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

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

*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.). You may print one copy of this document at no charge. However, if you require more than one copy, you must place a reprint order. Domestic reprint orders: [email protected]; international reprint orders: [email protected]. 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,

Summary of United States and estimated inpatient Methods Recommendations charges of greater than $5 billion per year (1). Though some patients are initially We used the GRADE (Grading of PICO 1: In patients with known or asymptomatic, the majority will eventually Recommendations, Assessment, suspected malignant pleural effusion develop dyspnea at rest. Likewise, as MPE is Development, and Evaluation) approach (MPE), we suggest that ultrasound imaging associated with an average survival of 4–7 (10, 11) to formulate clinical questions in be used to guide pleural interventions. months (2), treatment should aim to relieve PICO (Patient, Intervention, Comparator, PICO 2: In patients with known or dyspnea in a minimally invasive manner, and Outcome) format, summarize relevant suspected MPE who are asymptomatic, and ideally minimize repeated procedures evidence, and develop recommendations we suggest that therapeutic pleural and interaction with the healthcare system for clinical practice. To identify the best interventions should not be performed. (i.e., to provide a definitive pleural available evidence, we identified existing PICO 3: In patients with symptomatic intervention) (3). With increasing focus on systematic reviews and performed MPE, we suggest large-volume thoracentesis patient-centered outcomes, many of these additional systematic reviews, including if it is uncertain whether the patient’s techniques, including thoracoscopy and a systematic review for PICO4 that will symptoms are related to the effusion and/or placement of indwelling pleural catheters be published separately. Full methodologic if the lung is expandable (the latter if (IPCs), can be performed in the outpatient details and tables supporting the pleurodesis is contemplated), to assess lung setting (4–6). The American Thoracic recommendations here can be found in expansion. Society published the first guidelines for theonlinesupplement. PICO 4: In patients with symptomatic management of MPE in 2000 (7), followed MPE with known (or likely) suspected by the British Thoracic Society guidelines, expandable lung, and no prior definitive published in 2010 (8). Both were based on therapy, we suggest that either an indwelling the consensus of a group of international Recommendations for pleural catheter (IPC) or chemical experts in the field who reviewed the Specific Treatment pleurodesis be used as first-line definitive available literature at that time. However, Questions pleural intervention for management of recent data suggest that these guidelines dyspnea. are followed less than 50% of the time PICO 1: In Patients with Known or PICO 5: In patients with symptomatic (9). Since publication of the British Suspected MPE, Should Thoracic MPE and expandable lung undergoing talc Thoracic Society guidelines, there Ultrasound Be Used to Guide Pleural pleurodesis, we suggest the use of either talc have been several large, multicenter, Interventions? poudrage or talc slurry. randomized trials, as well as other well- PICO 6: In patients with symptomatic conducted studies that have substantially Background. Pleural interventions (e.g., malignant pleural effusions with impacted the way patients with MPE thoracentesis, pleural drainage catheter nonexpandable lung, failed pleurodesis, or are evaluated and treated. A recent insertion) are frequently performed for loculated effusion, we suggest the use of survey by the European Society of diagnostic or therapeutic purposes in IPCs over chemical pleurodesis. Thoracic Surgeons found a majority of patients with MPE. These procedures may PICO 7: In patients with IPC- respondents who were aware of existing be performed with or without imaging associated infections, treating through the guidelines suggested that they are in guidance, in both inpatient and outpatient infection without catheter removal is usually need of updating/revisions (9). settings. adequate. We suggest catheter removal if the This document aims to provide Iatrogenic pneumothorax is the most infection fails to improve. practicing clinicians with the synthesis of common complication of thoracentesis, latest evidence along with recommendations and, in a minority of cases, requires chest to improve patient centered outcomes. tube placement, which can necessitate or Introduction Because the clinical questions surrounding lengthen hospital stay. Historically, the rate the management of MPEs can be broad and of pneumothorax after thoracentesis for Malignant pleural effusions (MPEs) are beyond the scope of a single document, any/all causes of pleural effusions has been the second leading cause (next to this panel opted to narrow the focus of reported to be as high as 39% (12), although parapneumonic effusions) of exudative the guidelines to key issues that are more recent and larger studies have shown effusions, accounting for greater than of the most relevance to clinicians and substantially lower rates of pneumothorax 125,000 hospital admissions per year in the patients/caregivers. in all cases, but especially when ultrasound

