Patient-Reported Outcomes in Pleural Effusions: A Systematic Review.

Pleural effusions cause breathlessness, decreased activity levels, and impaired quality of life. Clinical trials of drainage of pleural effusion use patient-reported outcome measures (PROMs) to assess these variables. This systematic review aimed to identify which PROMs have been used in clinical trials in pleural effusions, what variables were assessed, whether they were responsive to pleural interventions, and whether they have been validated in patients with pleural effusions, including a defined minimal clinically important difference (MCID). A systematic review was performed to identify relevant clinical trials from Medline, EMBASE, Emcare, and CINAHL and data were extracted. From 329 abstracts, 29 clinical trials of pleural effusion drainage that used PROMs as an outcome measure were identified. A total of 16 different PROMs were used. The most used PROMs were unidimensional measurements of breathlessness, particularly the visual analogue scale for dyspnoea (VASD), all of which nearly showed improvements in breathlessness following pleural fluid drainage. Other variables commonly assessed included activity levels and health-related quality of life. Multidimensional PROMs showed inconsistent responsiveness to pleural fluid drainage. Only the VASD was validated in this patient group with a defined MCID. A range of PROMs are used in clinical trials of pleural fluid drainage. No single PROM measures all the outcomes of interest. Unidimensional measurements of breathlessness are responsive to pleural fluid drainage. Only the VASD is validated with an MCID. There is a need for properly validated, response PROMs which measure the key outcomes of interest in this patient group.

Staging by Thoracoscopy in potentially radically treatable Lung Cancer associated with Minimal Pleural Effusion (STRATIFY): protocol of a prospective, multicentre, observational study.

INTRODUCTION: Recurrence rate following radical therapy for lung cancer remains high, potentially reflecting occult metastatic disease, and better staging tools are required. Minimal pleural effusion (mini-PE) is associated with particularly high recurrence risk and is defined as an ipsilateral pleural collection (<1/3 hemithorax on chest radiograph), which is either too small to safely aspirate fluid for cytology using a needle, or from which fluid cytology is negative. Thoracoscopy (local anaesthetic thoracoscopy (LAT) or video-assisted thoracoscopic surgery (VATS)) is the gold-standard diagnostic test for pleural malignancy in patients with larger symptomatic effusions. Staging by Thoracoscopy in potentially radically treatable Lung Cancer associated with Minimal Pleural Effusion (STRATIFY) will prospectively evaluate thoracoscopic staging in lung cancer associated-mini-PE for the first time. METHODS AND ANALYSIS: STRATIFY is a prospective multicentre observational study. Recruitment opened in January 2020. The primary objective is to determine the prevalence of detectable occult pleural metastases (OPM). Secondary objectives include assessment of technical feasibility and safety, and the impact of thoracoscopy results on treatment plans, overall survival and recurrence free survival. Inclusion criteria are (1) suspected/confirmed stages I-III lung cancer, (2) mini-PE, (3) Performance Status 0-2 (4), radical treatment feasible if OPM excluded, (5) ≥16 years old and (6) informed consent. Exclusion criteria are any metastatic disease or contraindication to the chosen thoracoscopy method (LAT/VATS). All patients have LAT or VATS within 7 (±5) days of registration, with results returned to lung cancer teams for treatment planning. Following an interim analysis, the sample size was reduced from 96 to 50, based on a lower-than-expected OPM rate. An MRI substudy was removed in November 2022 due to pandemic-related site setup/recruitment delays. These also necessitated a no-cost recruitment extension until October 2023. ETHICS AND DISSEMINATION: Protocol approved by the West of Scotland Research Ethics Committee (Ref: 19/WS/0093). Results will be published in peer-reviewed journals and presented at international meetings. TRIAL REGISTRATION NUMBER: ISRCTN13584097.

Silver Nitrate-coated versus Standard Indwelling Pleural Catheter for Malignant Effusions: The SWIFT Randomized Trial.

