Toloza EM, D’Amico TA, Sutherland S, guided pigtail catheters for drainage of various pleural diseases. et al.; Cancer and Leukemia Group B. Optimal management of Am J Emerg Med 2010;28:915–921. malignant pleural effusions (results of CALGB 30102). J Natl Compr 19. Abusedera M, Alkady O. Ultrasound-guided pleural effusion drainage Canc Netw 2012;10:975–982. with a small catheter using the single-step trocar or modified 39. Thomas R, Fysh ETH, Smith NA, Lee P, Kwan BCH, Yap E, et al. seldinger technique. J Bronchology Interv Pulmonol 2016;23: Effect of an indwelling pleural catheter vs talc pleurodesis on 138–145. hospitalization days in patients with malignant pleural effusion: the 20. Salamonsen M, Dobeli K, McGrath D, Readdy C, Ware R, Steinke K, AMPLE randomized clinical trial. JAMA 2017;318:1903–1912. et al. Physician-performed ultrasound can accurately screen for a 40. Freeman RK, Ascioti AJ, Mahidhara RS. A propensity-matched vulnerable intercostal artery prior to chest drainage procedures. comparison of pleurodesis or tunneled pleural catheter in patients Respirology 2013;18:942–947. undergoing diagnostic thoracoscopy for malignancy. Ann Thorac 21. Salamonsen MR, Lo AKC, Ng ACT, Bashirzadeh F, Wang WYS, Surg 2013;96:259–263. [Discussion, pp. 263–264.] Fielding DIK. Novel use of pleural ultrasound can identify malignant 41. Hunt BM, Farivar AS, Vallieres ` E, Louie BE, Aye RW, Flores EE, et al. entrapped lung prior to effusion drainage. Chest 2014;146:1286– Thoracoscopic talc versus tunneled pleural catheters for palliation of 1293. malignant pleural effusions. Ann Thorac Surg 2012;94:1053–1057. 22. Tremblay A, Robbins S, Berthiaume L, Michaud G. Natural history [Discussion, pp. 1057–1059.]. of asymptomatic pleural effusions in lung cancer patients. 42. Putnam JB Jr, Walsh GL, Swisher SG, Roth JA, Suell DM, Vaporciyan AA, J Bronchology 2007;14:98–100. et al. Outpatient management of malignant pleural effusion by a 23. Ryu JS, Ryu HJ, Lee SN, Memon A, Lee SK, Nam HS, et al. Prognostic chronic indwelling pleural catheter. Ann Thorac Surg 2000;69:369–375. impact of minimal pleural effusion in non–small-cell lung cancer. 43. Srour N, Amjadi K, Forster A, Aaron S. Management of malignant J Clin Oncol 2014;32:960–967. pleural effusions with indwelling pleural catheters or talc pleurodesis. 24. Huggins JT, Sahn SA, Heidecker J, Ravenel JG, Doelken P. Can Respir J 2013;20:106–110. Characteristics of trapped lung: pleural fluid analysis, manometry, 44. Fysh ETH, Waterer GW, Kendall PA, Bremner PR, Dina S, Geelhoed E, and air-contrast chest CT. Chest 2007;131:206–213. et al. Indwelling pleural catheters reduce inpatient days over 25. Dresler CM, Olak J, Herndon JE II, Richards WG, Scalzetti E, Fleishman pleurodesis for malignant pleural effusion. Chest 2012;142: SB, et al.; Cooperative Groups Cancer and Leukemia Group B; 394–400. Eastern Cooperative Oncology Group; North Central Cooperative 45. Diacon AH, Wyser C, Bolliger CT, Tamm M, Pless M, Perruchoud AP, Oncology Group; Radiation Therapy Oncology Group. Phase III et al. Prospective randomized comparison of thoracoscopic talc intergroup study of talc poudrage vs talc slurry sclerosis for poudrage under local anesthesia versus bleomycin instillation for malignant pleural effusion. Chest 2005;127:909–915. pleurodesis in malignant pleural effusions. Am J Respir Crit Care 26. Feller-Kopman D. Therapeutic thoracentesis: the role of ultrasound and Med 2000;162:1445–1449. pleural manometry. Curr Opin Pulm Med 2007;13:312–318. 46. Yim AP, Chan AT, Lee TW, Wan IY, Ho JK. Thoracoscopic talc 27. Bhatnagar R, Corcoran JP, Maldonado F, Feller-Kopman D, Janssen J, insufflation versus talc slurry for symptomatic malignant pleural Astoul P, et al. Advanced medical interventions in pleural disease. effusion. Ann Thorac Surg 1996;62:1655–1658. Eur Respir Rev 2016;25:199–213. 