Early switch from intravenous to oral antibiotic therapy in patients with cancer who have low-risk neutropenic sepsis: the EASI-SWITCH RCT.

Background: Neutropenic sepsis is a common complication of systemic anticancer treatment. There is variation in practice in timing of switch to oral antibiotics after commencement of empirical intravenous antibiotic therapy. Objectives: To establish the clinical and cost effectiveness of early switch to oral antibiotics in patients with neutropenic sepsis at low risk of infective complications. Design: A randomised, multicentre, open-label, allocation concealed, non-inferiority trial to establish the clinical and cost effectiveness of early oral switch in comparison to standard care. Setting: Nineteen UK oncology centres. Participants: Patients aged 16 years and over receiving systemic anticancer therapy with fever (≥ 38°C), or symptoms and signs of sepsis, and neutropenia (≤ 1.0 × 109/l) within 24 hours of randomisation, with a Multinational Association for Supportive Care in Cancer score of ≥ 21 and receiving intravenous piperacillin/tazobactam or meropenem for < 24 hours were eligible. Patients with acute leukaemia or stem cell transplant were excluded. Intervention: Early switch to oral ciprofloxacin (750 mg twice daily) and co-amoxiclav (625 mg three times daily) within 12-24 hours of starting intravenous antibiotics to complete 5 days treatment in total. Control was standard care, that is, continuation of intravenous antibiotics for at least 48 hours with ongoing treatment at physician discretion. Main outcome measures: Treatment failure, a composite measure assessed at day 14 based on the following criteria: fever persistence or recurrence within 72 hours of starting intravenous antibiotics; escalation from protocolised antibiotics; critical care support or death. Results: The study was closed early due to under-recruitment with 129 patients recruited; hence, a definitive conclusion regarding non-inferiority cannot be made. Sixty-five patients were randomised to the early switch arm and 64 to the standard care arm with subsequent intention-to-treat and per-protocol analyses including 125 (intervention n = 61 and control n = 64) and 113 (intervention n = 53 and control n = 60) patients, respectively. In the intention-to-treat population the treatment failure rates were 14.1% in the control group and 24.6% in the intervention group, difference = 10.5% (95% confidence interval 0.11 to 0.22). In the per-protocol population the treatment failure rates were 13.3% and 17.7% in control and intervention groups, respectively; difference = 3.7% (95% confidence interval 0.04 to 0.148). Treatment failure predominantly consisted of persistence or recurrence of fever and/or physician-directed escalation from protocolised antibiotics with no critical care admissions or deaths. The median length of stay was shorter in the intervention group and adverse events reported were similar in both groups. Patients, particularly those with care-giving responsibilities, expressed a preference for early switch. However, differences in health-related quality of life and health resource use were small and not statistically significant. Conclusions: Non-inferiority for early oral switch could not be proven due to trial under-recruitment. The findings suggest this may be an acceptable treatment strategy for some patients who can adhere to such a treatment regimen and would prefer a potentially reduced duration of hospitalisation while accepting increased risk of treatment failure resulting in re-admission. Further research should explore tools for patient stratification for low-risk de-escalation or ambulatory pathways including use of biomarkers and/or point-of-care rapid microbiological testing as an adjunct to clinical decision-making tools. This could include application to shorter-duration antimicrobial therapy in line with other antimicrobial stewardship studies. Trial registration: This trial is registered as ISRCTN84288963. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/140/05) and is published in full in Health Technology Assessment; Vol. 28, No. 14. See the NIHR Funding and Awards website for further award information.

Neutropenic sepsis, or infection with a low white blood cell count, can occur following cancer treatment. Usually patients receive treatment with intravenous antibiotics (antibiotics delivered into a vein) for two or more days. Patients at low risk of complications from their infection may be able to have a shorter period of intravenous antibiotics benefitting both patients and the NHS. The trial compared whether changing from intravenous to oral antibiotics (antibiotics taken by mouth as tablets or liquid) 12­24 hours after starting antibiotic treatment ('early switch') is as effective as usual care. Patients could take part if they had started intravenous antibiotics for low-risk neutropenic sepsis. Patients were randomly allocated to 'early switch' or to usual care. The main outcome measured was treatment failure. Treatment failure happened if fever persisted or recurred despite antibiotics, if patients needed to change antibiotics, if they needed to be re-admitted to hospital or needed to be admitted to intensive care within 14 days or died. We had originally intended that 628 patients would take part, but after review of the design of the study the number needed to take part was revised to 230. We were not able to complete the trial as planned as unfortunately only 129 patients took part. As the trial was smaller than expected we were not able to draw conclusions as to whether 'early switch' is no less effective than usual care. Our findings suggest that 'early switch' might result in a shorter time in hospital initially; however, treatment failure was more likely to occur, meaning some patients had to return to hospital for further antibiotics. There were no differences in side effects and no serious complications from treatment or treatment failure (such as intensive care admission or death) among the 65 patients in the 'early switch' group. Patients were satisfied with 'early switch'. Early switch may be a treatment option for some patients with low-risk neutropenic sepsis who would prefer a shorter duration of hospital admission but accept a risk of needing hospital re-admission.

Early switch to oral antibiotic therapy in patients with low-risk neutropenic sepsis (EASI-SWITCH): a randomized non-inferiority trial.

