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Abstract Background Opioids kill more people than any other class of drug. Naloxone is an opioid antagonist which can be distributed in kits for peer administration. We assessed the feasibility of implementing a Take-home Naloxone (THN) intervention in emergency settings, as part of designing a definitive randomised controlled trial (RCT). Methods We undertook a clustered RCT on sites pairing UK Emergency Departments (ED) and ambulance services. At intervention sites, we recruited emergency healthcare practitioners to supply THN to patients presenting with opioid overdose or related condition, with recruitment across 2019–2021. We assessed feasibility of intervention implementation against four predetermined progression criteria covering site sign up and staff training; identification of eligible patients; issue of THN kits and Serious Adverse Events. Results At two intervention sites, randomly selected from 4, 299/687 (43.5%) clinical staff were trained (ED1 = 107, AS1 = 121, ED2 = 25, AS2 = 46). Sixty THN kits were supplied to eligible patients (21.7%) (n: ED1 = 36, AS1 = 4, ED2 = 16, AS2 = 4). Across sites, kits were not issued to eligible patients on a further 164 occasions, with reasons reported including: staff forgot (n = 136), staff too busy (n = 15), and suspected intentional overdose (n = 3), no kit available (n = 2), already given by drugs nurse (n = 4), other (n = 4). Staff recorded 626 other patients as ineligible but considered for inclusion, with reasons listed as: patient admitted to hospital (n = 194), patient absconded (n = 161) already recruited (n = 64), uncooperative or abusive (n = 55), staff not trained (n = 43), reduced consciousness level (n = 41), lack of capacity (n = 35), patient in custody (n = 21), other (n = 12). No adverse events were reported. Conclusion Staff and patient recruitment were low and varied widely by site. This feasibility study did not meet progression criteria; a fully powered RCT is not planned. Trial Registration ISRCTN13232859 (Registered 16/02/2018).

Background Calls have been made for paramedics to have some form of care pathway that they could use to safely divert adults with epilepsy away from emergency departments and instigate ambulatory care improvements. Different configurations are possible. To know which to prioritise for implementation/evaluation, there is a need to determine which are acceptable to service users and likely National Health Service-feasible. Objective(s) (1) Identify configurations being considered, (2) understand service users’ views of them and current provision, (3) identify what sort of care service users want and (4) determine which configuration(s) is considered to achieve optimal balance in meeting users’ preference and being National Health Service-feasible. Design Service providers were surveyed to address objective 1. Interviews with service users addressed objective 2. Objective 3 was addressed by completing discrete choice experiments. These determined users’ care preferences for different seizure scenarios. Objective 4 was addressed by completing ‘knowledge exchange’ workshops. At these, stakeholders considered the findings on users’ stated preferences and judged different pathway configurations against Michie’s ‘acceptability, practicability, effectiveness, affordability, side-effects and equity’ feasibility criteria. Setting This project took place in England. The survey recruited representatives from neurology and neuroscience centres and from urgent and emergency care providers. For the interviews, recruitment occurred via third-sector support groups. Recruitment for discrete choice experiments occurred via the North West Ambulance Service NHS Trust and public advert. Workshop participants were recruited from neurology and neuroscience centres, urgent and emergency care providers, support groups and commissioning networks. Participants Seventy-two services completed the survey. Interviews were conducted with 25 adults with epilepsy (and 5 relatives) who had emergency service contact in the prior 12 months. Discrete choice experiments were completed by 427 adults with epilepsy (and 167 relatives) who had ambulance service contact in the prior 12 months. Workshops were completed with 27 stakeholders. Results The survey identified a range of pathway configurations. They differed in where they would take the patient and their potential to instigate ambulatory care improvements. Users had been rarely consulted in designing them. The discrete choice experiments found that users want a configuration of care markedly different to that offered. Across the seizure scenarios, users wanted their paramedic to have access to their medical records; for an epilepsy specialist (e.g. an epilepsy nurse, neurologist) to be available to advise; for their general practitioner to receive a report; for the incident to generate an appointment with an epilepsy specialist; for