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AMERICAN THORACIC SOCIETY DOCUMENTS guidance is used (13, 14). The use of ultrasound guidance was associated with a management (21), or to determine if ultrasound guidance for thoracentesis has lower risk of pneumothorax (4.0% vs. 9.3%; pleurodesis was successful. also been shown to reduce the rates of odds ratio = 0.3, 95% CI = 0.2–0.7) (13). “dry taps” and less common complications, Moreover, 34.1% of pneumothoraces in PICO 2: In Patients with Known such as solid organ puncture or hemothorax this meta-analysis required chest tube or Suspected MPE Who Are (12, 15). placement (13). Asymptomatic, Should Pleural Although the largest studies in A more recent, large, retrospective Drainage Be Performed? the literature have assessed the use of cohort study published in 2013 that ultrasound for thoracentesis in all types of reviewed 62,261 thoracenteses for pleural Background. Asymptomatic MPEs are a pleural effusions, this question appraised the effusions of all causes reported an overall commonly encountered scenario for evidence for whether ultrasound is superior risk of pneumothorax of 2.7% and found clinicians. All invasive pleural procedures for guiding pleural interventions specifically that ultrasound guidance reduced the risk of carry a small risk of complications, and, for MPE. pneumothorax by 19% (odds ratio = 0.81, therefore, any intervention must have Summary of the evidence. The search 95% CI = 0.74–0.90) (14). The frequency benefits that outweigh these risks. One strategy for this question obtained one of chest tube placement was not reported potential benefit of early intervention that retrospective observational study that for this study, but pneumothorax was has been regularly proposed is the possible specifically assessed complication rates associated with a significantly longer length reduced risk of developing a nonexpandable for thoracentesis in MPE with or of hospital stay and total patient lung at a later stage in the disease process. without ultrasound guidance (16). Three hospitalization cost (14). Despite the lack of Summary of the evidence. The search retrospective observational studies assessed a randomized trial comparing thoracentesis revealed two studies pertinent to the clinical safety and efficacy for ultrasound guidance with and without ultrasound specifically in question. Improvement in quality of life, of pleural effusions, including, but not patients with MPE, the panel agrees that breathlessness, and other symptoms (e.g., limited to, MPE were also included in ultrasound guidance, which has no pain), future need of interventions, and days the initial review (17–19). In addition, significant harms associated with its usage, spent in hospital during the patient’s two studies comprised of larger patient has an important benefit of reducing remaining lifespan were considered critical populations, including a meta-analysis pneumothorax rates. outcomes, and healthcare costs for fluid (13) and large retrospective cohort (14) Recommendation. In patients with management in remaining lifespan and that reviewed complication rates after known or suspected MPE, we suggest walking distance or other exertional thoracentesis for all causes of pleural that ultrasound imaging be used to guide activities were considered important effusion were included to help formulate pleural interventions (conditional outcomes. Tremblay and colleagues (22) the recommendation. recommendation, very low confidence in undertook a retrospective review of 113 The outcomes of pneumothorax, and estimate of effects; see Tables E4A and E5A patients presenting to a lung cancer clinic pneumothorax requiring chest tube in the online supplement). over a 3-month period in Canada with a placement, were considered critical. No Justification and implementation pleural effusion on chest radiography or studies assessed other complication rates considerations. This recommendation is computed tomography (CT) thorax. A total (i.e., hemothorax, pain at site) or procedural based not only on the limited observational of 14 of these were asymptomatic or did not success specifically for malignant