OBJECTIVES: To determine whether early switch to oral antibiotic treatment in adults with neutropenic sepsis at low risk of complications is non-inferior to switching later. METHODS: This non-inferiority, parallel-group, randomized, open-label clinical trial enrolled UK adults hospitalized with neutropenic sepsis. Participants were randomly assigned to either switch to oral ciprofloxacin plus co-amoxiclav within 12-24 hours or to continue intravenous treatment for at least 48 hours. The primary outcome was a composite measure of treatment failure, 14 days after randomization. The non-inferiority margin was 15%. RESULTS: There were 129 participants from 16 centres and 125 were assessed for the primary outcome. Of these, 113 patients completed protocolized treatment and comprised the per-protocol population. In total, 9 (14.1%) of 64 patients in the standard care arm met the primary end point, compared with 15 (24.6%) of 61 in the early switch arm, giving a risk difference of 10.5% (1-sided 95% CI, -∞% to 22%; p 0.14). In the per-protocol population, 8 (13.3%) of the 60 patients in the standard care arm met the primary end point, compared with 9 (17%) of 53 in the intervention arm giving a risk difference of 3.7% (one-sided 95% CI, -∞% to 14.8%; p 0.59). Duration of hospital stay was shorter in the intervention arm (median 2 [inter-quartile range (IQR) 2-3] vs. 3 days [IQR 2-4]; p 0.002). DISCUSSION: Although non-inferiority of early oral switch was found in the per-protocol population, the intervention was not non-inferior in the intent-to-treat population.

Extracorporeal carbon dioxide removal compared to ventilation alone in patients with acute hypoxaemic respiratory failure: cost-utility analysis of the REST RCT.

Background: Acute hypoxaemic respiratory failure requiring mechanical ventilation is a major cause of morbidity and mortality and has significant resource implications in terms of intensive care unit and hospital stay. Objective: To assess the cost-effectiveness of extracorporeal carbon dioxide removal compared to ventilation alone in patients with acute hypoxaemic respiratory failure. Design: A cost-utility analysis embedded within a pragmatic, multicentre, allocation-concealed, open-label, randomised controlled trial. Participants: Four hundred and twelve (of a planned sample size of 1120) adult patients receiving mechanical ventilation for acute hypoxaemic respiratory failure, were recruited between May 2016 and December 2019 from 51 intensive care units in the UK. Interventions: Participants were randomised (1 : 1) to receive extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with ventilation alone (n = 210). Outcomes: Health-related quality of life via the EuroQol-5 Dimensions, five-level version, health resource use and associated costs were measured over the study period. The cost per quality-adjusted life-year was estimated at 12 months post randomisation. Results: Mean EuroQol-5 Dimensions, five-level version utility scores were low and similar for each group. Quality-adjusted life-years were calculated for those patients with complete EuroQol-5 Dimensions, five-level version data (extracorporeal carbon dioxide removal n = 140, ventilation alone n = 143) and there was no discernible difference in quality-adjusted life-years at 12 months (mean difference -0.01; 95% confidence interval -0.06 to 0.05; 140). Total 12-month health resource use cost (including intervention costs) was calculated for those patients with complete cost data (extracorporeal carbon dioxide removal n = 125, ventilation alone n = 126) and costs were statistically significantly higher in the extracorporeal carbon dioxide removal group (mean difference £7668.76, 95% confidence interval 159.75, 15,177.77). Multiple imputation was used for missing total cost and quality-adjusted life-year data in the cost-utility analysis. Ventilation alone dominated extracorporeal carbon dioxide removal and there was 0% probability of extracorporeal carbon dioxide removal being cost-effective compared to ventilation alone for all willingness to pay thresholds per quality-adjusted life-year considered (£0-50,000). Conclusions: Extracorporeal carbon dioxide removal was associated with significantly higher costs, but no benefit in health-related quality of life. Given the data, extracorporeal carbon dioxide removal is not considered to be a cost-effective approach to treating patients with acute hypoxaemic respiratory failure. Limitations: These included the absence of a baseline healthy utility score, minor data loss related to not obtaining complete intensive care unit readmission data for Scottish participants, and not estimating long-term cost-effectiveness due to the study closing early. Future work: Measuring baseline health-related quality of life in critical care studies is difficult; future economic evaluations in this setting should consider measuring health-related quality of life as soon as possible after the patients regain capacity. Trial registration: This trial is registered as NCT02654327 and ISRCTN 31262122. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 13/143/02.

Acute hypoxaemic respiratory failure after treatment with lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal: long-term outcomes from the REST randomised trial.

INTRODUCTION: Lower tidal volume ventilation, facilitated by veno-venous extracorporeal carbon dioxide removal (vv-ECCO2R), does not improve 90-day mortality in patients with acute hypoxaemic respiratory failure (AHRF). The aim of this analysis was to evaluate the effect of this therapeutic strategy on long-term outcomes. METHODS: This was a prespecified analysis of the REST trial, a UK-wide multicentre randomised clinical trial that compared lower tidal volume ventilation, facilitated by vv-ECCO2R (intervention), with standard care in the treatment of patients with moderate-to-severe AHRF. Mortality to 2 years was assessed, while respiratory function, post-traumatic stress disorder, cognitive function and health-related quality of life were evaluated in survivors at 1 year using standardised questionnaires. RESULTS: Of 412 patients enrolled into the REST trial, 391 (95%) had 2-year mortality outcome data available. There was no difference in the time to death between intervention and standard care (HR 1.08 (0.81, 1.44); log-rank test p=0.61). 161 patients alive at 1 year provided at least one questionnaire response. There was no difference in respiratory function, post-traumatic stress disorder, cognitive dysfunction or health-related quality of life between patients allocated to intervention or standard care. CONCLUSION: Lower-tidal volume ventilation facilitated by vv-ECCO2R does not affect 1-year mortality in patients with moderate-to-severe AHRF. Of the patients who provided questionnaire responses, there was no treatment effect on long-term respiratory function, post-traumatic stress disorder, cognitive dysfunction or health-related quality of life. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02654327.

