The Pleural Effusion And Symptom Evaluation (PLEASE) study of breathlessness in patients with a symptomatic pleural effusion.

INTRODUCTION: Pathophysiology changes associated with pleural effusion, its drainage and factors governing symptom response are poorly understood. Our objective was to determine: 1) the effect of pleural effusion (and its drainage) on cardiorespiratory, functional and diaphragmatic parameters; and 2) the proportion as well as characteristics of patients with breathlessness relief post-drainage. METHODS: Prospectively enrolled patients with symptomatic pleural effusions were assessed at both pre-therapeutic drainage and at 24-36 h post-therapeutic drainage. RESULTS: 145 participants completed pre-drainage and post-drainage tests; 93% had effusions ≥25% of hemithorax. The median volume drained was 1.68 L. Breathlessness scores improved post-drainage (mean visual analogue scale (VAS) score by 28.0±24 mm; dyspnoea-12 (D12) score by 10.5±8.8; resting Borg score before 6-min walk test (6-MWT) by 0.6±1.7; all p<0.0001). The 6-min walk distance (6-MWD) increased by 29.7±73.5 m, p<0.0001. Improvements in vital signs and spirometry were modest (forced expiratory volume in 1 s (FEV1) by 0.22 L, 95% CI 0.18-0.27; forced vital capacity (FVC) by 0.30 L, 95% CI 0.24-0.37). The ipsilateral hemi-diaphragm was flattened/everted in 50% of participants pre-drainage and 48% of participants exhibited paradoxical or no diaphragmatic movement. Post-drainage, hemi-diaphragm shape and movement were normal in 94% and 73% of participants, respectively. Drainage provided meaningful breathlessness relief (VAS score improved ≥14 mm) in 73% of participants irrespective of whether the lung expanded (mean difference 0.14, 95% CI 10.02-0.29; p=0.13). Multivariate analyses found that breathlessness relief was associated with significant breathlessness pre-drainage (odds ratio (OR) 5.83 per standard deviation (sd) decrease), baseline abnormal/paralyzed/paradoxical diaphragm movement (OR 4.37), benign aetiology (OR 3.39), higher pleural pH (OR per sd increase 1.92) and higher serum albumin level (OR per sd increase 1.73). CONCLUSIONS: Breathlessness and exercise tolerance improved in most patients with only a small mean improvement in spirometry and no change in oxygenation. Breathlessness improvement was similar in participants with and without trapped lung. Abnormal hemi-diaphragm shape and movement were independently associated with relief of breathlessness post-drainage.

Pleural effusions and pneumothorax: Beyond simple plumbing: Expert opinions on knowledge gaps and essential next steps.

Pleural diseases affect millions of people worldwide. Pleural infection, malignant pleural diseases and pneumothorax are common clinical challenges. A large number of recent clinical trials have provided an evidence-based platform to evaluate conventional and novel methods to drain pleural effusions/air which reduce morbidity and unnecessary interventions. These successes have generated significant enthusiasm and raised the profile of pleural medicine as a new subspecialty. The ultimate goal of pleural research is to prevent/stop development of pleural effusions/pneumothorax. Current research studies mainly focus on the technical aspects of pleural drainage. Significant knowledge gaps exist in many aspects such as understanding of the pathobiology of the underlying pleural diseases, pharmacokinetics of pleural drug delivery, etc. Answers to these important questions are needed to move the field forward. This article collates opinions of leading experts in the field in highlighting major knowledge gaps in common pleural diseases to provoke thinking beyond pleural drainage. Recognizing the key barriers will help prioritize future research in the quest to ultimately cure (rather than just drain) these pleural conditions.

Use of indwelling pleural/peritoneal catheter in the management of malignant ascites: a retrospective study of 48 patients.

BACKGROUND: Patients suffering from malignant ascites usually require repeated large volume paracentesis (LVP) for symptomatic relief. This often requires hospital admission and has inherent risks. AIMS: To report the first Australian experience of placing tunnelled indwelling peritoneal catheters (IPeC) for management of recurrent malignant ascites. METHODS: A retrospective study was conducted of tunnelled IPeC use in patients with symptomatic malignant ascites in four hospitals in Western Australia (from 2010 to 2018). Procedure data, success rate and safety profile were collected from a database. RESULTS: Forty-eight patients (median age 65 years; female 56%) underwent 51 peritoneal catheter insertion procedures that were performed mostly by pleural specialists. The majority of patients (96%) had prior LVP (median two drainages, interquartile range (IQR) 1-4) before IPeC insertion. The IPeC was inserted successfully under ultrasound guidance in all patients. The median length of hospital stay for IPeC insertion and initial ascites drainage was 2 days (IQR 2-3 days) and most patients (96%) did not require further paracentesis after IPeC placement. The majority (96%) of patients experienced relief from ascites symptoms after catheter insertion. Most IPeC-related adverse events were self-limiting, including pain (in 25% cases), transient hypotension after initial fluid drainage (10%), peritoneal fluid leakage (10%), bacterial peritonitis (8%), fluid loculation (2%) and catheter dislodgement (2%). Six (12%) patients had IPeC removed. All patients with bacterial peritonitis responded to antibiotics and one required catheter removal. CONCLUSIONS: Use of tunnelled IPeC improves symptoms and can minimise further invasive drainage procedures in patients with symptomatic malignant ascites. Placement of IPeC was associated with a low rate of adverse events, most of which could be managed conservatively.