effusions. evidence for ultrasound guidance for require intervention; 13 patients were then The use of ultrasound guidance management of malignant effusions, but followed up for a median time of 98 days, reduced the risk of pneumothorax after also on the stronger evidence from larger and none required intervention during thoracentesis for malignant effusions (1.0% studies in the management of pleural this period. The study’s conclusions were vs. 8.9%, relative risk [RR] = 0.10, 95% effusions of all types described previously limited by the small number of patients and confidence interval [CI] = 0.03–0.37) (16). here. its retrospective design. It was also limited There were no chest tubes placed in the The decision to use ultrasound to patients with lung cancer, and the ultrasound guidance group compared guidance for pleural interventions in follow-up period was relatively short. with three (2.2%) chest tubes in the patients with malignant effusions will Porcel and colleagues (2) published a group without image guidance (95% CI depend on local expertise, availability, and retrospective study of 556 patients with not estimable) (16). The other three access to ultrasound machines. newly diagnosed lung cancer. They found observational studies (17–19) assessed Research priorities. Future studies that 40% of patients with lung cancer safety and success of ultrasound guidance should further investigate the use of developed a pleural effusion during the in pleural effusions of all causes, and did ultrasound in expanded roles for pleural course of their disease, half of which not report complication rates specifically interventions in patients with malignant were too small for any sampling or for malignant effusions. effusions. For example, ultrasound can be intervention. Of these 112 (20%) cases Two larger studies assessed the risk of used to identify intercostal vessels, with the with small/minimal pleural effusions, none pneumothorax after thoracentesis with or goal of decreasing the small, but real, risk required an interventional procedure without ultrasound guidance for all causes of hemorrhagic complications associated during follow up (mean 6 SD = 10 6 11 of pleural effusion. A meta-analysis of 24 with pleural procedures (20). In addition, mo). Although these small effusions did not studies and 6,605 thoracenteses published in ultrasound can be used to evaluate for go on to become symptomatic, they did 2010 found that the overall pneumothorax nonexpandable lung before thoracentesis, confer a survival disadvantage compared risk after thoracentesis was 6.0%, and that which may aid in guiding definitive with those without a pleural effusion

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P , (median survival, 7.5 vs. 12.7 mo; literature) (24). Nonexpandable lung occurs of 19 cm H2O or greater did not achieve 0.001). This finding was mirrored in a in at least 30% of patients with MPEs, and pleurodesis. The small cohort size, lack of a larger Korean series (7.7 mo vs. 17.7 mo; may be a contraindication for pleurodesis validation group, and longer-term follow- P , 0.001) (23). (8, 25–27). The absence of lung expansion up preclude a more definitive conclusion. Recommendation. In patients with after fluid evacuation should ideally steer Likewise, there are no studies that demonstrate known or suspected MPE who are the clinician to avoid futile attempts at the benefits of a therapeutic thoracentesis to asymptomatic, we suggest that therapeutic pleurodesis and use IPCs as the treatment guide definitive pleural intervention. Despite pleural interventions not be performed of choice in these patients. the sparse evidence, the panel agreed that (conditional recommendation, very low Measurement of pleural pressures or the potential benefits of large-volume confidence in estimate of effects; Tables E4B elastance (change in pressure over volume thoracentesis, including identification of lung and E5B). drained) is one of the most studied entrapment and nonresolution of dyspnea, Justification. Data are insufficient to approaches to predict if the lung will expand outweighed the harms. recommend sampling or draining these after drainage. Studies to date generally Recommendation. In patients with asymptomatic effusions. Unless there are included both malignant and benign symptomatic MPE, we suggest large-volume clinical indications, such as obtaining fluid effusions, and the majority investigated thoracentesis if it is uncertain whether the to define clinical stage/obtain molecular the “safety” limit of how much fluid patient’s symptoms are related to the markers, the drainage of asymptomatic can be removed, and prediction of effusion and/or if the lung is expandable effusions would only subject the patient to nonexpandable lungs was based on the (the latter if pleurodesis is contemplated) the