Australasian Malignant PLeural Effusion (AMPLE)-4 trial: study protocol for a multi-centre randomised trial of topical antibiotics prophylaxis for infections of indwelling pleural catheters.

BACKGROUND: Malignant pleural effusion (MPE) is a debilitating condition as it commonly causes disabling breathlessness and impairs quality of life (QoL). Indwelling pleural catheter (IPC) offers an effective alternative for the management of MPE. However, IPC-related infections remain a significant concern and there are currently no long-term strategies for their prevention. The Australasian Malignant PLeural Effusion (AMPLE)-4 trial is a multicentre randomised trial that evaluates the use of topical mupirocin prophylaxis (vs no mupirocin) to reduce catheter-related infections in patients with MPE treated with an IPC. METHODS: A pragmatic, multi-centre, open-labelled, randomised trial. Eligible patients with MPE and an IPC will be randomised 1:1 to either regular topical mupirocin prophylaxis or no mupirocin (standard care). For the interventional arm, topical mupirocin will be applied around the IPC exit-site after each drainage, at least twice weekly. Weekly follow-up via phone calls or in person will be conducted for up to 6 months. The primary outcome is the percentage of patients who develop an IPC-related (pleural, skin, or tract) infection between the time of catheter insertion and end of follow-up period. Secondary outcomes include analyses of infection (types and episodes), hospitalisation days, health economics, adverse events, and survival. Subject to interim analyses, the trial will recruit up to 418 participants. DISCUSSION: Results from this trial will determine the efficacy of mupirocin prophylaxis in patients who require IPC for MPE. It will provide data on infection rates, microbiology, and potentially infection pathways associated with IPC-related infections. ETHICS AND DISSEMINATION: Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee has approved the study (RGS0000005920). Results will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry ACTRN12623000253606. Registered on 9 March 2023.

Patient and surgical prognostic factors for inpatient functional recovery following THA and TKA: a prospective cohort study.

BACKGROUND: The introduction of enhanced recovery pathways has demonstrated both patient and organisational benefits. However, enhanced recovery pathways implemented for total hip arthroplasty (THA) and total knee arthroplasty (TKA) vary between health-care organisations, as do their measures of success, particularly patient-related outcomes. Despite inpatient functional recovery being essential for safe and timely hospital discharge, there is currently no gold standard method for its assessment, and the research undertaken to establish prognostic factors is limited. This study aimed to identify prognostic factors and subsequently develop prognostic models for inpatient functional recovery following primary, unilateral THA and TKA; identify factors associated with acute length of stay; and assess the relationships between inpatient function and longer-term functional outcomes. METHODS: Correlation and multiple regression analyses were used to determine prognostic factors for functional recovery (assessed using the modified Iowa Level of Assistance Scale on day 2 post-operatively) in a prospective cohort study of 354 patients following primary, unilateral THA or TKA. RESULTS: For the overall cohort and TKA group, significant prognostic factors included age, sex, pre-operative general health, pre-operative function, and use of general anaesthesia, local infiltration analgesia, and patient-controlled analgesia. In addition, arthroplasty site was a prognostic factor for the overall cohort, and surgery duration was prognostic for the TKA group. For the THA group, significant prognostic factors included pre-operative function, Risk Assessment and Prediction Tool score, and surgical approach. Several factors were associated with acute hospital length of stay. Inpatient function was positively correlated with functional outcomes assessed at 6 months post-operatively. CONCLUSIONS: Prognostic models may facilitate the prediction of inpatient flow thus optimising organisational efficiency. Surgical prognostic factors warrant consideration as potential key elements in enhanced recovery pathways, associated with early post-operative functional recovery. Standardised measures of inpatient function serve to evaluate patient-centred outcomes and facilitate the benchmarking and improvement of enhanced recovery pathways.

Relationship of pleural fluid pH and glucose: a multi-centre study of 2,971 cases.