An external pilot cluster randomised controlled trial of a theory-based intervention to improve appropriate polypharmacy in older people in primary care (PolyPrime).

BACKGROUND: For older populations with multimorbidity, polypharmacy (use of multiple medications) is a standard practice. PolyPrime is a theory-based intervention developed to improve appropriate polypharmacy in older people in primary care. This pilot study aims to assess the feasibility of the PolyPrime intervention in primary care in Northern Ireland (NI) and the Republic of Ireland (ROI). METHODS: This external pilot cluster randomised controlled trial (cRCT) aimed to recruit 12 general practitioner (GP) practices (six in NI; six in the ROI counties that border NI) and ten older patients receiving polypharmacy (≥ 4 medications) per GP practice (n = 120). Practices allocated to the intervention arm watched an online video and scheduled medication reviews with patients on two occasions. We assessed the feasibility of collecting GP record (medication appropriateness, health service use) and patient self-reported data [health-related quality of life (HRQoL), health service use)] at baseline, 6 and 9 months. HRQoL was measured using the EuroQol-5 dimension-5 level questionnaire (EQ-5D-5L) and medication-related burden quality-of-life (MRB-QoL) tool. An embedded process evaluation and health economics analysis were also undertaken. Pre-specified progression criteria were used to determine whether to proceed to a definitive cRCT. RESULTS: Twelve GP practices were recruited and randomised. Three GP practices withdrew from the study due to COVID-related factors. Sixty-eight patients were recruited, with 47 (69.1%) being retained until the end of the study. GP record data were available for 47 patients for medication appropriateness analysis at 9 months. EQ-5D-5L and MRB-QoL data were available for 46 and 41 patients, respectively, at 9 months. GP record and patient self-reported health service use data were available for 47 patients at 9 months. Health service use was comparable in terms of overall cost estimated from GP record versus patient self-reported data. The intervention was successfully delivered as intended; it was acceptable to GPs, practice staff, and patients; and potential mechanisms of action have been identified. All five progression criteria were met (two 'Go', three 'Amend'). CONCLUSION: Despite challenges faced during the COVID-19 pandemic, this study has demonstrated that it may be feasible to conduct an intervention to improve appropriate polypharmacy in older people in primary care across two healthcare jurisdictions. TRIAL REGISTRATION: ISRCTN, ISRCTN41009897 . Registered 19 November 2019. CLINICALTRIALS: gov, NCT04181879 . Registered 02 December 2019.

Using tranexamic acid for an additional 24 hours postoperatively in hip and knee arthroplasty saves money: a cost analysis from the TRAC-24 randomized control trial.

AIMS: Tranexamic acid (TXA) is now commonly used in major surgical operations including orthopaedics. The TRAC-24 randomized control trial (RCT) aimed to assess if an additional 24 hours of TXA postoperatively in primary total hip (THA) and total knee arthroplasty (TKA) reduced blood loss. Contrary to other orthopaedic studies to date, this trial included high-risk patients. This paper presents the results of a cost analysis undertaken alongside this RCT. METHODS: TRAC-24 was a prospective RCT on patients undergoing TKA and THA. Three groups were included: Group 1 received 1 g intravenous (IV) TXA perioperatively and an additional 24-hour postoperative oral regime, Group 2 received only the perioperative dose, and Group 3 did not receive TXA. Cost analysis was performed out to day 90. RESULTS: Group 1 was associated with the lowest mean total costs, followed by Group 2 and then Group 3. The differences between Groups 1 and 3 (-£797.77 (95% confidence interval -1,478.22 to -117.32) were statistically significant. Extended oral dosing reduced costs for patients undergoing THA but not TKA. The reduced costs in Groups 1 and 2 resulted from reduced length of stay, readmission rates, emergency department attendances, and blood transfusions. CONCLUSION: This study demonstrated significant cost savings when using TXA in primary THA or TKA. Extended oral dosing reduced costs further in THA but not TKA. Cite this article: Bone Jt Open 2022;3(7):536-542.

Telecare Service Use in Northern Ireland: Exploratory Retrospective Cohort Study.