risks of the procedure (albeit a small changes in pressure curves, rather than a to assess lung expansion (conditional risk) without providing clinical benefit. post-drainage chest CT (26, 28, 29). Lung recommendation, very low confidence in Clearly, if pleural fluid is required for expansion can be assessed with positive- estimate of effects; Tables E4C and E5C). diagnostic purposes, fluid and/or tissue pressure ventilation if the patient Justification. There is limited evidence sampling would be appropriate. undergoes thoracoscopy performed under defining the benefits on clinical outcomes in Research priorities. Published general anesthesia (30). Post-procedure patients with MPEs to support the routine literature on this topic has focused imaging after draining all/most-all of the use of pleural pressure measurements or exclusively on MPE in the lung cancer pleural fluid can also assess lung therapeutic thoracentesis to guide definitive setting. A large prospective study of all expansion. Another benefitofalarge- pleural palliation. Despite the sparse MPEs is needed with longer follow up of volume drainage procedure lies in evidence, the panel agreed that the potential subjects. A prospective study evaluating confirming that the patient’s dyspnea is due to benefits of large-volume thoracentesis, whether delay in draining asymptomatic the effusion. This may not be apparent if only including identification of nonexpandable pleural effusions increases the risk of a small-volume diagnostic thoracentesis is lung entrapment and nonresolution of subsequent nonexpandable lung should performed (31). If the patient does not receive dyspnea, outweighed the harms. It is also also be investigated. Likewise, as pleural benefit from the thoracentesis, the clinician noteworthy (see the subsequent PICOs) that palliation can still be achieved in patients needstoinvestigateothercausesofdyspnea IPC is an option suitable for both patients with who develop symptoms even with (i.e., pulmonary embolism, pericardial expandable and nonexpandable lung, and is nonexpandable lung, trials defining the effusion, etc.), and further attempts at pleural now considered an adequate alternative to optimal way to palliate effusions from a palliation are not required. Likewise, a pleurodesis in patients who have expandable patient and cost perspective are essential. large-volume thoracentesis may offer lung. As such, if the plan is to manage the It is also vital for us to improve our further insight into the speed of pleural MPE with an IPC, a large-volume understanding of what biological role an fluid reaccumulation after drainage. Recent thoracentesis to assess lung expansion, MPE may play in disease progression and data suggest that up to 60% of patients will regardless of whether the lung expands an why survival is significantly worsened by the require another procedure within 9 days additional procedure (therapeutic development of asymptomatic pleural after initial drainage (3). thoracentesis), may not be required. effusion in patients with known lung cancer. Summary of the evidence. Studies of Research priorities. Research is needed drainage/manometry are limited by to establish better means to predict PICO 3: Should the Management of variation in how manometry was symptomatic response from MPE drainage, Patients with Symptomatic Known performed, cut-off values selected, exact and also to predict lung expansion to guide or Suspected MPE Be Guided by parameter(s) captured, heterogeneity of individualized treatment. Future studies Large-Volume Thoracentesis and patient populations enrolled, and lack of of manometry should first focus on Pleural Manometry? long-term follow up. Only one study has standardizing measurement parameters, and examined the use of manometry in then applying it to the algorithm of MPE Background. Performing a therapeutic predicting “longer-term” outcomes. Lan management to assess its role (if any) on long- drainage before a definitive pleural and colleagues (32) reported results of term clinical outcomes. In addition, prospective intervention in patients with MPE can serve 55 patients with MPE who underwent studies investigating the utility of performing a two purposes: confirming symptomatic bleomycin pleurodesis. An elastance of less therapeutic thoracentesis before definitive improvement after fluid drainage and than 19 cm H2O measured after draining therapy, especially focusing on patient-centered identifying the presence of nonexpandable 500 ml of fluid predicted a 98% chance of outcomes, are needed. Advanced ultrasound lung (also referred to as “unexpandable success, defined as pleural fluid control at methods are also being investigated to identify lung” or “lung entrapment” in the 1 month. All 11 patients with an elastance nonexpandablelungbeforethoracentesis(21).