BACKGROUND: Pleural fluid pH and glucose levels are both recommended in the workup of pleural effusions. Whether their levels correlate and predict each other or contribute independent knowledge is unclear. We aimed to investigate the pH/glucose relationship, assess their concordance and ascertain whether performing both tests provides additional information to performing either test alone. METHODS: The pH and glucose measurements from 2,971 pleural fluid samples, from three centers in Spain, UK and Australia, were categorized into Cancer (n=1,045), Infection (n=544), Tuberculosis (n=249) and Others (n=1,133) groups. The relationship between pH and glucose values and their concordance at clinically relevant cutoffs (pH 7.2 and glucose 3.3 mmol/L) were assessed. RESULTS: The mean pH of the cohort was 7.38 (SD 0.22) and median glucose 5.99 (range, 0.00-29.36) mmol/L. A regression model of the relationship between glucose (log-transformed) and pH with a restricted cubic spline showed linear (P<0.01) and nonlinear effects (P<0.01). The relationship was strong with a narrow confidence interval but the prediction interval was wide. Most (91.9%) samples were concordant using pH and glucose levels at cutoffs of 7.20 and 3.30 mmol/L respectively. Using pH alone, without glucose, captured 95.0% of the infection-related effusions with either pH or glucose below cutoff and glucose alone identified 91.7%. CONCLUSIONS: Pleural fluid pH and glucose have a strong non-linear relationship but, in most situations, the level of one cannot accurately predict the other. Concordance rates were high and either test is sufficient in the majority of cases.

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.

Dose De-escalation of Intrapleural Tissue Plasminogen Activator Therapy for Pleural Infection. The Alteplase Dose Assessment for Pleural Infection Therapy Project.

RATIONALE: Intrapleural therapy with a combination of tissue plasminogen activator (tPA) 10 mg and DNase 5 mg administered twice daily has been shown in randomized and open-label studies to successfully manage over 90% of patients with pleural infection without surgery. Potential bleeding risks associated with intrapleural tPA and its costs remain important concerns. The aim of the ongoing Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) project is to investigate the efficacy and safety of dose de-escalation for intrapleural tPA. The first of several planned studies is presented here. OBJECTIVES: To evaluate the efficacy and safety of a reduced starting dose regimen of 5 mg of tPA with 5 mg of DNase administered intrapleurally for pleural infection. METHODS: Consecutive patients with pleural infection at four participating centers in Australia, the United Kingdom, and New Zealand were included in this observational, open-label study. Treatment was initiated with tPA 5 mg and DNase 5 mg twice daily. Subsequent dose escalation was permitted at the discretion of the attending physician. Data relating to treatment success, radiological and systemic inflammatory changes (blood C-reactive protein), volume of fluid drained, length of hospital stay, and treatment complications were extracted retrospectively from the medical records. RESULTS: We evaluated 61 patients (41 males; age, 57 ± 16 yr). Most patients (n = 58 [93.4%]) were successfully treated without requiring surgery for pleural infection. Treatment success was corroborated by clearance of pleural opacities visualized by chest radiography (from 42% [interquartile range, 22-58] to 16% [8-31] of hemithorax; P < 0.001), increase in pleural fluid drainage (from 175 ml in the 24 h preceding treatment to 2,025 ml [interquartile range, 1,247-2,984] over 72 h of therapy; P < 0.05) and a reduction in blood C-reactive protein (P < 0.05). Seven patients (11.5%) had dose escalation of tPA to 10 mg. Three patients underwent surgery. Three patients (4.9%) received blood transfusions for gradual pleural blood loss; none were hemodynamically compromised. Pain requiring escalation of analgesia affected 36% of patients; none required cessation of therapy. CONCLUSIONS: These pilot data suggest that a starting dose of 5 mg of tPA administered intrapleurally twice daily in combination with 5 mg of DNase for the treatment of pleural infection is safe and effective. This regimen should be tested in future randomized controlled trials.

Protocol of the Australasian Malignant Pleural Effusion (AMPLE) trial: a multicentre randomised study comparing indwelling pleural catheter versus talc pleurodesis.