the care episode to last < 6 hours; and there was a pattern of preference to avoid conveyance to emergency departments and stay where they were. Stakeholders judged this configuration to be National Health Service-feasible within 5–10 years, with some elements being immediately deployable. Limitations The discrete choice experiment sample was broadly representative, but those reporting recent contact with an epilepsy specialist were over-represented. Conclusions Users state they want a configuration of care that is markedly different to current provision. The configuration they prefer was, with support and investment, judged to likely be National Health Service-feasible. The preferred configuration should now be developed and evaluated to determine its actual deliverability and efficacy. Study registration The study is registered as researchregistry4723. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 17/05/62) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 24. See the NIHR Funding and Awards website for further award information. Plain language summary Ambulances often attend to people with epilepsy. Most of them are taken to the hospital’s accident and emergency department. This typically has little benefit since most patients are already diagnosed and visit the accident and emergency department with non-emergency states. To change things, National Health Service organisations want an ‘alternative care pathway’ for paramedics to use. It could mean the person is not taken to the accident and emergency department but cared for elsewhere. Our project brought stakeholders together to develop an alternative care pathway that includes things important to patients and carers but is also National Health Service-feasible. Seventy National Health Service organisations first told us via a survey and a workshop which pathways they were considering and which might be feasible. Thirty people with epilepsy and their family members and friends were then interviewed. They explained what is wanted after a seizure and problems with current care. One problem was that going to the accident and emergency department does not lead to them getting a follow-up appointment with an epilepsy specialist to check their treatment is right. Using ‘discrete choice experiments’, around 430 people with epilepsy who recently contacted the ambulance service and 170 of their family and friends were asked to make a choice between alternative packages of care, to say which pathway they would prefer in different seizure situations. The results were clear. People wanted care different from what National Health Service organisations told us was available. The choice experiment showed everyone prefers pathways where paramedics have access to their medical records, an epilepsy specialist is available to advise the paramedic, the general practitioner gets a report and they get an appointment with an epilepsy specialist in the future. Everyone wants to avoid long episodes of care (6 hours) and after a typical seizure people with epilepsy want to stay at home. Three workshops were run with paramedics, epilepsy specialists and managers. They said the alternative care pathway wanted by users could be National Health Service-feasible. There is a need to implement and evaluate it now. Scientific summary Background Emergency department (ED) visits for epilepsy are common, costly, often clinically unnecessary and typically lead to little benefit for epilepsy management. An alternative care pathway (CP), which diverts people with epilepsy (PWE) away from ED when ‘999’ is called and leads to care elsewhere, could potentially generate savings and instigate improvements in the person’s ambulatory care. This project sought to identify the optimal configuration, ensuring the CP is both acceptable to service users and NHS-feasible. A key method used was discrete choice experiments (DCEs). They involved users being presented with hypothetical seizure scenarios and making a number of choices to say which CP configuration, described according to a fixed set of characteristics (attributes), they would prefer. The project’s aims were as follows. Aims and objectives Work Package 1 Systematically identify alternative CPs being considered by NHS services and describe extent to which service users have been involved in their design. Understand decision-making processes of PWE and their significant others (SOs) for seeking ED care and their concerns and expectations regarding alternative CPs. Identify attributes of postseizure care that PWE and their SOs (close family and friends) consider important. Work Package 2 Determine users’ and SOs’ preferences for postseizure care using DCEs and identify subgroup differences. Estimate utility of different CP configurations to service users and subgroup differences. Work Package 3 Hold expert workshops at which stakeholders, informed of the DCE evidence, would identify the optimal alternative CP/s for seizures that