47. Terra RM, Junqueira JJM, Teixeira LR, Vargas FS, Pego-Fernandesˆ 28. Feller-Kopman D, Berkowitz D, Boiselle P, Ernst A. Large-volume PM, Jatene FB. Is full postpleurodesis lung expansion a determinant thoracentesis and the risk of reexpansion pulmonary edema. Ann of a successful outcome after talc pleurodesis? Chest 2009;136: Thorac Surg 2007;84:1656–1661. 361–368. 29. Lee HJ, Yarmus L, Kidd D, Ortiz R, Akulian J, Gilbert C, et al. 48. Stefani A, Natali P, Casali C, Morandi U. Talc poudrage versus talc Comparison of pleural pressure measuring instruments. Chest 2014; slurry in the treatment of malignant pleural effusion: a prospective 146:1007–1012. comparative study. Eur J Cardiothorac Surg 2006;30:827–832. 30. Hallifax RJ, Corcoran JP, Psallidas I, Rahman NM. Medical 49. Walker S, Zubrinic M, Massey C, Shargall Y, Bedard ´ E, Darling G. thoracoscopy: survey of current practice—how successful are A prospective study of patient-centred outcomes in the medical thoracoscopists at predicting malignancy? Respirology management of malignant pleural effusions. Int J Palliat Nurs 2016;21:958–960. 2016;22:351–358. 31. Psallidas I, Yousuf A, Talwar A, Hallifax RJ, Mishra EK, Corcoran JP, 50. Xia H, Wang XJ, Zhou Q, Shi HZ, Tong ZH. Efficacy and safety of talc et al. Assessment of patient-reported outcome measures in pleural pleurodesis for malignant pleural effusion: a meta-analysis. PLoS interventions. BMJ Open Respir Res 2017;4:e000171. One 2014;9:e87060. 32. Lan RS, Lo SK, Chuang ML, Yang CT, Tsao TC, Lee CH. Elastance of 51. Tan C, Sedrakyan A, Browne J, Swift S, Treasure T. The evidence on the pleural space: a predictor for the outcome of pleurodesis in the effectiveness of management for malignant pleural effusion: a patients with malignant pleural effusion. Ann Intern Med 1997;126: systematic review. Eur J Cardiothorac Surg 2006;29:829–838. 768–774. 52. Mummadi S, Kumbam A, Hahn PY. Malignant pleural effusions and the 33. Clive AO, Jones HE, Bhatnagar R, Preston NJ, Maskell N. role of talc poudrage and talc slurry: a systematic review and meta- Interventions for the management of malignant pleural effusions: a analysis. F1000 Res 2014;3:254. network meta-analysis. Cochrane Database Syst Rev 2016;(5): 53. Shaw P, Agarwal R. Pleurodesis for malignant pleural effusions. CD010529. Cochrane Database Syst Rev 2004;(1):CD002916. 34. Estenne M, Yernault JC, De Troyer A. Mechanism of relief of dyspnea 54. Bhatnagar R, Laskawiec-Szkonter M, Piotrowska HE, Kahan BC, after thoracocentesis in patients with large pleural effusions. Am J Hooper CE, Davies HE, et al. Evaluating the efficacy of thoracoscopy Med 1983;74:813–819. and talc poudrage versus pleurodesis using talc slurry (TAPPS trial): 35. Putnam JB Jr, Light RW, Rodriguez RM, Ponn R, Olak J, Pollak JS, protocol of an open-label randomised controlled trial. BMJ Open et al. A randomized comparison of indwelling pleural catheter and 2014;4:e007045. doxycycline pleurodesis in the management of malignant pleural 55. Boshuizen RC, Onderwater S, Burgers SJA, van den Heuvel MM. The effusions. Cancer 1999;86:1992–1999. use of indwelling pleural catheters for the management of malignant 36. Boshuizen RC, Vd Noort V, Burgers JA, Herder GJM, Hashemi SMS, pleural effusion—direct costs in a Dutch hospital. Respiration 2013; Hiltermann TJN, et al. A randomized controlled trial comparing 86:224–228. indwelling pleural catheters with talc pleurodesis (NVALT-14). Lung 56. Qureshi RA, Collinson SL, Powell RJ, Froeschle PO, Berrisford RG. Cancer 2017;108:9–14. Management of malignant pleural effusion associated with trapped 37. Davies HE, Mishra EK, Kahan BC, Wrightson JM, Stanton AE, Guhan A, lung syndrome. Asian Cardiovasc Thorac Ann 2008;16:120–123. et al. Effect of an indwelling pleural catheter vs chest tube and talc 57. Thornton RH, Miller Z, Covey AM, Brody L, Sofocleous CT, Solomon pleurodesis for relieving dyspnea in patients with malignant pleural SB, et al. Tunneled pleural catheters for treatment of recurrent effusion: the TIME2 randomized controlled trial. JAMA 2012;307: malignant pleural effusion following failed pleurodesis. J Vasc Interv 2383–2389. Radiol 2010;21:696–700.