BACKGROUND: Telecare is a health service that involves the home installation of a number of information technology support systems for individuals with complex needs, such as people with reduced mobility or disabilities and the elderly. It involves the use of sensors in patients' homes to detect events, such as smoke in the kitchen, a front door left open, or a patient fall. In Northern Ireland (NI), outputs from these sensors are monitored remotely by the telecare team, who can provide assistance as required by telephone or through the emergency services. The facilitation of such rapid responses has the aim of promoting early intervention and therefore maintaining patient well-being. OBJECTIVE: The aims of this study were to construct a descriptive summary of the telecare program in NI and evaluate hospital-based service use by telecare patients before and after the installation of telecare equipment. METHODS: An exploratory retrospective cohort study was conducted involving more than 2000 patients. Data analysis included the evaluation of health care use before and after the telecare service was initiated for individual participants. Individuals with data for a minimum of 6 months before and after the installation of the telecare service were included in this analysis. RESULTS: A total of 2387 patients were enrolled in the telecare service during the observation period (February 26, 2010-February 22, 2016). The mean age was 78 years (median 81 years). More women (1623/2387, 68%) were enrolled in the service. Falls detectors were the most commonly deployed detectors in the study cohort (824/1883, 43.8% of cases). The average number of communications (calls and/or alarms) between participants and the coordinating center was the highest for patients aged ≥85 years (mean 86 calls per year). These contacts were similarly distributed by gender. The mortality rate over the study period was higher in men than women (98/770, 14.4% in men compared to 107/1617, 6.6% in women). The number of nonelective hospital admissions, emergency room visits, and outpatient clinic visits and the length of hospital stays per year were significantly higher (P<.001) after the installation of the telecare equipment than during the period before installation. CONCLUSIONS: Despite the likely benefits of the telecare service in providing peace of mind for patients and their relatives, hospital-based health care use significantly increased after enrollment in the service. This likely reflects the increasing health care needs over time in an aging population.

Co-ordinated multidisciplinary intervention to reduce time to successful extubation for children on mechanical ventilation: the SANDWICH cluster stepped-wedge RCT.

BACKGROUND: Daily assessment of patient readiness for liberation from invasive mechanical ventilation can reduce the duration of ventilation. However, there is uncertainty about the effectiveness of this in a paediatric population. OBJECTIVES: To determine the effect of a ventilation liberation intervention in critically ill children who are anticipated to have a prolonged duration of mechanical ventilation (primary objective) and in all children (secondary objective). DESIGN: A pragmatic, stepped-wedge, cluster randomised trial with economic and process evaluations. SETTING: Paediatric intensive care units in the UK. PARTICIPANTS: Invasively mechanically ventilated children (aged < 16 years). INTERVENTIONS: The intervention incorporated co-ordinated multidisciplinary care, patient-relevant sedation plans linked to sedation assessment, assessment of ventilation parameters with a higher than usual trigger for undertaking an extubation readiness test and a spontaneous breathing trial on low levels of respiratory support to test extubation readiness. The comparator was usual care. Hospital sites were randomised sequentially to transition from control to intervention and were non-blinded. MAIN OUTCOME MEASURES: The primary outcome measure was the duration of invasive mechanical ventilation until the first successful extubation. The secondary outcome measures were successful extubation, unplanned extubation and reintubation, post-extubation use of non-invasive ventilation, tracheostomy, post-extubation stridor, adverse events, length of intensive care and hospital stay, mortality and cost per respiratory complication avoided at 28 days. RESULTS: The trial included 10,495 patient admissions from 18 paediatric intensive care units from 5 February 2018 to 14 October 2019. In children with anticipated prolonged ventilation (n = 8843 admissions: control, n = 4155; intervention, n = 4688), the intervention resulted in a significantly shorter time to successful extubation [cluster and time-adjusted median difference -6.1 hours (interquartile range -8.2 to -5.3 hours); adjusted hazard ratio 1.11, 95% confidence interval 1.02 to 1.20; p = 0.02] and a higher incidence of successful extubation (adjusted relative risk 1.01, 95% confidence interval 1.00 to 1.02; p = 0.03) and unplanned extubation (adjusted relative risk 1.62, 95% confidence interval 1.05 to 2.51; p = 0.03), but not reintubation (adjusted relative risk 1.10, 95% confidence interval 0.89 to 1.36; p = 0.38). In the intervention period, the use of post-extubation non-invasive ventilation was significantly higher (adjusted relative risk 1.22, 95% confidence interval 1.01 to 1.49; p = 0.04), with no evidence of a difference in intensive care length of stay or other harms, but hospital length of stay was longer (adjusted hazard ratio 0.89, 95% confidence interval 0.81 to 0.97; p = 0.01). Findings for all children were broadly similar. The control period was associated with lower, but not statistically significantly lower, total costs (cost difference, mean £929.05, 95% confidence interval -£516.54 to £2374.64) and significantly fewer respiratory complications avoided (mean difference -0.10, 95% confidence interval -0.16 to -0.03). LIMITATIONS: The unblinded intervention assignment may have resulted in performance or detection bias. It was not possible to determine which components were primarily responsible for the observed effect. Treatment effect in a more homogeneous group remains to be determined. CONCLUSIONS: The intervention resulted in a statistically significant small reduction in time to first successful extubation; thus, the clinical importance of the effect size is uncertain. FUTURE WORK: Future work should explore intervention sustainability and effects of the intervention in other paediatric populations. TRIAL REGISTRATION: This trial is registered as ISRCTN16998143. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 18. See the NIHR Journals Library website for further project information.