Rationale: Tunneled, indwelling pleural catheters (IPCs) have been demonstrated to be an effective method of managing malignant pleural effusions. However, they allow pleurodesis and can therefore be removed in only a subset of patients. A novel, silver nitrate-coated IPC was developed with the intention of creating a rapid, effective chemical pleurodesis to allow more frequent and earlier catheter removal. This study represents the pivotal clinical trial evaluating that catheter versus the standard IPC. Objectives: To compare the efficacy of a novel silver nitrate-eluting indwelling pleural catheter (SNCIPC) with that of a standard, uncoated catheter. Methods: The SWIFT [A Pivotal Multi-Center, Randomized, Controlled, Single-Blinded Study Comparing the Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) to the Uncoated PleurX® Pleural Catheter for the Management of Symptomatic, Recurrent, Malignant Pleural Effusions] trial was a multicenter, parallel-group, randomized, controlled, patient-blind trial. Central randomization occurred according to a computer-generated schedule, stratified by site. Recruitment was from 17 secondary or tertiary care hospitals in the United States and 3 in the United Kingdom and included adult patients with malignant pleural effusion needing drainage, without evidence of lung entrapment or significant loculation. The intervention group underwent insertion of an SNCIPC with maximal fluid drainage, followed by a tapering drainage schedule. The control group received a standard, uncoated catheter. Follow-up was conducted until 90 days. The primary outcome measure was pleurodesis efficacy, measured by fluid drainage, at 30 days. Results: A total of 119 patients were randomized. Five withdrew before receiving treatment, leaving 114 (77 SNCIPC, 37 standard IPC) for analysis. The mean age was 66 years (standard deviation, 11). More patients in the SNCIPC group were inpatients (39% vs. 14%; P = 0.009). For the primary outcome, pleurodesis rates were 12 (32%) of 37 in the control group and 17 (22%) of 77 in the SNCIPC group (rate difference, -0.10; 95% confidence interval, -0.30 to 0.09). Median time to pleurodesis was 11 days (interquartile range, 9 to 23) in the control group and 4 days (interquartile range, 2 to 15) in the SNCIPC group. No significant difference in treatment-related adverse event rates was noted between groups. Conclusions: The SNCIPC did not improve pleurodesis efficacy compared with a standard IPC. This study does not support the wider use of the SNCIPC device. Clinical trial registered with www.clinicaltrials.gov (NCT02649894).

Prolonged air leak after IPC insertion: An unusual complication.

Indwelling pleural catheters [IPC] have an important role in the management of malignant pleural effusions. We report the development of a significant air leak following IPC insertion with resultant extensive subcutaneous emphysema. The air leak developed, presumably, as a result of visceral pleural disruption, which occurred at the time of vacuum drainage of pleural fluid after IPC placement and not due to lung injury during insertion. The patient required insertion of a large bore intercostal drain connected to low-pressure negative suction. He was eventually discharged home with the aid of an ambulatory system. Although commonly seen in the surgical setting, we believe emergency and respiratory physicians should be aware of the risk of such a complication, and the challenges in its management.

Prospective validation of the RAPID clinical risk prediction score in adult patients with pleural infection: the PILOT study.

BACKGROUND: Over 30% of adult patients with pleural infection either die and/or require surgery. There is no robust means of predicting at baseline presentation which patients will suffer a poor clinical outcome. A validated risk prediction score would allow early identification of high-risk patients, potentially directing more aggressive treatment thereafter. OBJECTIVES: To prospectively assess a previously described risk score (the RAPID (Renal (urea), Age, fluid Purulence, Infection source, Dietary (albumin)) score) in adults with pleural infection. METHODS: Prospective observational cohort study that recruited patients undergoing treatment for pleural infection. RAPID score and risk category were calculated at baseline presentation. The primary outcome was mortality at 3 months; secondary outcomes were mortality at 12 months, length of hospital stay, need for thoracic surgery, failure of medical treatment and lung function at 3 months. RESULTS: Mortality data were available in 542 out of 546 patients recruited (99.3%). Overall mortality was 10% at 3 months (54 out of 542) and 19% at 12 months (102 out of 542). The RAPID risk category predicted mortality at 3 months. Low-risk mortality (RAPID score 0-2): five out of 222 (2.3%, 95% CI 0.9 to 5.7%); medium-risk mortality (RAPID score 3-4): 21 out of 228 (9.2%, 95% CI 6.0 to 13.7%); and high-risk mortality (RAPID score 5-7): 27 out of 92 (29.3%, 95% CI 21.0 to 39.2%). C-statistics for the scores at 3 months and 12 months were 0.78 (95% CI 0.71-0.83) and 0.77 (95% CI 0.72-0.82), respectively. CONCLUSIONS: The RAPID score stratifies adults with pleural infection according to increasing risk of mortality and should inform future research directed at improving outcomes in this patient population.