could be recommended for implementation and evaluation. Methods Work Package 1 Work Package 1a. Survey of service providers England’s ambulance services, epilepsy services and a random sample of its EDs were surveyed (April–June 2019). They were asked what alternative CPs they were considering and the extent to which they had consulted users. Work Package 1b. Interviews with service users Semistructured interviews were conducted in Southeast England with a purposive sample of PWE (April–September 2019). They also completed a ranking exercise to identify the characteristics (attributes) of postseizure care they considered most important. Participants were recruited from third-sector user groups and via a research newsletter. To be eligible, the person needed to be (1) aged ≥ 18, (2) have been diagnosed with epilepsy for ≥ 1 year, (3) had contacted the emergency services in the previous 12 months and (4) be able to provide informed consent and complete an interview in English. People with epilepsy were invited to be interviewed along with a SO. Work Package 1c. Knowledge exchange event Work Package (WP) 1b and 1c findings were used to select a set of candidate attributes that could be used to describe CPs within the DCE. To ensure attributes were features of alternative CPs and the levels likely NHS-feasible, a 1-day ‘knowledge exchange’ event was run (October 2019). Participants were representatives from ambulance and epilepsy services. They were identified for participation via WP1a. Work Package 2 Work Package 2a. Discrete choice experiment design panel and pilot A DCE design panel used evidence from WPs 1a–c to generate the DCE survey, using a D-efficient experimental design (Ngene 1.2.1, ChoiceMetrics, Sydney, Australia). The survey’s purpose was to obtain data of users’ care preferences for three separate scenarios, namely, a ‘typical seizure at home’, a ‘typical seizure in public’ and an ‘atypical seizure’. It, and vignettes describing the different seizure scenarios, was iteratively refined and finalised based on piloting. Work Package 2b. Formal discrete choice experiment A sample of n = 348 adults with epilepsy (and their SOs) from the target population was sought to complete the DCE. They filled in the DCE via an online platform. Participants were recruited via two routes between July and November 2020: (1) from the Merseyside area via the North West Ambulance Service and (2) nationally via public advert. PWE needed to (1) be aged ≥ 18 years, have a diagnosis of epilepsy, (2) have been seen by the ambulance service in prior 12 months and (3) be able to provide informed consent and independently complete the survey in English. Significant others needed to be aged ≥ 16. Data were analysed using a random-effects logit model. Preference weights were estimated for each attribute. Data from PWE and SOs were analysed separately, thus creating six seizure contexts for which preferences were modelled (three seizure scenarios × two participant types). Work Package 3 To identify which CP configuration(s) represented the optimal balance between user preference and NHS feasibility, three online ‘knowledge exchange’ workshops were run. Attendees were representatives from the ambulance service, from epilepsy services and commissioning. Service user representatives were also present. Commissioning and managerial representation was secured via national professional bodies. The DCE findings from WP2 were disseminated, and attendees were introduced to Michie et al.’s affordability, practicability, effectiveness, acceptability, side-effects and equity (APEASE) feasibility criteria. Nominal group techniques were then utilised, with stakeholders sharing views on the extent to which they considered the attribute levels favoured by users to be NHS-feasible. The groups then specified the levels for each attribute they believed represented the optimal balance. Results Work Package 1 Work Package 1a. Survey of service providers Clinical leads and managers from 72 (82.8%) of the invited services responded. Sixty per cent were considering or using an alternative CP change; only 21.2% had consulted service users on it. A range of CP configurations were reported. Some involved caring for PWE at home, ‘on scene’ or in some instances conveying them to an urgent treatment centre. The potential of configurations to improve ambulatory care varied. Work Package 1b. Semistructured interviews with service users Thirty service users (25 PWE and 5 SOs) were interviewed. The average age of PWE was 37 years; mean years was diagnosed 21. Participants provided insights into the challenges service users experience and disruptions they experience due to inadequate information transfer and co-ordination between ambulatory and urgent and emergency care services. Interviews highlighted some initial concerns users had with some possible CP configurations. The ranking exercise provided an approximation of the factors contributing to the ‘decision calculus’ users use when considering postseizure care options. Six attributes appeared most important: (1) whether the ambulance crew would have access to their medical records or care plan, (2) where the CP would take them, (3) how long it would take for them to be assessed, monitored and treated during the emergency episode, (4) extent to which the emergency care provider could request advice from an epilepsy specialist (e.g. epilepsy nurse, neurologist), (5) whether the CP would mean their usual care provider/s would be informed of the incident and, finally, (6) whether any follow-up from the epilepsy specialist would be instigated. Work Package 1c. Knowledge exchange event Thirteen representatives attended the workshop (n = 6 paramedics, n = 4 neurologists, n = 2 epilepsy nurse specialists and n = 1 user group representative). Participants agreed the six attributes identified by WP1b were all characteristics of an alternative CP, plausible and could be ‘traded’. Much of the event focused on identifying attribute levels that were considered feasible. Work Package 2 Work Package 2a. Discrete choice experiment design panel and pilot The panel decided that the six attributes identified in the formative work should be used to describe the CP options within the DCEs. Accordingly, DCEs for the three seizure scenarios were developed with the intention that participants would be randomised to each complete DCEs for two of three seizure scenarios, achieving a 1 : 1 : 1 allocation ratio. The six attributes and their associated levels (between 2 and 4) had the potential to generate 288 possible CP configurations. Use of an efficient experimental design meant that for each of the seizure scenarios a person would consider 24 CPs that were paired into 12 binary choices. The presentation of the DCE was finalised following pilot interviews. The final labels used for the attributes were as follows: (1) ‘The paramedic has access to medical records or a care plan’; (2) ‘What happens next’; (3) ‘Time’; (4) ‘Epilepsy specialists today’; (5) ‘GP told’; (6) ‘Additional contact with an epilepsy specialist’. Work Package 2b. Formal discrete choice experiment Useable submissions to the DCE survey were secured from n = 594 participants (n = 427 PWE; n = 167 SOs). Most (81.1%) were recruited via the public advertisement route. When participants from the two recruitment routes were merged to form a single sample, it was broadly representative of the target population. Two exceptions were its younger age and higher proportion reporting recent contact with an epilepsy specialist. The main ways that the SO participants knew someone with epilepsy was that they were the patient’s parents. The characteristics of the PWE known by SOs differed from those of the PWE taking part themselves (e.g. more learning disability). Across the three seizure scenarios, both PWE and SOs preferred CP configurations that differed from the way care is currently provided. Using coefficients from the random-effects logit models, the expected utility to service users for all possible CP configurations was calculated for the six seizure contexts. Care pathways were then ranked: rank 1 = most preferred; 288 = least preferred. The highest rank that the CP configuration approximating current care achieved was 220/288. There was similarity across the seizure contexts in terms of which attribute levels featured in the top-ranked configurations. In fact, three of the six contexts shared the same top-ranked configuration. For all six contexts, the highest-ranked CP configurations included (1) the paramedic having access to medical records or a care plan, (2) an epilepsy specialist (e.g. epilepsy nurse, neurologist) being available to advise the attending paramedic, (3) the patient’s GP being notified of the incident and (4) an appointment with an epilepsy specialist within 2–3 weeks being booked for the patient. The only attributes that varied within the top-ranked configurations were ‘What happens next’ and ‘Time’. For five of them, the top configuration involved the patient staying ‘where they were’. For the remaining ones – namely, for an ‘atypical seizure’ when considered by a SO – it involved the patient being conveyed to an urgent treatment centre. Different attributes had different levels of effect on preference. Providing crews with access to the medical records or care plan of the patient being attended to and having a specialist able to advise the paramedics had the strongest and consistent positive effect. Not all intended subgroup analyses could be completed due to insufficient cases. Those which could, showed social deprivation, recruitment route, presence of an intellectual impairment, contact with an epilepsy specialist in the prior 12 months, familiarity with the seizure scenario and whether the person with epilepsy had a care plan were not significantly related to preference. Work Package 3 Twenty-seven stakeholders attended a