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PICO 4: In Patients with Symptomatic favored IPCs (mean difference of 214.0 mm, treatment failure as critical, patient- MPE with Known or Suspected 95% CI = 225.2 to 22.8; P = 0.01) (37). centered outcomes; cellulitis, although Expandable Lung and No Prior There was no significant difference in ranked below the critical outcomes, was so Definitive Therapy, Should IPCs or survival between the two interventions, strongly associated with IPCs as to result in Chemical Pleurodesis Be Used although no study examined survival as a a neutral recommendation for either option as First-Line Definitive Pleural primary outcome. Two studies reporting for relief of dyspnea. Clearly, when Intervention for Management of 3-month mortality showed no difference performed as an inpatient, chemical Dyspnea? between IPC and pleurodesis (RR = 1.25, pleurodesis will have an increased initial 95% CI = 0.45–3.45) (25, 37). hospital stay compared with an outpatient Background. Historically, the treatment For hospital LOS, IPCs were favored in IPC placement. When choosing one option of choice for patients with MPE has all studies that reported this outcome. In the over the other, care providers should factor been pleurodesis, with talc being the AMPLE study, the difference in median LOS in the specific patient’s values and recommended agent of choice (8, 33). was 2.92 days (95% CI = 0.43–5.84) (30). preferences by taking into consideration To achieve pleurodesis, it is necessary to NVALT-14 also reported fewer median thatIPCsreducetimeinhospital,butare have the visceral and parietal pleura in hospital days for patients who underwent associated with an increased risk of apposition. Given that at least 30% of IPC compared with chemical pleurodesis cellulitis. A recently published RCT, the patients with MPE have nonexpandable (2 d vs. 7 d, respectively; P , 0.001) (27), IPC-Plus study (6), showed that the lung (25), and the fact that dyspnea in whereas the TIME-2 reported a median combination of IPC and talc slurry patients with pleural effusion relates more of 3.5 fewer hospital days (95% CI = 24.8 resulted in higher pleurodesis rates and to diaphragmatic inefficiency than lung to 21.5) (36, 37). improved quality of life in the IPC-talc expansion (34), IPCs have become the For treatment failure as assessed by the group as compared with the IPC-saline treatment of choice for patients with known need for additional ipsilateral interventions, group. Our recommendation is an nonexpandable lung (8). There are currently pooled results from four studies favored important advance in the management no recommendations as to whether IPCs IPCs over chemical pleurodesis (RR = 0.32, of MPE, as previous guidelines had or pleurodesis should be used in patients 95% CI = 0.18–0.55) (36, 37, 39, 42). recommended IPCs as a treatment option with known or suspected expandable Infectious complications were reported onlyforpatientswithnonexpandable lung. more frequently with IPCs. Pooled results lungs, and some physicians had refrained Summary of the evidence. The search from four randomized controlled trials fromplacingIPCsinpatientswith strategy for this question yielded 10 studies, (RCTs) showed a fivefold-increased risk of expandable lungs. including 1,279 participants. Studies cellulitis with IPCs when compared with Research priorities. Additional studies included pleurodesis via surgical or medical chemical pleurodesis (RR = 5.83, 95% CI = should be conducted to validate the findings thoracoscopy with talc poudrage, chest 1.56–21.87) (36, 37, 39, 42); there was a of the aforementioned studies and further tube with talc slurry, repeat thoracentesis, similar trend for increased rates of pleural assess whether IPCs may be superior to or no treatment. Of the studies included, infection with IPCs (RR = 3.32, 95% CI = pleurodesis for outcomes, such as total five were randomized controlled trials 0.82–13.44). days spent in the hospital, patient-reported (Putnam and colleagues [35], NVALT No RCTs reported bleeding quality of life, and other patient-centered [Dutch Society of Pulmonologists]-14 complications requiring intervention. measures. Other factors that should be [36], TIME [Therapeutic Intervention in Pooled results from 174 patients in two addressed in future studies include Malignant Effusion]-2 [37], CALGB retrospective studies showed no difference patients’ preference, cost implications, [Cancer and Leukemia Group B] 30102 between treatment arms (IPC 2.2% vs. and variation in practice and resources in [38], and AMPLE [Australian Malignant chemical pleurodesis 3.7%) (41, 43). different regions of the world. Studies Pleural Effusion] [39]), four were Recommendation. In patients with combining IPCs with chemical retrospective observational studies MPE with known (or likely) suspected pleurodesis are being conducted, and (40–43), and one was a prospective expandable lung and no prior definitive the results from these trials may provide observational study (44). The critical therapy, and whose symptoms are additional options that can be beneficial to outcomes included improvement in attributable to the effusion, we the patients. dyspnea, survival, mortality, hospital suggest that either IPCs or chemical length of stay (LOS), and treatment failure, pleurodesis be used as first-line definitive PICO 5: In Patients with Symptomatic as 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