Manometry performed at indwelling pleural catheter insertion to predict unexpandable lung.

BACKGROUND: The finding of unexpandable lung (UL) at an early timepoint is of increasing importance in guiding treatment decisions in patients with malignant pleural effusion (MPE). Pleural manometry is the most common technique to delineate UL, however it has never been measured via an indwelling pleural catheter (IPC). To further the evidence base we analysed all patients in the IPC-PLUS study who had manometry performed during IPC insertion for the ability to predict substantial UL using manometry. METHODS: All patients enrolled in IPC-PLUS who had manometry performed at IPC insertion and radiographic assessment of UL at day 10 were included. Elastance curves were visually inspected for each patient. Initial pleural pressure, closing pleural pressure, and terminal elastance were analysed for their differences and predictive ability in those with substantial UL, defined as ≥25% entrapment on chest radiography. RESULTS: A total of 89 patients had manometry performed at IPC insertion with subsequent radiographic assessment of UL and interpretable elastance curves. Those with substantial UL had a significantly lower median closing pleural pressure (-15.00 vs. 0.00 cmH2O, P=0.012) and higher terminal elastance (12.03 vs. 8.59 cmH2O/L, P=0.021) compared to a combined group with no or partial UL. However, the predictive ability of these factors to discriminate substantial UL was poor, with areas under the receiver operating characteristic curves of 0.695 and 0.680 for closing pleural pressure and elastance respectively. CONCLUSIONS: Our results suggest that manometry is not useful in accurately predicting substantial UL when used via an IPC at the time of insertion.

Is it safe to SCUBA dive with asthma?

Introduction: Internationally it is estimated that six million people participate in self-contained underwater breathing apparatus (SCUBA) diving each year. Registries suggest a significant proportion of divers have a current or historical diagnosis of asthma. Previously individuals with asthma were prohibited from diving, however, several contemporary guidelines suggest a select population of patients with asthma may be able to dive with an acceptable degree of risk. Areas covered: Divers with asthma may be at an increased risk of a variety of diving-related medical injuries including; pulmonary barotrauma (PBT), pneumothorax, pneumomediastinum, arterial gas embolism (AGE), reduction in pulmonary function, bronchospasm and decompression sickness (DCS). This article will discuss the latest evidence on the incidence of adverse events in diving with a focus on those caused by asthma. Expert opinion: Physicians can be faced with the difficult task of counseling patients with asthma who wish to dive. This review article will aim to explore the current guidelines which can assist a physician in providing a comprehensive dive safety assessment.

Life threatening polyserositis post oesophagectomy.

A 46 year old lady presented three weeks after an oesophagectomy for oesophageal carcinoma with increasing breathlessness and a large left-sided pleural effusion. Computed tomography (CT) scan of her thorax, abdomen and pelvis revealed a large left-sided and small right-sided pleural effusions, a pericardial effusion, ascites and intra-abdominal lymphadenopathy. The patient underwent both pericardial and pleural fluid drainage, however, unfortunately, deteriorated despite these interventions with increasing oxygen requirements requiring nasal high flow oxygen on the Intensive Care Unit. Her pleural and pericardial collections resolved with colchicine and later introduction of prednisolone over a period of 5 weeks. Polyserositis is well recognised after cardiac surgery, but such a dramatic complication after thoracotomy for non-cardiac surgery has as not previously been reported. The polyserositis may relate to the induction chemotherapy combined with surgery.

A simulation study assessing the accuracy and reliability of orchidometer estimation of testicular volume.