Management of Malignant Pleural Effusions-What Is New.

Malignant pleural effusion (MPE) is a common and challenging problem. Patients affected by MPE have a poor prognosis and suffer from breathlessness and impaired quality of life. The management of MPE has barely changed for many decades; however, recent research has driven new paradigms in the diagnosis and treatment of MPE and stimulated novel concepts that are being evaluated in many ongoing studies. This review provides an overview of recent advances in the diagnosis of MPE, including new cytopathology and imaging techniques, and the landmark studies that provide a solid evidence base to support the use of indwelling pleural catheters as first-line treatment in MPE. Lingering management dilemmas, including optimal chest drainage tube and role of surgery in MPE, and key knowledge gaps that are the focus of ongoing research are also highlighted.

Exercise training for advanced lung cancer.

BACKGROUND: Patients with advanced lung cancer have a high symptom burden, which is often complicated by coexisting conditions. These issues, combined with the indirect effects of cancer treatment, can cumulatively lead patients to continued deconditioning and low exercise capacity. This is a concern as exercise capacity is considered a measure of whole body health, and is critical in a patient's ability to participate in life activities and tolerate difficult treatments. There is evidence that exercise training improves exercise capacity and other outcomes, such as muscle force and health-related quality of life (HRQoL), in cancer survivors. However, the effectiveness of exercise training on these outcomes in people with advanced lung cancer is currently unclear. OBJECTIVES: The primary aim of this review was to investigate the effects of exercise training on exercise capacity in adults with advanced lung cancer. Exercise capacity was defined as the six-minute walk distance (6MWD; in meters) measured during a six-minute walk test (6MWT; i.e. how far an individual can walk in six minutes on a flat course), or the peak oxygen uptake (i.e. VO2peak) measured during a maximal incremental cardiopulmonary exercise test (CPET).The secondary aims were to determine the effects of exercise training on the force-generating capacity of peripheral muscles, disease-specific global HRQoL, physical functioning component of HRQoL, dyspnoea, fatigue, feelings of anxiety and depression, lung function, level of physical activity, adverse events, performance status, body weight and overall survival in adults with advanced lung cancer. SEARCH METHODS: We searched CENTRAL, MEDLINE (via PubMed), Embase (via Ovid), CINAHL, SPORTDiscus, PEDro, and SciELO on 7 July 2018. SELECTION CRITERIA: We included randomised controlled trials (RCTs) which compared exercise training versus no exercise training in adults with advanced lung cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the studies and selected those for inclusion. We performed meta-analyses for the following outcomes: exercise capacity, disease-specific global HRQoL, physical functioning HRQoL, dyspnoea, fatigue, feelings of anxiety and depression, and lung function (forced expiratory volume in one second (FEV1)). Two studies reported force-generating capacity of peripheral muscles, and we presented the results narratively. Limited data were available for level of physical activity, adverse events, performance status, body weight and overall survival. MAIN RESULTS: We identified six RCTs, involving 221 participants. The mean age of participants ranged from 59 to 70 years; the sample size ranged from 20 to 111 participants. Overall, we found that the risk of bias in the included studies was high, and the quality of evidence for all outcomes was low.Pooled data from four studies demonstrated that, on completion of the intervention period, exercise capacity (6MWD) was significantly higher in the intervention group than the control group (mean difference (MD) 63.33 m; 95% confidence interval (CI) 3.70 to 122.96). On completion of the intervention period, disease-specific global HRQoL was significantly better in the intervention group compared to the control group (standardised mean difference (SMD) 0.51; 95% CI 0.08 to 0.93). There was no significant difference between the intervention and control groups in physical functioning HRQoL (SMD 0.11; 95% CI -0.36 to 0.58), dyspnoea (SMD -0.27; 95% CI -0.64 to 0.10), fatigue (SMD 0.03; 95% CI -0.51 to 0.58), feelings of anxiety (MD -1.21 units on Hospital Anxiety and Depression Scale; 95% CI -5.88 to 3.45) and depression (SMD -1.26; 95% CI -4.68 to 2.17), and FEV1 (SMD 0.43; 95% CI -0.11 to 0.97). AUTHORS' CONCLUSIONS: Exercise training may improve or avoid the decline in exercise capacity and disease-specific global HRQoL for adults with advanced lung cancer. We found no significant effects of exercise training on dyspnoea, fatigue, feelings of anxiety and depression, or lung function. The findings of this review should be viewed with caution because of the heterogeneity between studies, the small sample sizes, and the high risk of bias of included studies. Larger, high-quality RCTs are needed to confirm and expand knowledge on the effects of exercise training in this population.