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AMERICAN THORACIC SOCIETY DOCUMENTS priority. Guidelines recommend the use important. Other complications (cellulitis and There were no extractable data for of a “definitive” pleural procedure after fever) were considered not important for this important outcomes, such as breathlessness recurrence of pleural fluid after an initial outcome. and time in hospital. thoracentesis; however, a recent large Of the randomized trials, the largest A published network meta-analysis retrospective study of 23,431 patients one compared surgical thoracoscopic talc (33) assessed optimal management for with MPE demonstrated that only 24% poudrage to talc slurry pleurodesis in prevention of malignant effusion underwent a definitive pleural procedure 482 patients, assessing only those with recurrence, and included 62 randomized (as opposed to repeat thoracentesis) after greater than 90% expansion of the lung studies of all pleurodesis agents, including rapid reaccumulation of fluid (3). Those on chest radiograph (25). No difference talc and IPCs. This analysis rated talc undergoing definitive pleural procedures was found between pleurodesis success at pleurodesis as highly effective for experienced fewer additional pleural 1 month (78% for poudrage vs. 72% prevention of fluid recurrence. Both talc procedures, fewer procedures performed in for slurry). Yim and colleagues (46) poudrage and slurry were ranked highly, the emergency department, and fewer randomized 57 patients with expandable but one method was not significantly better complications than those undergoing lung and good performance status to talc than the other, consistent with our findings repeat thoracentesis, underlining the poudrage or slurry pleurodesis, with no described previously here. importance of definitive pleural difference between groups in terms of Recommendation. In patients with intervention at the appropriate time in pleurodesis success or hospital stay. Terra symptomatic MPE and expandable lung the treatment process. and colleagues (47) randomized 60 patients undergoing talc pleurodesis, we suggest the Pleurodesis involves the administration to surgical poudrage or talc slurry use of either talc poudrage or talc slurry of a drug or material in the pleural space to pleurodesis and demonstrated a higher rate (conditional recommendation, low cause adhesions between the parietal and of immediate lung expansion (.90% on confidence in estimate of effects; Tables E4E visceral pleura, and prevention of fluid CT) in the surgical group, but no difference and E5E). reaccumulation. Talc is the most widely in any other outcome over 6 months. Justification and implementation used pleurodesis agent, and has been shown Collating all the evidence, there were considerations. Given the low confidence in previous meta-analysis (33) and a head- inconclusive findings for mortality in estimates for critical outcomes, the panel to-head RCT (45) to be the most effective the randomized trials (RR = 0.70, 95% could not recommend one approach over pleurodesis agent. There are two delivery CI = 0.33–1.12). There was a larger and the other. The decision to use poudrage or methods: talc poudrage (also known as statistically significant effect seen in the slurry should depend on several factors, insufflation), which is conducted during observational studies (RR = 0.22, 95% CI = including local expertise (i.e., availability either surgical or medical thoracoscopy, 0.06–0.80) favoring talc poudrage, but it is of thoracoscopy), whether additional tissue when talc is blown in as a dry powder; or likely that selection bias seriously affects is needed for molecular-marker analysis talc slurry, when talc mixed with sterile this result (as fitter patients will be (would favor thoracoscopy), as well as fluid is injected through a chest tube at the selected for talc poudrage over slurry in patient-related factors (i.e., if a chest tube is bedside. observational studies). already in place). Summary of the evidence. The search Findings were also inconclusive, Research priorities. A prospective, strategy for this question found three with no significant differences between randomized study of patients with expandable randomized trials (25, 46, 47), two treatment arms for respiratory failure lung comparing talc poudrage via medical prospective observational studies (48, 49), (RR = 1.74, 95% CI = 0.81–3.74) or for thoracoscopy and slurry via “small bore” four meta-analyses (50–53), and a network treatment failure in either the randomized (,14F) chest tubes is ongoing (54). There are meta-analysis (33). Studies included both trials (RR = 1.02, 95% CI = 0.31–3.31) or a number of important research areas that general anesthetic and local anesthetic the observational studies (RR = 0.74, require further evidence. These should focus thoracoscopic talc poudrage under either 95% CI = 0.51–1.06). on patient-centered outcome measures of general or local anesthesia, and poudrage Therewerenosignificant differences breathlessness/quality of life, if patients conducted either by pulmnologists or in complications between poudrage and undergoing talc pleurodesis (via either surgeons. Data from the published meta- slurry (see evidence table), with the poudrage or slurry) require hospital analyses were not used for evidence exception of an increase in pneumonia admission and if aggressive pleural synthesis, as they were outdated, included favoring talc slurry, but this was drainage schedules can lead to lower total unpublished data, or reported outcomes imprecisely estimated (RR = 2.18, 95% catheter days in patients treated with both that were poorly defined. For example, CI = 1.02–4.64). IPC and talc than the more conservative Mummadi and colleagues (52) pooled In a post hoc subgroup analysis, the schedule used in the IPC-plus study (6). all respiratory complications as one largest study to date (25) reported results outcome, whereas Tan and colleagues (51) did that favored poudrage compared with PICO 6: In Patients with Symptomatic not define the outcome of effusion recurrence. slurry in patients with expandable lung, and MPE with Nonexpandable Lung, In our review, the outcomes of mortality, MPE due to either lung cancer or breast Failed Pleurodesis, or Loculated respiratory failure, and treatment success cancer (82% vs. 67% pleurodesis success Effusion, Should an IPC or Chemical (defined as no further ipsilateral pleural at 1 mo in those alive to be assessed; Pleurodesis Be Used? intervention) were considered critical, and the P = 0.022). However, care should be taken outcomes of complications (empyema, in interpretation of this finding in isolation Background. At least 30% of patients with bleeding, pneumonia) were considered and as a post hoc subgroup analysis. MPE will have nonexpandable lung (25).