Mechanical ventilation is a life-saving therapy, but may involve related risks because of the breathing tube in the mouth and throat, the sedative drugs required to reduce anxiety and remaining confined to bed. Therefore, getting off the ventilator (called weaning) is an important patient outcome. Previous studies have shown that an organised approach involving nurses, doctors and physiotherapists reduces the time that patients spend on the ventilator. Our study involved more than 10,000 patients admitted to 18 children's intensive care units. We tested a co-ordinated staff approach for managing a child's sedation and ventilator needs against usual care, which was mainly consultant led and did not involve bedside nurses. We wanted to find out if this approach improved the outcomes for children and did not cause additional harm. We first collected information in the intensive care units when children were weaned from the ventilator using usual care. Following staff training in the new approach, we compared children's outcomes between the two approaches. Compared with usual care, the new approach reduced the time that children spent on the ventilator by between 5 and 9 hours, and increased children's chances of having their breathing tube removed successfully. Some children pulled out their breathing tubes themselves before it was medically planned to do so. This happened more with the new approach, but the chance of needing the breathing tube put back in was not different from usual care. With the new approach, more children needed to use a mask ventilator than those receiving usual care, although the length of time that this was required was not different from usual care. The intensive care length of stay was the same for children receiving the new approach and usual care. However, with the new approach, children stayed in hospital 1 day longer, which resulted in higher costs (£715 per child); thus, the clinical relevance is uncertain.

The impact of an enhanced recovery programme on length of stay and post-discharge resource usage following hip and knee arthroplasty : a service evaluation and cost analysis.

AIMS: The aim of this study is to assess the impact of a pilot enhanced recovery after surgery (ERAS) programme on length of stay (LOS) and post-discharge resource usage via service evaluation and cost analysis. METHODS: Between May and December 2019, 100 patients requiring hip or knee arthroplasty were enrolled with the intention that each would have a preadmission discharge plan, a preoperative education class with nominated helper, a day of surgery admission and mobilization, a day one discharge, and access to a 24/7 dedicated helpline. Each was matched with a patient under the pre-existing pathway from the previous year. RESULTS: Mean LOS for ERAS patients was 1.59 days (95% confidence interval (CI) 1.14 to 2.04), significantly less than that of the matched cohort (3.01 days; 95% CI 2.56 to 3.46). There were no significant differences in readmission rates for ERAS patients at both 30 and 90 days (six vs four readmissions at 30 days, and nine vs four at 90 days). Despite matching, there were significantly more American Society of Anesthesiologists (ASA) grade 3 patients in the ERAS cohort. There was a mean cost saving of £757.26 (95% CI £-1,200.96 to £-313.56) per patient. This is despite small increases in postoperative resource usage in the ERAS patients. CONCLUSION: ERAS represents a safe and effective means of reducing LOS in primary joint arthroplasty patients. Implementation of ERAS principles has potential financial savings and could increase patient throughput without compromising care. In elective care, a preadmission discharge plan is key. Cite this article: Bone Jt Open 2021;2(11):966-973.

Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial.

Importance: In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. Objective: To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. Design, Setting, and Participants: This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Interventions: Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). Main Outcomes and Measures: The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Results: Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02654327.

Effect of a Sedation and Ventilator Liberation Protocol vs Usual Care on Duration of Invasive Mechanical Ventilation in Pediatric Intensive Care Units: A Randomized Clinical Trial.

Importance: There is limited evidence on the optimal strategy for liberating infants and children from invasive mechanical ventilation in the pediatric intensive care unit. Objective: To determine if a sedation and ventilator liberation protocol intervention reduces the duration of invasive mechanical ventilation in infants and children anticipated to require prolonged mechanical ventilation. Design, Setting, and Participants: A pragmatic multicenter, stepped-wedge, cluster randomized clinical trial was conducted that included 17 hospital sites (18 pediatric intensive care units) in the UK sequentially randomized from usual care to the protocol intervention. From February 2018 to October 2019, 8843 critically ill infants and children anticipated to require prolonged mechanical ventilation were recruited. The last date of follow-up was November 11, 2019. Interventions: Pediatric intensive care units provided usual care (n = 4155 infants and children) or a sedation and ventilator liberation protocol intervention (n = 4688 infants and children) that consisted of assessment of sedation level, daily screening for readiness to undertake a spontaneous breathing trial, a spontaneous breathing trial to test ventilator liberation potential, and daily rounds to review sedation and readiness screening and set patient-relevant targets. Main Outcomes and Measures: The primary outcome was the duration of invasive mechanical ventilation from initiation of ventilation until the first successful extubation. The primary estimate of the treatment effect was a hazard ratio (with a 95% CI) adjusted for calendar time and cluster (hospital site) for infants and children anticipated to require prolonged mechanical ventilation. Results: There were a total of 8843 infants and children (median age, 8 months [interquartile range, 1 to 46 months]; 42% were female) who completed the trial. There was a significantly shorter median time to successful extubation for the protocol intervention compared with usual care (64.8 hours vs 66.2 hours, respectively; adjusted median difference, -6.1 hours [interquartile range, -8.2 to -5.3 hours]; adjusted hazard ratio, 1.11 [95% CI, 1.02 to 1.20], P = .02). The serious adverse event of hypoxia occurred in 9 (0.2%) infants and children for the protocol intervention vs 11 (0.3%) for usual care; nonvascular device dislodgement occurred in 2 (0.04%) vs 7 (0.1%), respectively. Conclusions and Relevance: Among infants and children anticipated to require prolonged mechanical ventilation, a sedation and ventilator liberation protocol intervention compared with usual care resulted in a statistically significant reduction in time to first successful extubation. However, the clinical importance of the effect size is uncertain. Trial Registration: isrctn.org Identifier: ISRCTN16998143.

An external pilot cluster randomised controlled trial of a theory-based intervention to improve appropriate polypharmacy in older people in primary care (PolyPrime): study protocol.