Simplified Criteria Using Pleural Fluid Cholesterol and Lactate Dehydrogenase to Distinguish between Exudative and Transudative Pleural Effusions.

BACKGROUND: An important part of the investigation of pleural effusion is the identification of markers that help separate exudate from transudate. OBJECTIVES: The purposes of this study were to compare the accuracy of published and new sets of criteria to distinguish between exudative and transudative pleural effusions, and to determine whether serum biochemical analysis is necessary. METHODS: An externally validated cohort study was performed. Pleural effusions were determined to be transudative or exudative on the basis of an assessment of the medical record by two clinicians blinded to biochemical results. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and area under the receiver operating characteristic curve were determined for each proposed combination of criteria. RESULTS: Pleural fluid analysis was available for 311 thoracenteses in the main cohort and for 112 thoracenteses in the validation cohort. The best sensitivity (97% [95% CI 94-99]) and negative likelihood ratio (0.04 [95% CI 0.02-0.08]) for identifying exudative effusions were observed with criteria combining pleural fluid lactate dehydrogenase greater than 0.6 the upper limit of normal serum lactate dehydrogenase and pleural fluid cholesterol greater than 1.04 mmol/L (40 mg/dL). The overall diagnostic accuracy was similar to Light's criteria. Findings were similar in the validation cohort. CONCLUSIONS: Our proposed criteria using simultaneously pleural fluid lactate dehydrogenase and pleural fluid cholesterol can identify an exudate with a sensitivity and an overall diagnostic accuracy similar to Light's criteria. It avoids simultaneous blood sampling, thus reducing patient discomfort and potential costs.

Malignant pleural fluid from mesothelioma has potent biological activities.

BACKGROUND AND OBJECTIVE: Malignant pleural effusion (MPE) affects >90% of mesothelioma patients. Research on MPE has focused on its physical impact on breathlessness; MPE is rich in growth mediators but its contribution to tumour biology has not been investigated. We aimed to examine the potential effects of MPE in promoting growth, migration and chemo-resistance of mesothelioma. METHODS: Pleural fluid samples from 151 patients (56 mesothelioma, 60 metastatic pleural cancer and 35 benign) were used. Seven validated human mesothelioma cell lines and three primary cultured mesothelioma lines were employed. RESULTS: Pleural fluid from mesothelioma patients (diluted to 30%) consistently stimulated cell proliferation (trypan-blue cell viability assay) in five mesothelioma cell lines tested by (median) 2.23-fold over controls (all P < 0.0001). The fluid also induced cell migration by (median) 2.13-fold in six mesothelioma cell lines using scratch-wound assay. In a murine flank model of mesothelioma, tumour infused with daily instillations of pleural fluid grew significantly faster over saline controls (median 52.5 cm2 vs 28.0 cm2 at day 13, P = 0.028). Addition of MPE (diluted to 30%) to culture media significantly protected mesothelioma from cisplatin/pemetrexed-induced cell death in all three cell lines tested (median fold reduction of 1.29, 1.98 and 3.90, all P < 0.001 vs control). The growth effects of matched pleural fluid and cultured mesothelioma cells from the same patients did not differ significantly from unmatched pairs. CONCLUSION: This 'proof-of-concept' study reveals potent biological capabilities of malignant pleural fluid in mesothelioma pathobiology.

Effect of an Indwelling Pleural Catheter vs Talc Pleurodesis on Hospitalization Days in Patients With Malignant Pleural Effusion: The AMPLE Randomized Clinical Trial.

