Trial Protocol: Reaccumulation rate of pleural effusions after therapeutic aspiration: An observational cohort study to determine baseline factors associated with rate of pleural fluid reaccumulation following therapeutic aspiration in patients with malignant pleural effusion attending a pleural clinic (REPEAT) [version 1; peer review: 2 approved]

Background: Malignant pleural effusion (MPE) is the build-up of pleural fluid in the space between the lung and chest wall due to advanced cancer. It is treated initially by large volume drainage (therapeutic aspiration). If the fluid reaccumulates, a definitive procedure is performed. There is wide variation in rate of reaccumulation. Patients with rapid reaccumulation often attend hospital as an emergency. Conversely, patients with slow reaccumulation do not need a definitive procedure and may experience cancelled or unnecessary procedures. This study aims to create and validate a multivariable prediction model to predict how quickly pleural fluid will reaccumulate in patients with MPE following therapeutic aspiration. Research question: Can we predict how quickly pleural fluid will reaccumulate in patients with MPEs? Methods: A total of 200 patients with known or suspected MPE attending for therapeutic aspiration will be recruited from 5-10 UK hospitals over 20 months. Patients will be enrolled prior to undergoing aspiration. Following this, they will undergo chest X-ray, which will be repeated one week later (treatment as usual). Rate of reaccumulation will be calculated based on change of size of the effusion seen on X-ray. Data will be collected on common clinical biomarkers e.g., size of effusion on pre-aspiration chest X-ray, volume of fluid drained. This data will be analysed to create a clinical score. A further validation cohort of 40 patients will be enrolled in parallel with creation of the score. Anticipated impact: The ability to predict rate of reaccumulation of MPE will enable patients and clinicians to make better informed treatment decisions. For patients with predicted rapid reaccumulation, a definitive procedure could be offered as first-line treatment, rather than a therapeutic aspiration. This will prevent emergency hospital admissions and decrease number of procedures. By contrast, patients whose effusions will recur slowly may avoid an unnecessary procedure

Antibiotic Review Kit for Hospitals (ARK-Hospital): a stepped wedge cluster randomised controlled trial

Background: Strategies to reduce antibiotic overuse in hospitals depend on clinicians reviewing antibiotics which have been started empirically. There is a lack of evidence on how to do this effectively. We evaluated a multifaceted behaviour change intervention (ARK) aimed at reducing antibiotic consumption in hospitals by increasing prescriber decisions to stop antibiotics at clinical review. Methods: We performed a stepped-wedge, hospital-level, cluster -randomised controlled trial using computer-generated sequence randomisation of 39 acute hospitals to 7 calendar-time blocks (12/February/2018–01/July/2019). Co-primary outcomes were monthly antibiotic defined-dailydoses (DDD) per acute/medical admission (organisation-level, superiority) and all-cause 30-day mortality (patient-level, non-inferiority, margin 5%). Clusters were eligible if they admitted nonelective medical patients, could identify an intervention “champion” and provide pre-intervention data from February/2016. Sites were followed up for a minimum of 14 months. Intervention effects were assessed using interrupted time series analyses in each cluster. Overall effects were derived through random-effects meta-analysis, using meta-regression to assess heterogeneity in effects across prespecified factors. Trial registration was ISRCTN12674243. Findings: Adjusted estimates showed a year-on-year reduction in antibiotic consumption (-4.8%, 95%CI: -9.1%,-0.2%, p=0.042) following the ARK intervention. Among 7,160,421 acute/medicaladmissions, we observed a -2.7% (95%CI: -5.7%,+0.3%, p=0.079) immediate and +3.0% (95%CI: - 0.1%,+6.2%, p=0.060) sustained change in adjusted 30-day mortality. This mortality trend was not related to the magnitude of antibiotic reduction achieved (Spearman’s ρ=0.011, p=0.949). Whilst 90- day mortality odds appeared to increase over time (+3.9%, 95%CI:+0.5%,+7.4%, p=0.023), this was not observed among admissions before COVID-19 onset (+3.2%, 95%CI:-1.5%,+8.2%, p=0.182). Length of hospital stay was unaffected. Interpretation: The weak, inconsistent effects of the intervention on mortality are likely to be explained by the COVID-19 pandemic onset during the post-implementation phase. We conclude that the ARK-intervention resulted in sustained, safe reductions in hospital antibiotic use

Antibiotic Review Kit for Hospitals (ARK-Hospital): a stepped wedge cluster randomised controlled trial