BACKGROUND: The use of multiple medications (polypharmacy) is a concern in older people (≥65 years) and is associated with negative health outcomes. For older populations with multimorbidity, polypharmacy is the reality and the key challenge is ensuring appropriate polypharmacy (as opposed to inappropriate polypharmacy). This external pilot cluster randomised controlled trial (cRCT) aims to further test a theory-based intervention to improve appropriate polypharmacy in older people in primary care in two jurisdictions, Northern Ireland (NI) and the Republic of Ireland (ROI). METHODS: Twelve GP practices across NI (n=6) and the six counties in the ROI that border NI will be randomised to either the intervention or usual care group. Members of the research team have developed an intervention to improve appropriate polypharmacy in older people in primary care using the Theoretical Domains Framework of behaviour change. The intervention consists of two components: (1) an online video which demonstrates how a GP may prescribe appropriate polypharmacy during a consultation with an older patient and (2) a patient recall process, whereby patients are invited to scheduled medication review consultations with GPs. Ten older patients receiving polypharmacy (≥4 medications) will be recruited per GP practice (n=120). GP practices allocated to the intervention arm will be asked to watch the online video and schedule medication reviews with patients on two occasions; an initial and a 6-month follow-up appointment. GP practices allocated to the control arm will continue to provide usual care to patients. The study will assess the feasibility of recruitment, retention and study procedures including collecting data on medication appropriateness (from GP records), quality of life and health service use (i.e. hospitalisations). An embedded process evaluation will assess intervention fidelity (i.e. was the intervention delivered as intended), acceptability of the intervention and potential mechanisms of action. DISCUSSION: This pilot cRCT will provide evidence of the feasibility of a range of study parameters such as recruitment and retention, data collection procedures and the acceptability of the intervention. Pre-specified progression criteria will also be used to determine whether or not to proceed to a definitive cRCT. TRIAL REGISTRATION: ISRCTN, ISRCTN41009897 . Registered 19 November 2019. ClinicalTrials.gov, NCT04181879 . Registered 02 December 2019.

The Effectiveness of Individual or Group Physiotherapy in the Management of Sub-Acromial Impingement: A Randomised Controlled Trial and Health Economic Analysis.

Background: Shoulder pain is common in primary care. The management of subacromial impingement (SAI) can include corticosteroid injections and physiotherapy. Physiotherapy can be on an individual or group basis. Aim: To examine the clinical effectiveness and make an economic analysis of individual versus group physiotherapy, following corticosteroid injection for SAI. Design and Setting: A single-blind, open-label, randomised equivalence study comparing group and individual physiotherapy. Patients referred by local general practitioners and physiotherapists were considered for inclusion. Method: Patients were randomised to individual or group physiotherapy groups, and all received corticosteroid injection before physiotherapy. The primary outcome measure was shoulder pain and disability index (SPADI) at 26 weeks. An economic analysis was conducted. Results and Conclusion: 136 patients were recruited, 68 randomised to each group. Recruitment was 68% of the target 200 participants. SPADI (from baseline to 26 weeks) demonstrated a difference (SE) in mean change between groups of -0.43 (5.7) (p-value = 0.050001), and the TOST (two-one-sided test for equivalence) 90% CI for this difference was (-10.0 to 9.14). This was borderline. In a secondary analysis using inputted data, patients without SPADI at week 26 were analysed by carrying forward scores at week 12 (mean difference (95% CI) = -0.14 (-7.5 to 7.3), p-value = 0.014). There is little difference in outcome at 26 weeks. Group physiotherapy was cheaper to deliver per patient (£252 versus £84). Group physiotherapy for SAI produces similar clinical outcomes to individual physiotherapy with potential cost savings. Due to low recruitment to our study, firm conclusions are difficult and further research is required to give a definitive answer to this research question. (NCT Clinical Trial Registration Number NCT04058522).

Early switch from intravenous to oral antibiotic therapy in patients with cancer who have low-risk neutropenic sepsis (the EASI-SWITCH trial): study protocol for a randomised controlled trial.

BACKGROUND: Neutropenic sepsis remains a common treatment complication for patients receiving systemic anti-cancer treatment. The UK National Institute for Health and Care Excellence have not recommended switching from empirical intravenous antibiotics to oral antibiotics within 48 h for patients assessed as low risk for septic complications because of uncertainty about whether this would achieve comparable outcomes to using intravenous antibiotics for longer. The UK National Institute for Health Research funded the EASI-SWITCH trial to tackle this uncertainty. METHODS: The trial is a pragmatic, randomised, non-inferiority trial that aims to establish the clinical and cost-effectiveness of early switching from intravenous to oral antibiotics in cancer patients with low-risk neutropenic sepsis. Patients ≥ 16 years, receiving systemic anti-cancer treatment (acute leukaemics/stem cell transplants excluded), with a temperature of > 38 °C, neutrophil count ≤ 1.0 × 109/L, MASCC (Multinational Association of Supportive Care in Cancer) score ≥ 21 and receiving IV piperacillin/tazobactam or meropenem for less than 24 h are eligible to participate. Patients are randomised 1:1 either (i) to switch to oral ciprofloxacin and co-amoxiclav within 12-24 h of commencing intravenous antibiotics, completing at least 5 days total antibiotics (intervention), or (ii) to continue intravenous antibiotics for at least 48 h, with ongoing antibiotics being continued at the physician's discretion (control). Patients are discharged home when their physician deems it appropriate. The primary outcome measure is a composite of treatment failures as assessed at day 14. The criteria for treatment failure include fever persistence or recurrence 72 h after starting intravenous antibiotics, escalation from protocolised antibiotics, hospital readmission related to infection/antibiotics, critical care support or death. Based on a 15% treatment failure rate in the control group and a 15% non-inferiority margin, the recruitment target is 230 patients. DISCUSSION: If the trial demonstrates non-inferiority of early switching to oral antibiotics, with potential benefits for patient quality of life and resource savings, this finding will have significant implications for the routine clinical management of those with low-risk neutropenic sepsis. TRIAL REGISTRATION: ISRCTN: 84288963. Registered on the 1 July 2015. https://doi.org/10.1186/ISRCTN84288963. EudraCT: 2015-002830-35.