workshop. They included 10 ambulance clinicians, 8 epilepsy specialists, 5 commissioners and 4 patient and public involvement (PPI) representatives. Stakeholders believed the attribute levels preferred by service users were broadly feasible in the next 5–10 years. They identified those where most investment/work was required for them to be deliverable. Stakeholders were of the view that there was sufficient commonality in users’ preferences across the six seizure contexts for a single CP to be deployed. The groups were of the same position as to which configurations represented the optimum. They comprised of the following: (1) ambulance clinicians having access to medical records, (2) the person typically staying where they were, (3) the time taken being < 6 hours (be it 1, 2 or 3 hours), (4) crews being able to be advised by a specialist (an epilepsy nurse or neurologist) on the day, (5) for the person’s GP to be notified and, finally, for the incident to result in an appointment being made for the patient to have a follow-up appointment with an epilepsy specialist (be it within 1 week or 2–3 weeks). When attribute levels were restricted to these, the number of CP configurations for consideration reduced from 288 to 18. Evidence from WP2b showed these 18 included the configurations most preferred by service users for each scenario. Moreover, the evidence indicated that all 18 would be expected to hold more utility to users than the configuration representing current care. Conclusions By working collaboratively with service users from the target population, clinicians and commissioners, this project has provided clear answers to a pressing service delivery question. It provides evidence indicating that for common seizure scenarios, users appear open to paramedics not conveying them to ED and how poorly current care aligns with their preferences. Our project has also shown what postseizure care service users appear to want and that limited differences exist for different seizure scenarios. This appears to support the deployment of a single CP configuration. The study also provided evidence on the estimated improvement in utility that would result from individual attribute changes. This could be used to prioritise CP changes. Importantly, service providers and commissioners were found to be of the view that the CP configuration favoured by users could be NHS-feasible within 5–10 years, and they identified which attribute levels require the most work. It is important to now take the evidence this project has captured on people’s stated preferences and views and seek to implement one of the possible 18 CP configurations and evaluate it to determine its actual feasibility and efficacy in practice. Implications for NHS service commissioning, policy and practice The project identified a refined set of CP configurations that are considered optimal and the most promising candidates for formal evaluation. Pressures on acute services have intensified since our project was completed. This may incentivise ambulance services to use our findings and implement some form of alternative CP before an evaluation has occurred. Not all ambulance services would have the infrastructure and/or relationships with partner organisations to immediately implement the entire CP configuration considered optimal. Commissioners, policy-makers and service providers could support the development of the systems – such as shared record initiatives – to permit it to be offered. Identifying eligible people for the DCE survey via the NHS ambulance service was time-consuming compared to using public adverts. This could be made for efficient by embedding processes within NHS records systems to temporarily ‘strip’ them, including free-text fields, of confidential data. This would enable trained individuals not involved in a person’s care to screen anonymised records. Recommendations for research Using the attribute levels specified by stakeholders as representing the optimum, one of the possible 18 CP configurations should be evaluated for its efficacy. Any evaluation should consider short- (e.g. rates of recontact, death) and long-term outcomes (e.g. proportion of PWE ‘unknown’ to specialists brought to their attention). A cluster-randomised controlled trial would likely provide the most rigorous evidence. However, an alternative, faster evaluation approach may be needed to ensure evidence is generated in an acceptable time frame. Other ways to reduce unnecessary ED attendance warrant research attention. One is how to address ambulance crews’ requests for support in identifying persons suitable for non-conveyance. Attention is also needed on users’ seizure first aid confidence and knowledge. Study registration This study is registered as researchregistry4723. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 17/05/62) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 24. See the NIHR Funding and Awards website for further award information.