Background: Strategies to reduce antibiotic overuse in hospitals depend on prescribers taking decisions to stop unnecessary antibiotics. There is limited evidence on how to support this. We evaluated a multifaceted behaviour change intervention (ARK) designed to reduce antibiotic use among adult acute/medical inpatients by increasing appropriate decisions to stop antibiotics at clinical review. Methods: We performed a stepped-wedge, cluster (hospital)-randomised controlled trial using computer-generated sequence randomisation of 39 hospitals in 7 calendar-time blocks in the United Kingdom (25/September/2017-01/July/2019). Randomised implementation date was concealed until 12 weeks before implementation, when local preparations were designed to start. Co-primary outcomes were monthly antibiotic defined-daily-doses (DDD) per adult acute/medical admission (hospital-level, superiority) and all-cause 30-day mortality (patient level, non-inferiority, margin 5%). Sites were eligible if they admitted non-elective medical patients, could identify an intervention “champion”, and provide study data. Sites werefollowed for at least 14 months. Intervention effects were assessed using interrupted timeseries analyses within each site, estimating overall effects through random-effects meta analysis, with heterogeneity across prespecified potential modifiers assessed using meta regression.Trial registration: ISRCTN12674243.Findings: Adjusted estimates showed reductions in total antibiotic DDDs per acute/medicaladmission (-4.8% per year, 95% CI: -9.1%,-0.2%) following the intervention. Among7,160,421 acute/medical admissions, there were trends towards -2.7% (95% CI: -5.7%,+0.3%) immediate and +3.0% (95% CI: -0.1%,+6.2%) sustained changes in adjusted30-day mortality. Site-specific mortality trends were unrelated to the site-specific magnitudeof antibiotic reduction (Spearman’s ρ=0.011, p=0.949). Whilst 90-day mortality oddsappeared to increase (+3.9%, 95% CI: +0.5%,+7.4%), this was attenuated excludingadmissions after COVID-19 onset (+3.2%, 95% CI:-1.5%,+8.2%). There was no evidence ofintervention effects on length-of-stay (p>0.4).Interpretation: The weak, inconsistent intervention effects on mortality are likely explained by the post-implementation onset of the COVID-19 pandemic. The ARK intervention resulted in sustained, safe reductions in antibiotic use among adult acute/medical inpatients. Funding: NIHR Programme Grants for Applied Research, RP-PG-0514-20015

Effect of Thoracoscopic Talc Poudrage vs Talc Slurry via Chest Tube on Pleurodesis Failure Rate Among Patients With Malignant Pleural Effusions: A Randomized Clinical Trial.

Importance Malignant pleural effusion (MPE) is challenging to manage. Talc pleurodesis is a common and effective treatment. There are no reliable data, however, regarding the optimal method for talc delivery, leading to differences in practice and recommendations. Objective To test the hypothesis that administration of talc poudrage during thoracoscopy with local anesthesia is more effective than talc slurry delivered via chest tube in successfully inducing pleurodesis. Design, Setting, and Participants Open-label, randomized clinical trial conducted at 17 UK hospitals. A total of 330 participants were enrolled from August 2012 to April 2018 and followed up until October 2018. Patients were eligible if they were older than 18 years, had a confirmed diagnosis of MPE, and could undergo thoracoscopy with local anesthesia. Patients were excluded if they required a thoracoscopy for diagnostic purposes or had evidence of nonexpandable lung. Interventions Patients randomized to the talc poudrage group (n = 166) received 4 g of talc poudrage during thoracoscopy while under moderate sedation, while patients randomized to the control group (n = 164) underwent bedside chest tube insertion with local anesthesia followed by administration of 4 g of sterile talc slurry. Main Outcomes and Measures The primary outcome was pleurodesis failure up to 90 days after randomization. Secondary outcomes included pleurodesis failure at 30 and 180 days; time to pleurodesis failure; number of nights spent in the hospital over 90 days; patient-reported thoracic pain and dyspnea at 7, 30, 90, and 180 days; health-related quality of life at 30, 90, and 180 days; all-cause mortality; and percentage of opacification on chest radiograph at drain removal and at 30, 90, and 180 days. Results Among 330 patients who were randomized (mean age, 68 years; 181 [55%] women), 320 (97%) were included in the primary outcome analysis. At 90 days, the pleurodesis failure rate was 36 of 161 patients (22%) in the talc poudrage group and 38 of 159 (24%) in the talc slurry group (adjusted odds ratio, 0.91 [95% CI, 0.54-1.55]; P = .74; difference, -1.8% [95% CI, -10.7% to 7.2%]). No statistically significant differences were noted in any of the 24 prespecified secondary outcomes. Conclusions and Relevance Among patients with malignant pleural effusion, thoracoscopic talc poudrage, compared with talc slurry delivered via chest tube, resulted in no significant difference in the rate of pleurodesis failure at 90 days. However, the study may have been underpowered to detect small but potentially important differences. Trial Registration ISRCTN Identifier: ISRCTN47845793