Developing evidence-based guidance for assessment of suspected infections in care home residents.

BACKGROUND: The aim of this study was to update and refine an algorithm, originally developed in Canada, to assist care home staff to manage residents with suspected infection in the United Kingdom care home setting. The infections of interest were urinary tract infections, respiratory tract infections and skin and soft tissue infection. METHOD: We used a multi-faceted process involving a literature review, consensus meeting [nominal group technique involving general practitioners (GPs) and specialists in geriatric medicine and clinical microbiology], focus groups (care home staff and resident family members) and interviews (GPs), alongside continual iterative internal review and analysis within the research team. RESULTS: Six publications were identified in the literature which met inclusion criteria. These were used to update the algorithm which was presented to a consensus meeting (four participants all with a medical background) which discussed and agreed to inclusion of signs and symptoms, and the algorithm format. Focus groups and interview participants could see the value in the algorithm, and staff often reported that it reflected their usual practice. There were also interesting contrasts between evidence and usual practice informed by experience. Through continual iterative review and analysis, the final algorithm was finally presented in a format which described management of the three infections in terms of initial assessment of the resident, observation of the resident and action by the care home staff. CONCLUSIONS: This study has resulted in an updated algorithm targeting key infections in care home residents which should be considered for implementation into everyday practice.

Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluation.

BACKGROUND: Ventilator-associated pneumonia is the most common intensive care unit (ICU)-acquired infection, yet accurate diagnosis remains difficult, leading to overuse of antibiotics. Low concentrations of IL-1ß and IL-8 in bronchoalveolar lavage fluid have been validated as effective markers for exclusion of ventilator-associated pneumonia. The VAPrapid2 trial aimed to determine whether measurement of bronchoalveolar lavage fluid IL-1ß and IL-8 could effectively and safely improve antibiotic stewardship in patients with clinically suspected ventilator-associated pneumonia. METHODS: VAPrapid2 was a multicentre, randomised controlled trial in patients admitted to 24 ICUs from 17 National Health Service hospital trusts across England, Scotland, and Northern Ireland. Patients were screened for eligibility and included if they were 18 years or older, intubated and mechanically ventilated for at least 48 h, and had suspected ventilator-associated pneumonia. Patients were randomly assigned (1:1) to biomarker-guided recommendation on antibiotics (intervention group) or routine use of antibiotics (control group) using a web-based randomisation service hosted by Newcastle Clinical Trials Unit. Patients were randomised using randomly permuted blocks of size four and six and stratified by site, with allocation concealment. Clinicians were masked to patient assignment for an initial period until biomarker results were reported. Bronchoalveolar lavage was done in all patients, with concentrations of IL-1ß and IL-8 rapidly determined in bronchoalveolar lavage fluid from patients randomised to the biomarker-based antibiotic recommendation group. If concentrations were below a previously validated cutoff, clinicians were advised that ventilator-associated pneumonia was unlikely and to consider discontinuing antibiotics. Patients in the routine use of antibiotics group received antibiotics according to usual practice at sites. Microbiology was done on bronchoalveolar lavage fluid from all patients and ventilator-associated pneumonia was confirmed by at least 104 colony forming units per mL of bronchoalveolar lavage fluid. The primary outcome was the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage. Data were analysed on an intention-to-treat basis, with an additional per-protocol analysis that excluded patients randomly assigned to the intervention group who defaulted to routine use of antibiotics because of failure to return an adequate biomarker result. An embedded process evaluation assessed factors influencing trial adoption, recruitment, and decision making. This study is registered with ISRCTN, ISRCTN65937227, and ClinicalTrials.gov, NCT01972425. FINDINGS: Between Nov 6, 2013, and Sept 13, 2016, 360 patients were screened for inclusion in the study. 146 patients were ineligible, leaving 214 who were recruited to the study. Four patients were excluded before randomisation, meaning that 210 patients were randomly assigned to biomarker-guided recommendation on antibiotics (n=104) or routine use of antibiotics (n=106). One patient in the biomarker-guided recommendation group was withdrawn by the clinical team before bronchoscopy and so was excluded from the intention-to-treat analysis. We found no significant difference in the primary outcome of the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage in the intention-to-treat analysis (p=0·58). Bronchoalveolar lavage was associated with a small and transient increase in oxygen requirements. Established prescribing practices, reluctance for bronchoalveolar lavage, and dependence on a chain of trial-related procedures emerged as factors that impaired trial processes. INTERPRETATION: Antibiotic use remains high in patients with suspected ventilator-associated pneumonia. Antibiotic stewardship was not improved by a rapid, highly sensitive rule-out test. Prescribing culture, rather than poor test performance, might explain this absence of effect. FUNDING: UK Department of Health and the Wellcome Trust.