Objective To determine the balance of costs, risks, and benefits for different thromboprophylaxis strategies for medical patients during hospital admission.Design Decision analysis modelling study.Setting NHS hospitals in England.Population Eligible adult medical inpatients, excluding patients in critical care and pregnant women.Interventions Pharmacological thromboprophylaxis (low molecular weight heparin) for all medical inpatients, thromboprophylaxis for none, and thromboprophylaxis given to higher risk inpatients according to risk assessment models (Padua, Caprini, IMPROVE, Intermountain, Kucher, Geneva, and Rothberg) previously validated in medical cohorts.Main outcome measures Lifetime costs and quality adjusted life years (QALYs). Costs were assessed from the perspective of the NHS and Personal Social Services in England. Other outcomes assessed were incidence and treatment of venous thromboembolism, major bleeds including intracranial haemorrhage, chronic thromboembolic complications, and overall survival.Results Offering thromboprophylaxis to all medical inpatients had a high probability (>99%) of being the most cost effective strategy (at a threshold of £20 000 (€23 440; $25 270) per QALY) in the probabilistic sensitivity analysis, when applying performance data from the Padua risk assessment model, which was typical of that observed across several risk assessment models in a medical inpatient cohort. Thromboprophylaxis for all medical inpatients was estimated to result in 0.0552 additional QALYs (95% credible interval 0.0209 to 0.1111) while generating cost savings of £28.44 (−£47 to £105) compared with thromboprophylaxis for none. No other risk assessment model was more cost effective than thromboprophylaxis for all medical inpatients when assessed in deterministic analysis. Risk based thromboprophylaxis was found to have a high (76.6%) probability of being the most cost effective strategy only when assuming a risk assessment model with very high sensitivity is available (sensitivity 99.9% and specificity 23.7% v base case sensitivity 49.3% and specificity 73.0%).Conclusions Offering pharmacological thromboprophylaxis to all eligible medical inpatients appears to be the most cost effective strategy. To be cost effective, any risk assessment model would need to have a very high sensitivity resulting in widespread thromboprophylaxis in all patients except those at the very lowest risk, who could potentially avoid prophylactic anticoagulation during their hospital stay.

Introduction: Previous studies deriving and validating triage scores for patients with suspected COVID-19 in Emergency Department settings have been conducted in high- or middle-income settings. We assessed eight triage scores’ accuracy for death or organ support in patients with suspected COVID-19 in Sudan. Methods: We conducted an observational cohort study using Covid-19 registry data from eight emergency unit isolation centres in Khartoum State, Sudan. We assessed performance of eight triage scores including: PRIEST, LMIC-PRIEST, NEWS2, TEWS, the WHO algorithm, CRB-65, Quick COVID-19 Severity Index and PMEWS in suspected COVID-19. A composite primary outcome included death, ventilation or ICU admission. Results: In total 874 (33.84 %, 95 % CI:32.04 % to 35.69 %) of 2,583 patients died, required intubation/non-invasive ventilation or HDU/ICU admission . All risk-stratification scores assessed had worse estimated discrimination in this setting, compared to studies conducted in higher-income settings: C-statistic range for primary outcome: 0.56–0.64. At previously recommended thresholds NEWS2, PRIEST and LMIC-PRIEST had high estimated sensitivities (≥0.95) for the primary outcome. However, the high baseline risk meant that low-risk patients identified at these thresholds still had a between 8 % and 17 % risk of death, ventilation or ICU admission. Conclusion: None of the triage scores assessed demonstrated sufficient accuracy to be used clinically. This is likely due to differences in the health care system and population (23 % of patients died) compared to higher-income settings in which the scores were developed. Risk-stratification scores developed in this setting are needed to provide the necessary accuracy to aid triage of patients with suspected COVID-19.