Importance: Indwelling pleural catheter and talc pleurodesis are established treatments for malignant pleural effusions among patients with poor prognosis. Objective: To determine whether indwelling pleural catheters are more effective than talc pleurodesis in reducing total hospitalization days in the remaining lifespan of patients with malignant pleural effusion. Design, Setting, and Participants: This open-label, randomized clinical trial included participants recruited from 9 centers in Australia, New Zealand, Singapore, and Hong Kong between July 2012 and October 2014; they were followed up for 12 months (study end date: October 16, 2015). Patients (n = 146) with symptomatic malignant pleural effusion who had not undergone indwelling pleural catheter or pleurodesis treatment were included. Interventions: Participants were randomized (1:1) to indwelling pleural catheter (n = 74) or talc pleurodesis (n = 72), minimized by malignancy (mesothelioma vs others) and trapped lung (vs not), and stratified by region (Australia vs Asia). Main Outcomes and Measures: The primary end point was the total number of days spent in hospital from procedure to death or to 12 months. Secondary outcomes included further pleural interventions, patient-reported breathlessness, quality-of-life measures, and adverse events. Results: Among the 146 patients who were randomized (median age, 70.5 years; 56.2% male), 2 withdrew before receiving the randomized intervention and were excluded. The indwelling pleural catheter group spent significantly fewer days in hospital than the pleurodesis group (median, 10.0 [interquartile range [IQR], 3-17] vs 12.0 [IQR, 7-21] days; P = .03; Hodges-Lehmann estimate of difference, 2.92 days; 95% CI, 0.43-5.84). The reduction was mainly in effusion-related hospitalization days (median, 1.0 [IQR, 1-3] day with the indwelling pleural catheter vs 4.0 (IQR, 3-6) days with pleurodesis; P < .001; Hodges-Lehmann estimate, 2.06 days; 95% CI, 1.53-2.58). Fewer patients randomized to indwelling pleural catheter required further ipsilateral invasive pleural drainages (4.1% vs 22.5%; difference, 18.4%; 95% CI, 7.7%-29.2%). There were no significant differences in improvements in breathlessness or quality of life offered by indwelling pleural catheter or talc pleurodesis. Adverse events were seen in 22 patients in the indwelling pleural catheter group (30 events) and 13 patients in the pleurodesis group (18 events). Conclusions and Relevance: Among patients with malignant pleural effusion, treatment with an indwelling pleural catheter vs talc pleurodesis resulted in fewer hospitalization days from treatment to death, but the magnitude of the difference is of uncertain clinical importance. These findings may help inform patient choice of management for pleural effusion. Trial Registration: anzctr.org.au Identifier: ACTRN12611000567921.

Histopathology of removed indwelling pleural catheters from patients with malignant pleural diseases.

BACKGROUND AND OBJECTIVE: Indwelling pleural catheters (IPC), used for management of malignant pleural effusions, are often left in situ for a long duration. This study reports for the first time the histological findings of IPCs removed from patients with underlying pleural malignancy. METHODS: Forty-one IPCs (in situ for median 126 days, interquartile range 43-226) that were removed over a 54-month period from a single centre were examined. RESULTS: Mesothelioma (n = 18) was the predominant underlying malignancy followed by breast, tubo-ovarian and lung carcinomas. The catheter tubing was fully intact macroscopically in all IPCs. There was no evidence of direct tumour invasion or cancer cell growth on the catheter surfaces in none of the 29 IPCs that were histologically examined. Malignant cells were seen within organizing fibrinous tissues in the lumen of 11 IPCs (27%). A foreign body giant cell reaction was present at the cuff site in all the 29 IPC in which the subcutaneous cuff was examined. Acute (n = 10) and/or chronic inflammatory changes were seen in the luminal contents in all 41 IPCs. CONCLUSION: Our study provides reassuring evidence that the IPC material does not support direct tumour growth or invasion even in the setting of high mesothelioma prevalence. See Editorial, page 787.

Physiology of breathlessness associated with pleural effusions.

PURPOSE OF REVIEW: Pleural effusions have a major impact on the cardiorespiratory system. This article reviews the pathophysiological effects of pleural effusions and pleural drainage, their relationship with breathlessness, and highlights key knowledge gaps. RECENT FINDINGS: The basis for breathlessness in pleural effusions and relief following thoracentesis is not well understood. Many existing studies on the pathophysiology of breathlessness in pleural effusions are limited by small sample sizes, heterogeneous design and a lack of direct measurements of respiratory muscle function. Gas exchange worsens with pleural effusions and improves after thoracentesis. Improvements in ventilatory capacity and lung volumes following pleural drainage are small, and correlate poorly with the volume of fluid drained and the severity of breathlessness. Rather than lung compression, expansion of the chest wall, including displacement of the diaphragm, appears to be the principle mechanism by which the effusion is accommodated. Deflation of the thoracic cage and restoration of diaphragmatic function after thoracentesis may improve diaphragm effectiveness and efficiency, and this may be an important mechanism by which breathlessness improves. Effusions do not usually lead to major hemodynamic changes, but large effusions may cause cardiac tamponade and ventricular diastolic collapse. Patients with effusions can have impaired exercise capacity and poor sleep quality and efficiency. SUMMARY: Pleural effusions are associated with abnormalities in gas exchange, respiratory mechanics, respiratory muscle function and hemodynamics, but the association between these abnormalities and breathlessness remains unclear. Prospective studies should aim to identify the key mechanisms of effusion-related breathlessness and predictors of improvement following pleural drainage.