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Likewise, pleurodesis is unsuccessful in up for studies to directly compare IPC and of IPC-associated infection among 107 to 30% of patients (25), and as many as 14% pleurodesis for alleviating breathlessness patients. One case series comprising nearly of patients with MPE develop symptomatic in patients with partially expandable half of the pooled patient population did not loculations after prior treatment (8, 44). lung, loculated effusion, and failed talc comment on whether infected IPCs were The use of an IPC in these patient groups pleurodesis. Thomas and colleagues (61) removed (67). In the remaining case series, may enable further drainage of fluid, have shown significant increases in pleural 41 of 57 patients (72%) were managed alleviation of symptoms, and avoidance drainage and improvement in symptoms without removing the infected IPC (44, 64, of admission and multiple subsequent in selected patients with IPC-related 68–70). Although no comparative data were procedures. symptomatic loculations with the use of reported between the two groups, the pooled Summary of the evidence. The search fibrinolytics; however, there was a small mortality attributed to the IPC infection strategy for this question yielded five (3%) risk of nonfatal hemorrhagic among these 57 patients was 12.3%. When noncomparative case series (55–59) complications. A recent RCT, however, examining all case series with 107 patients, and a single prospective, comparative suggested no benefit of intrapleural the pooled mortality attributed to IPC observational study (60). The outcomes of urokinase (given via a chest tube) in infection was 9.3%. mortality and reduced hospital stay (LOS of patients with loculated MPE (62). There are no data suggesting that 2 d or less) were considered critical, and the Additional prospective studies are catheter removal is superior or inferior to outcomes of complications (i.e., empyema) required to define the role that keeping the catheter in place. were considered important. fibrinolytics have in the treatment of Recommendation. In patients with No difference was demonstrated in symptomatic loculations, including dose, IPC-associated infections, treating through mortality in the single comparative study dwell time, and clinical setting (inpatient the infection without catheter removal is (60). There appeared to be a large effect vs. outpatient). It should also be noted usually adequate. We suggest catheter of reduced hospital stay using IPCs in that “loculated effusion” can represent a removal if the infection fails to improve the single comparative study, with 19 very heterogenous group, and that patients (conditional recommendation, very low of 34 patients with IPC (56%) staying in with a few loculations may still benefit confidence in estimate of effects; Tables E4G the hospital less than 2 days compared from pleurodesis. Likewise, in a patient and E5G). with 0 of 7 patients receiving talc with a good performance status and low Justification. Given the lack of strong pleurodesis (60). LENT (pleural fluid lactate dehydrogenase, data supporting one method of treatment There were no comparative data on Eastern Cooperative Oncology Group over another, clinical experience suggests complications, but the pooled risk of performance score, neutrophil-to- that patients can be treated in a variety complications across case series for IPCs lymphocyte ratio, and tumor type) score (a of ways, including oral or intravenous used in patients with nonexpandable lung marker of expected relatively good survival antibiotics, as well as keeping the catheter or failed pleurodesis was relatively low for in MPE) (63), it may not be unreasonable in place, or removing the catheter. both empyema (2.4%) and cellulitis (3.8%) to offer minimally invasive (video-assisted Treatment decisions should be made on an (55, 56, 58, 59). thoracoscopic surgery or robotic assisted) individual basis. Considerations should be No studies reported breathlessness or decortication. made based on the clinical status of the treatment failure as an outcome. patient, including signs/symptoms of Recommendation. In patients with PICO 7: In Patients with IPC-associated pleural sepsis (i.e., fever, leukocytosis, symptomatic MPEs with nonexpandable Infection (Cellulitis, Tunnel Infection, failure to thrive), as well as the type lung, failed pleurodesis, or loculated or Pleural Infection), Should Medical of infection (pleural space vs. tunnel effusion, we suggest the use of IPCs over Therapy Alone or Medical Therapy and infection