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58. Sioris T, Sihvo E, Salo J, Rasanen J, Knuuttila A. Long-term indwelling 66. Tremblay A, Michaud G. Single-center experience with 250 tunnelled pleural catheter (PleurX) for malignant pleural effusion unsuitable for pleural catheter insertions for malignant pleural effusion. Chest 2006; talc pleurodesis. Eur J Surg Oncol 2009;35:546–551. 129:362–368. 59. Bazerbashi S, Villaquiran J, Awan MY, Unsworth-White MJ, Rahamim J, 67. Fysh ETH, Tremblay A, Feller-Kopman D, Mishra EK, Slade M, Garske Marchbank A. Ambulatory intercostal drainage for the management L, et al. Clinical outcomes of indwelling pleural catheter-related of malignant pleural effusion: a single center experience. Ann Surg pleural infections: an international multicenter study. Chest 2013; Oncol 2009;16:3482–3487. 144:1597–1602. 60. Ohm C, Park D, Vogen M, Bendick P, Welsh R, Pursel S, et al. Use of 68. Bibby AC, Clive AO, Slade GC, Morley AJ, Fallon J, Psallidas I, et al. an indwelling pleural catheter compared with thorascopic talc Survival in patients with malignant pleural effusions who developed pleurodesis in the management of malignant pleural effusions. Am pleural infection: a retrospective case review from six UK centers. Surg 2003;69:198–202. [Discussion, p. 202.]. Chest 2015;148:235–241. 61. Thomas R, Piccolo F, Miller D, MacEachern PR, Chee AC, Huseini T, 69. Gilbert CR, Lee HJ, Akulian JA, Hayes M, Ortiz R, Hashemi D, et al.A et al. Intrapleural fibrinolysis for the treatment of indwelling pleural quality improvement intervention to reduce indwelling tunneled pleural catheter-related symptomatic loculations: a multicenter observational catheter infection rates. Ann Am Thorac Soc 2015;12:847–853. study. Chest 2015;148:746–751. 70. Mahmood K, Bower C. Treatment of infection associated with tunneled 62. Mishra EK, Clive AO, Wills GH, Davies HE, Stanton AE, Al-Aloul M, et al. pleural catheters. J Bronchology Interv Pulmonol 2010;17:69–72. Randomized controlled trial of urokinase versus placebo for 71. Reddy C, Ernst A, Lamb C, Feller-Kopman D. Rapid pleurodesis nondraining malignant pleural effusion. Am J Respir Crit Care Med for malignant pleural effusions: a pilot study. Chest 2011;139: 2018;197:502–508. 1419–1423. 63. Clive AO, Kahan BC, Hooper CE, Bhatnagar R, Morley AJ, Zahan- 72. Antony VB, Nasreen N, Mohammed KA, Sriram PS, Frank W, Evans N, et al. Predicting survival in malignant pleural effusion: Schoenfeld N, et al. Talc pleurodesis: basic fibroblast growth factor development and validation of the LENT prognostic score. Thorax mediates pleural fibrosis. Chest 2004;126:1522–1528. 2014;69:1098–1104. 73. Nasreen N, Mohammed KA, Brown S, Su Y, Sriram PS, Moudgil B, 64. Gilbert CR, Lee HJ, Skalski JH, Maldonado F, Wahidi M, Choi PJ, et al. et al. Talc mediates angiostasis in malignant pleural effusions via The use of indwelling tunneled pleural catheters for recurrent pleural endostatin induction. Eur Respir J 2007;29:761–769. [Published effusions in patients with hematologic malignancies: a multicenter erratum appears in Eur Respir J 29:1286.] study. Chest 2015;148:752–758. 74. Sterman DH, Alley E, Stevenson JP, Friedberg J, Metzger S, Recio A, 65. Ost DE, Jimenez CA, Lei X, Cantor SB, Grosu HB, Lazarus DR, et al. et al. Pilot and feasibility trial evaluating immuno-gene therapy of Quality-adjusted survival following treatment of malignant pleural malignant mesothelioma using intrapleural delivery of adenovirus– effusions with indwelling pleural catheters. Chest 2014;145: IFNa combined with chemotherapy. Clin Cancer Res 2016;22: 1347–1356. 3791–3800.

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