CONTEXT: Measuring testicular volume (TV) by orchidometer is the standard method of male pubertal staging. A paucity of evidence exists as to its inter- and intra-observer reliability and the impact of clinicians' gender, training and experience on accuracy. OBJECTIVE: Prosthetic testicular models were engineered to investigate accuracy and reliability of TV estimation. DESIGN: Simulation study. SETTING: Conducted over three-day 2015 British Society for Paediatric Endocrinology and Diabetes (BSPED) meeting. PARTICIPANTS: Two hundred fifteen meeting delegates (161F, 54M): 50% consultants, 30% trainees, 9% clinical nurse specialists, 11% other professionals. INTERVENTION: Three child-sized mannequins displayed latex scrotum containing prosthetic testicles of 3, 4, 5, 10 and 20 mL. Demographic data, paediatric endocrinology experience, TV examination training, examination technique and TV estimations were collected. Delegates were asked to repeat their measurements later during the meeting. Scrotum order was changed daily. MAIN OUTCOME MEASURES: Accuracy by variance from the simulated TV. Inter- and intra-observer variability. RESULTS: One thousand two hundred eighty four individual estimations were obtained. Eighty-five participants repeated measurements. Delegates measured TV accurately on 33.4% (±2.6) of occasions: overestimations 37% (±2.3), underestimations 28% (±1.8) (Fleiss' Kappa score 0.04). The accuracy of assessing a 4 mL testis was 36%-39%. Observers underestimated the volume when paired with a 3 mL testis and overestimated when paired with a 5 mL testis demonstrating a tendency impose biological symmetry. Intra-observer reliability was lacking; individuals giving different estimations for the same size testicle on 61% (±4.2) of occasions, 20% (±3.5) of estimations were more than 1 size outside the previous measurement. On only 39% (±4.2) of occasions did individuals agree with their previous estimation (irrespective of whether or not it was initially accurate). Training did not impact on results but experience did improve accuracy. CONCLUSIONS: Overall TV estimation accuracy was poor. Considerable variation exists between and within subjects. Seniority slightly improved measurement estimation.

Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion.

BACKGROUND: Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone. METHODS: Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single-blind basis. Follow-up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization. RESULTS: The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (hazard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P=0.008). No significant between-group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group. CONCLUSIONS: Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. (Funded by Becton Dickinson; EudraCT number, 2012-000599-40 .).

Randomized Controlled Trial of Urokinase versus Placebo for Nondraining Malignant Pleural Effusion.

RATIONALE: Patients with malignant pleural effusion experience breathlessness, which is treated by drainage and pleurodesis. Incomplete drainage results in residual dyspnea and pleurodesis failure. Intrapleural fibrinolytics lyse septations within pleural fluid, improving drainage. OBJECTIVES: To assess the effects of intrapleural urokinase on dyspnea and pleurodesis success in patients with nondraining malignant effusion. METHODS: We conducted a prospective, double-blind, randomized trial. Patients with nondraining effusion were randomly allocated in a 1:1 ratio to intrapleural urokinase (100,000 IU, three doses, 12-hourly) or matched placebo. MEASUREMENTS AND MAIN RESULTS: Co-primary outcome measures were dyspnea (average daily 100-mm visual analog scale scores over 28 d) and time to pleurodesis failure to 12 months. Secondary outcomes were survival, hospital length of stay, and radiographic change. A total of 71 subjects were randomized (36 received urokinase, 35 placebo) from 12 U.K. centers. The baseline characteristics were similar between the groups. There was no difference in mean dyspnea between groups (mean difference, 3.8 mm; 95% confidence interval [CI], -12 to 4.4 mm; P = 0.36). Pleurodesis failure rates were similar (urokinase, 13 of 35 [37%]; placebo, 11 of 34 [32%]; adjusted hazard ratio, 1.2; P = 0.65). Urokinase was associated with decreased effusion size visualized by chest radiography (adjusted relative improvement, -19%; 95% CI, -28 to -11%; P < 0.001), reduced hospital stay (1.6 d; 95% CI, 1.0 to 2.6; P = 0.049), and improved survival (69 vs. 48 d; P = 0.026). CONCLUSIONS: Use of intrapleural urokinase does not reduce dyspnea or improve pleurodesis success compared with placebo and cannot be recommended as an adjunct to pleurodesis. Other palliative treatments should be used. Improvements in hospital stay, radiographic appearance, and survival associated with urokinase require further evaluation. Clinical trial registered with ISRCTN (12852177) and EudraCT (2008-000586-26).

Survival in Patients With Malignant Pleural Effusions Who Developed Pleural Infection: A Retrospective Case Review From Six UK Centers.