A 2 × 2 factorial, randomised, open-label trial to determine the clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care over 52 weeks in adults with bronchiectasis: a protocol for the CLEAR clinical trial.

BACKGROUND: Current guidelines for the management of bronchiectasis (BE) highlight the lack of evidence to recommend mucoactive agents, such as hypertonic saline (HTS) and carbocisteine, to aid sputum removal as part of standard care. We hypothesise that mucoactive agents (HTS or carbocisteine, or a combination) are effective in reducing exacerbations over a 52-week period, compared to usual care. METHODS: This is a 52-week, 2 × 2 factorial, randomized, open-label trial to determine the clinical effectiveness and cost effectiveness of HTS 6% and carbocisteine for airway clearance versus usual care - the Clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care (CLEAR) trial. Patients will be randomised to (1) standard care and twice-daily nebulised HTS (6%), (2) standard care and carbocisteine (750 mg three times per day until visit 3, reducing to 750 mg twice per day), (3) standard care and combination of twice-daily nebulised HTS and carbocisteine, or (4) standard care. The primary outcome is the mean number of exacerbations over 52 weeks. Key inclusion criteria are as follows: adults with a diagnosis of BE on computed tomography, BE as the primary respiratory diagnosis, and two or more pulmonary exacerbations in the last year requiring antibiotics and production of daily sputum. DISCUSSION: This trial's pragmatic research design avoids the significant costs associated with double-blind trials whilst optimising rigour in other areas of trial delivery. The CLEAR trial will provide evidence as to whether HTS, carbocisteine or both are effective and cost effective for patients with BE. TRIAL REGISTRATION: EudraCT number: 2017-000664-14 (first entered in the database on 20 October 2017). ISRCTN.com, ISRCTN89040295. Registered on 6 July/2018. Funder: National Institute for Health Research, Health Technology Assessment Programme (15/100/01). SPONSOR: Belfast Health and Social Care Trust. Ethics Reference Number: 17/NE/0339. Protocol version: v3.0 Final_14052018.

Sedation AND Weaning In Children (SANDWICH): protocol for a cluster randomised stepped wedge trial.

INTRODUCTION: Weaning from ventilation is a complex process involving several stages that include recognition of patient readiness to begin the weaning process, steps to reduce ventilation while optimising sedation in order not to induce distress and removing the endotracheal tube. Delay at any stage can prolong the duration of mechanical ventilation. We developed a multicomponent intervention targeted at helping clinicians to safely expedite this process and minimise the harms associated with unnecessary mechanical ventilation. METHODS AND ANALYSIS: This is a 20-month cluster randomised stepped wedge clinical and cost-effectiveness trial with an internal pilot and a process evaluation. It is being conducted in 18 paediatric intensive care units in the UK to evaluate a protocol-based intervention for reducing the duration of invasive mechanical ventilation. Following an initial 8-week baseline data collection period in all sites, one site will be randomly chosen to transition to the intervention every 4 weeks and will start an 8-week training period after which it will continue the intervention for the remaining duration of the study. We aim to recruit approximately 10 000 patients. The primary analysis will compare data from before the training (control) with that from after the training (intervention) in each site. Full details of the analyses will be in the statistical analysis plan. ETHICS AND DISSEMINATION: This protocol was reviewed and approved by NRES Committee East Midlands-Nottingham 1 Research Ethics Committee (reference: 17/EM/0301). All sites started patient recruitment on 5 February 2018 before randomisation in April 2018. Results will be disseminated in 2020. The results will be presented at national and international conferences and published in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: ISRCTN16998143.

Multifaceted intervention to Reduce Antimicrobial Prescribing in Care Homes: a process evaluation of a UK-based non-randomised feasibility study.

OBJECTIVES: To explore the facilitators and obstacles to the development and implementation of the Reduce Antimicrobial Prescribing in Care Homes intervention. DESIGN: We used a mixed-methods approach. We conducted focus groups with care home staff and relatives of residents, and interviews with general practitioners (GPs) and home managers, completed observational visits and collected demographic data, training attendance records and data on the use of a decision-making algorithm. We used normalisation process theory to inform topic guides and interpretation of the data. SETTING: Six care homes, three in Northern Ireland and three in the West Midlands, England. INTERVENTION: A decision-making algorithm for urinary tract, respiratory tract and skin and soft-tissue infections, plus small group interactive training for care home staff. RESULTS: We ran 21 training sessions across the six homes and trained 35/42 (83%) of nurses and 101/219 (46%) of all care staff. Care home staff reported using the decision-making algorithm 81 times. Postimplementation, staff reported being more knowledgeable about antimicrobial resistance but were unsure if the intervention would change how GPs prescribed antimicrobials. The pressures of everyday work in some homes meant that engagement was challenging at times. Staff felt that some of the symptoms included in decision-making algorithm, despite being evidence based, were not easy to detect in residents with dementia or urinary incontinence. Some staff did not use the decision-making algorithm, noting that their own knowledge of the resident was more important. CONCLUSION: We delivered a training package to a substantial number of key staff in care homes. A decision-making algorithm for common infections in care homes empowered staff but was challenging to operationalise at times. A future study should consider the findings from the process evaluation to help ensure the successful implementation on a larger scale.