INTRODUCTION: Malignant pleural effusion can complicate most cancers. It causes breathlessness and requires hospitalisation for invasive pleural drainages. Malignant effusions often herald advanced cancers and limited prognosis. Minimising time spent in hospital is of high priority to patients and their families. Various treatment strategies exist for the management of malignant effusions, though there is no consensus governing the best choice. Talc pleurodesis is the conventional management but requires hospitalisation (and substantial healthcare resources), can cause significant side effects, and has a suboptimal success rate. Indwelling pleural catheters (IPCs) allow ambulatory fluid drainage without hospitalisation, and are increasingly employed for management of malignant effusions. Previous studies have only investigated the length of hospital care immediately related to IPC insertion. Whether IPC management reduces time spent in hospital in the patients' remaining lifespan is unknown. A strategy of malignant effusion management that reduces hospital admission days will allow patients to spend more time outside hospital, reduce costs and save healthcare resources. METHODS AND ANALYSIS: The Australasian Malignant Pleural Effusion (AMPLE) trial is a multicentred, randomised trial designed to compare IPC with talc pleurodesis for the management of malignant pleural effusion. This study will randomise 146 adults with malignant pleural effusions (1:1) to IPC management or talc slurry pleurodesis. The primary end point is the total number of days spent in hospital (for any admissions) from treatment procedure to death or end of study follow-up. Secondary end points include hospital days specific to pleural effusion management, adverse events, self-reported symptom and quality-of-life scores. ETHICS AND DISSEMINATION: The Sir Charles Gairdner Group Human Research Ethics Committee has approved the study as have the ethics boards of all the participating hospitals. The trial results will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBERS: Australia New Zealand Clinical Trials Registry-ACTRN12611000567921; National Institutes of Health-NCT02045121.

Intrapleural tissue plasminogen activator and deoxyribonuclease for pleural infection. An effective and safe alternative to surgery.

RATIONALE: Intrapleural tissue plasminogen activator (tPA)/deoxyribonuclease (DNase) therapy for pleural infection given at the time of diagnosis has been shown to significantly improve radiological outcomes. Published cases are limited to only a single randomized controlled trial and a few case reports. OBJECTIVES: Multinational observation series to evaluate the pragmatic "real-life" application of tPA/DNase treatment for pleural infection in a large cohort of unselected patients. METHODS: All patients from eight centers who received intrapleural tPA/DNase for pleural infection between January 2010 and September 2013 were included. Measured outcomes included treatment success at 30 days, volume of pleural fluid drained, improvement in radiographic pleural opacity and inflammatory markers, need for surgery, and adverse events. MEASUREMENTS AND MAIN RESULTS: Of 107 patients treated, the majority (92.3%) were successfully managed without the need for surgical intervention. No patients died as a result of pleural infection. Most patients (84%) received tPA/DNase more than 24 hours after failing to respond to initial conservative management with antibiotics and thoracostomy. tPA/DNase increased fluid drained from a median of 250 ml (interquartile range [IQR], 100-654) in the 24 hours preceding commencement of intrapleural therapy to 2,475 ml (IQR 1,800-3,585) in the 72 hours following treatment initiation (P < 0.05). We observed a corresponding clearance of pleural opacity on chest radiographs from a median of 35% (IQR 25-31) to 14% (7-28) of the hemithorax (P < 0.001), as well as significant reduction in C-reactive protein (P < 0.05). Pain necessitating escalation of analgesia occurred in 19.6% patients, and nonfatal bleeding occurred in 1.8%. CONCLUSIONS: This large series of patients who received intrapleural tPA/DNase therapy provides important evidence that the treatment is effective and safe, especially as a "rescue therapy" in patients who do not initially respond to antibiotics and thoracostomy drainage.

Optimal chest drain size: the rise of the small-bore pleural catheter.

Drainage of the pleural space is not a modern concept, but the optimal size of chest drains to use remains debated. Conventional teaching advocates blunt dissection and large-bore tubes; but in recent years, small-bore catheters have gained popularity. In the absence of high-quality randomized data, this review summarizes the available literature on the choice of chest drains. The objective data supporting the use of large-bore tubes is scarce in most pleural diseases. Increasing evidence shows that small-bore catheters induce less pain and are of comparable efficacy to large-bore tubes, including in the management of pleural infection, malignant effusion, and pneumothoraces. The onus now is on those who favor large tubes to produce clinical data to justify the more invasive approach.

Environmental impact of the MV CITA on the foreshore of Porth Hellick, Isles of Scilly.

The grounding of the container feeder vessel MV CITA on Newfoundland Rocks, Isles of Scilly, had an effect on the surrounding biota and benthic environment. Included in the CITA's cargo were five 40 ft containers holding pallets of polyester film used in the production of audio and visual recording tapes. The wreckage presented a minor but potentially chronic source of pollution through the delayed release of polythene film, which was left on the seabed as it was considered insufficiently valuable to warrant salvage. The polythene disintegrated and was washed upon the foreshore of Porth Hellick in minute shreds. The adjacent foreshore and two control sites within the islands were analysed using a 5-strand line and vegetation survey with 10 random quadrats within each line to determine the environmental impact of the polythene.