OBJECTIVE: Malignant pleural effusion (MPE) incidence is increasing, and prognosis remains poor. Indwelling pleural catheters (IPCs) relieve symptoms but increase the risk of pleural infection. We reviewed cases of pleural infection in patients with IPCs for MPE from six UK centers between January 1, 2005, and January 31, 2014. METHODS: Survival in patients with pleural infection was compared with 788 patients with MPE (known as the LENT [pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type] cohort) and with national statistics. RESULTS: Of 672 IPCs inserted, 25 (3.7%) became infected. Most patients (20 of 25) had mesothelioma or lung cancer. Median survival in the pleural infection cohort appeared longer than in the LENT cohort, although this result did not achieve significance (386 days vs 132 days; hazard ratio, 0.67; P = .07). Median survival with mesothelioma and pleural infection was twice as long as national estimates for mesothelioma survival (753 days vs < 365 days) and double the median survival of patients with mesothelioma in the LENT cohort (339 days; 95% CI, nonoverlapping). Survival with lung and breast cancer did not differ significantly between the groups. Sixty-one percent of patients experienced early infection. There was no survival difference between patients with early and late infection (P = .6). CONCLUSIONS: This small series of patients with IPCs for MPE suggests pleural infection may be associated with longer survival, particularly in patients with mesothelioma. Results did not achieve significance, and a larger study is needed to explore this relationship further and investigate whether the local immune response, triggered by infection, is able to modulate mesothelioma progression.

Hepatic hydrothorax in the absence of ascites.

A previously well 66-year-old woman presented with a recurrent transudative right-sided pleural effusion. A nodular liver with coarse echotexture was demonstrated on ultrasound and subsequent MRI found hepatocellular carcinoma. In the absence of cardiopulmonary disease and significant protein uria, the recurrent pleural effusion was presumed to be hepatic hydrothorax despite the absence of ascites or other clinical features of chronic liver disease. The patient is currently awaiting liver transplantation.

Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial.

CONTEXT: Malignant pleural effusion causes disabling dyspnea in patients with a short life expectancy. Palliation is achieved by fluid drainage, but the most effective first-line method has not been determined. OBJECTIVE: To determine whether indwelling pleural catheters (IPCs) are more effective than chest tube and talc slurry pleurodesis (talc) at relieving dyspnea. DESIGN: Unblinded randomized controlled trial (Second Therapeutic Intervention in Malignant Effusion Trial [TIME2]) comparing IPC and talc (1:1) for which 106 patients with malignant pleural effusion who had not previously undergone pleurodesis were recruited from 143 patients who were treated at 7 UK hospitals. Patients were screened from April 2007-February 2011 and were followed up for a year. INTERVENTION: Indwelling pleural catheters were inserted on an outpatient basis, followed by initial large volume drainage, education, and subsequent home drainage. The talc group were admitted for chest tube insertion and talc for slurry pleurodesis. MAIN OUTCOME MEASURE: Patients completed daily 100-mm line visual analog scale (VAS) of dyspnea over 42 days after undergoing the intervention (0 mm represents no dyspnea and 100 mm represents maximum dyspnea; 10 mm represents minimum clinically significant difference). Mean difference was analyzed using a mixed-effects linear regression model adjusted for minimization variables. RESULTS: Dyspnea improved in both groups, with no significant difference in the first 42 days with a mean VAS dyspnea score of 24.7 in the IPC group (95% CI, 19.3-30.1 mm) and 24.4 mm (95% CI, 19.4-29.4 mm) in the talc group, with a difference of 0.16 mm (95% CI, −6.82 to 7.15; P = .96). There was a statistically significant improvement in dyspnea in the IPC group at 6 months, with a mean difference in VAS score between the IPC group and the talc group of −14.0 mm (95% CI, −25.2 to −2.8 mm; P = .01). Length of initial hospitalization was significantly shorter in the IPC group with a median of 0 days (interquartile range [IQR], 0-1 day) and 4 days (IQR, 2-6 days) for the talc group, with a difference of −3.5 days (95% CI, −4.8 to −1.5 days; P < .001). There was no significant difference in quality of life. Twelve patients (22%) in the talc group required further pleural procedures compared with 3 (6%) in the IPC group (odds ratio [OR], 0.21; 95% CI, 0.04-0.86; P = .03). Twenty-one of the 52 patients in the catheter group experienced adverse events vs 7 of 54 in the talc group (OR, 4.70; 95% CI, 1.75-12.60; P = .002). CONCLUSION: Among patients with malignant pleural effusion and no previous pleurodesis, there was no significant difference between IPCs and talc pleurodesis at relieving patient-reported dyspnea. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN87514420.