vs. cellulitis) and the risks of chemical pleurodesis (conditional Catheter Removal Be Used? symptomatic fluid reaccumulation should recommendation, very low confidence in the catheter be removed. Considerations estimate of effects; Tables E4F and E5F). Background. IPCs have become the as to resources available to provide Justification. This recommendation is treatment of choice for many patients with home intravenous antibiotic therapy, based primarily on the reduced LOS and low MPE (8, 38, 40, 64–66). Though the the proximity of the patient to the care observed incidence of complications incidence of IPC-related infection is low, team, as well as the patient’slocal associated with IPCs, as well as abundant catheter-related infection remains a support network should be taken into clinical experience that chemical pleurodesis concern, as well as a potential barrier to account. Patients with IPC-related is rarely effective in the setting of their use. Aggregated data from three RCTs pleural infection require close monitoring nonexpandable lung. None of the studies show IPC-related rates of cellulitis and to assure clinical improvement with the examined the success rate (resolution of pleural space infection of 7.3% and 4.6%, implemented treatment plan. Should symptoms or need for additional pleural respectively (35, 37, 44). Unfortunately, there be any worsening of the patient’s procedures) of talc pleurodesis in patients there are few data regarding the clinical status (i.e., development of who either had prior unsuccessful attempts management of IPC-related infection. pleural sepsis), it would be appropriate at pleurodesis or developed symptomatic Summary of the evidence. The search to escalate intervention (i.e., switch loculations after either pleurodesis or IPC strategy for this question yielded six from oral to intravenous antibiotics, placement. noncomparative observational studies (44, consider catheter removal, rediscuss Research priorities. Given the paucity 64, 67–70) and one nested case series within the patient’s course with a of robust clinical data, there is a clear need an RCT (37) that reported clinical outcomes multidisciplinary team).

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Research priorities. Future studies the IPC. Outcomes should include Discussion should investigate the best treatment for mortality, resource utilization, and need IPC-related pleural infection, including for escalation of care. Confounders in These recommendations (Figure 1) focus the need for catheter removal, the initial future studies include colonization versus on patient-centered outcomes, such as use of oral versus intravenous antibiotics, true infection, as well as distinguishing dyspnea, and the need for recurrent inpatient versus outpatient therapy, cellulitis versus tunnel infection versus procedures and hospitalizations. Clearly, and the use of rTPA-DNase through empyema. as with the PICO 3 recommendations that

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

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.

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IPCs or chemical pleurodesis can be used achieve the “best of both worlds” in the approach to these patients (74). Patient- for patients with MPE and expandable future, with approaches combining IPCs reported outcome measures should be lung, the specificrisksandbenefits of each with pleurodesis agents (6, 71). prioritized over secondary endpoints, procedure should be discussed in detail As our understanding of the molecular such as radiographic improvement (31). with the patient/caregiver, and decisions mechanisms of pleural fluid Given the “critical mass” of interested should be made on an individual basis. formation/resorption and pleurodesis researchers and collaboration between the Factors influencing this specificdecision evolve (72, 73), future trials can focus on traditionally siloed disciplines of surgery, can include the availability of a support “turning off” production, increasing medicine, and radiology, we anticipate network to help with IPC drainage, resorption, or creating pleurodesis with significant progress in the field of MPE and the patient’sdesiretoavoid minimally invasive techniques. In in the forthcoming years and the need hospitalization. Likewise, small studies addition, the role of gene therapy and to re-evaluate our practice on a have suggested that we may be able to immunotherapy may significantly alter our regular basis. n

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.

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