Background Pharmacological prophylaxis during hospital admission can reduce the risk of acquired blood clots (venous thromboembolism) but may cause complications, such as bleeding. Using a risk assessment model to predict the risk of blood clots could facilitate selection of patients for prophylaxis and optimise the balance of benefits, risks and costs. Objectives We aimed to identify validated risk assessment models and estimate their prognostic accuracy, evaluate the cost-effectiveness of different strategies for selecting hospitalised patients for prophylaxis, assess the feasibility of using efficient research methods and estimate key parameters for future research. Design We undertook a systematic review, decision-analytic modelling and observational cohort study conducted in accordance with Enhancing the QUAlity and Transparency Of health Research (EQUATOR) guidelines. Setting NHS hospitals, with primary data collection at four sites. Participants Medical and surgical hospital inpatients, excluding paediatric, critical care and pregnancy-related admissions. Interventions Prophylaxis for all patients, none and according to selected risk assessment models. Main outcome measures Model accuracy for predicting blood clots, lifetime costs and quality-adjusted life-years associated with alternative strategies, accuracy of efficient methods for identifying key outcomes and proportion of inpatients recommended prophylaxis using different models. Results We identified 24 validated risk assessment models, but low-quality heterogeneous data suggested weak accuracy for prediction of blood clots and generally high risk of bias in all studies. Decision-analytic modelling showed that pharmacological prophylaxis for all eligible is generally more cost-effective than model-based strategies for both medical and surgical inpatients, when valuing a quality-adjusted life-year at £20,000. The findings were more sensitive to uncertainties in the surgical population; strategies using risk assessment models were more cost-effective if the model was assumed to have a very high sensitivity, or the long-term risks of post-thrombotic complications were lower. Efficient methods using routine data did not accurately identify blood clots or bleeding events and several pre-specified feasibility criteria were not met. Theoretical prophylaxis rates across an inpatient cohort based on existing risk assessment models ranged from 13% to 91%. Limitations Existing studies may underestimate the accuracy of risk assessment models, leading to underestimation of their cost-effectiveness. The cost-effectiveness findings do not apply to patients with an increased risk of bleeding. Mechanical thromboprophylaxis options were excluded from the modelling. Primary data collection was predominately retrospective, risking case ascertainment bias. Conclusions Thromboprophylaxis for all patients appears to be generally more cost-effective than using a risk assessment model, in hospitalised patients at low risk of bleeding. To be cost-effective, any risk assessment model would need to be highly sensitive. Current evidence on risk assessment models is at high risk of bias and our findings should be interpreted in this context. We were unable to demonstrate the feasibility of using efficient methods to accurately detect relevant outcomes for future research. Future work Further research should evaluate routine prophylaxis strategies for all eligible hospitalised patients. Models that could accurately identify individuals at very low risk of blood clots (who could discontinue prophylaxis) warrant further evaluation. Study registration This study is registered as PROSPERO CRD42020165778 and Researchregistry5216. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127454) and will be published in full in Health Technology Assessment; Vol. 28, No. 20. See the NIHR Funding and Awards website for further award information. Plain language summary People who are admitted to hospital are at risk of blood clots that can cause serious illness or death. Patients are often given low doses of blood-thinning drugs to reduce this risk. However, these drugs can cause side effects, such as bleeding. Hospitals currently use complex risk assessment models (risk scores, which usually include patient, disease, mobility and intervention factors) to determine the individual risk of blood clots and identify people most likely to benefit from blood-thinning drugs. There are a lot of different risk scores and we do not know which one is best. We also do not know how these scores compare to each other or whether using scores to decide who should get blood-thinning drugs provides good value for money to the NHS. We reviewed all previous studies of risk scores. We found that they did not predict blood clots very well and we could not recommend one score over another. We then created a mathematical model to simulate the use of blood-thinning drugs in people admitted to hospital. The model suggested that giving blood-thinning drugs to everyone who could have them would probably provide the best value for money, in medical patients. Our findings were the same, but less certain, for surgical patients. We also collected information from four NHS hospitals to explore possibilities for future research. Our work showed that routinely collected electronic data on blood clots and bleeding events is not very accurate and that using different scores could result in variable use of blood-thinning medications. Our findings suggest that it may be better value to the NHS and better for patients if we were to offer blood-thinning medications to everyone on admission to hospital, without using any risk score. However, this approach needs further research to ensure it is safe and effective. Such research would not be able to rely on routine electronic data to identify blood clots or bleeding events, in isolation. Scientific summary Background Venous thromboembolism (VTE) is a composite diagnosis including deep-vein thrombosis (DVT) and pulmonary embolism (PE). The condition is a global health burden, affecting over 1:1000 adults worldwide, every year. Previous epidemiological studies have shown more than half of all VTE events to be hospital-associated (or acquired) thrombosis (HAT), occurring during admission or within 90 days of discharge. Current evidence suggests that many HAT events are potentially preventable. Pharmacological prophylaxis in medical and surgical inpatients has been shown to be clinically effective in several large studies and meta-analyses. However, although prophylaxis reduces the risk of VTE for hospital inpatients, it also incurs costs and potentially increases the risk of bleeding. As such, international guidelines recommend a process of individualised VTE risk assessment at the point of hospital admission. Several risk assessment models (RAMs) have been developed to aid this process. The accuracy and cost-effectiveness of these models are uncertain. Further prospective studies in this area are challenging due to national guidance, contract standards and high rates of routine prescribing (> 70%). We sought to assess the clinical and cost-effectiveness of VTE RAMs through secondary research methods, by conducting a systematic review of RAM accuracy and subsequent decision-analytic modelling. In addition, we sought to evaluate the accuracy of routine data sources to identify core VTE and bleeding outcomes and estimate key clinical parameters for any future implementation study. Objectives The prespecified and combined project objectives were as follows: Update existing systematic reviews to identify VTE RAMs for hospital inpatients and determine their comparative accuracy for predicting the risk of VTE. Undertake decision-analytic modelling to determine the cost-effectiveness of pharmacological prophylaxis guided by a RAM, compared to prophylaxis for all and prophylaxis for none. Use the decision-analytic model to identify key areas of uncertainty and determine the value of gathering additional information to reduce uncertainty. Pilot the use and evaluate the accuracy of efficient methods to measure core clinical VTE and bleeding outcomes. Estimate key parameters for planning a future implementation study. Methods Workstream 1 used a systematic review and economic analysis to address objectives 1, 2 and 3. We extended and updated overlapping systematic reviews of available RAMs, performed quality assessment of relevant studies and synthesised performance measures (e.g. sensitivity, specificity and concordance (C) statistics) to evaluate the prognostic accuracy of individual RAMs. We subsequently used this information to inform decision-analytic modelling. The target population for the conceptual model was hospital inpatients, including medical, surgical and trauma patients but excluding critical care patients, children and women admitted to hospital for pregnancy-related reasons. Patients at increased risk of bleeding were assumed not to receive pharmacological prophylaxis under any strategy and were excluded from the model. We compared strategies of using no pharmacological prophylaxis, pharmacological prophylaxis for all and pharmacological prophylaxis given in accordance with validated RAMs. The use of mechanical prophylaxis was considered out of scope for the modelling. We used a lifetime horizon and reported primary outcomes of costs and quality-adjusted life-years (QALYs). Multiple scenario and sensitivity analyses were conducted by subgroup. Workstream two used primary research to address objectives four and five. We conducted a multicentre observational cohort study across four hospitals to compare prespecified methods of efficient data collection to formal case note review. We identified a target population hospitalised during 2019 and extracted data from prospectively completed VTE risk assessments, when available. Research assistants undertook further retrospective case note review for each patient episode. We used electronic health records to evaluate additional risk characteristics and record all relevant clinical outcomes, including the subsequent diagnosis of HAT, major bleeding and clinically relevant non-major bleeding events. We then collated multiple routine data sources for each patient episode to determine the accuracy of these methods in identifying relevant clinical outcomes, compared to a gold standard of case note review. The primary outcome measures for workstream two were contingency tables with sensitivity, specificity and predictive values. Feasibility criteria for any future study using efficient data methods were set a priori. We also estimated the potential variation in prescribing recommendations using multiple validated RAMs and estimated key parameters for any future implementation study. The Venous ThromboEmbolism Assessment Methods study received a favourable opinion from the Proportionate Review Sub-committee of the London – West London & Gene Therapy Advisory Committee (GTAC) Research Ethics Committee and approval from the Health Research Authority (HRA) and Care Research Wales (HCRW) on 18 September 2019 (reference 19/LO/1303, IRAS project ID 262220). Results Workstream 1 Our updated systematic review included 51 studies, comprising 24 unique validated RAMs. The vast majority of studies evaluated VTE RAMs in medical (n = 21), surgical (n = 15) or mixed (n = 4) cohorts of hospital inpatients. The most widely evaluated models were the Caprini RAM (22 studies), the Padua prediction score (16 studies), the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) models (8 studies), the Geneva Risk Score (4 studies) and the Kucher Score (4 studies). All studies had a high or unclear risk of bias, with the main issues related to patient selection, outcome and analysis factors. C-statistics varied markedly between these studies and between models, with no RAM performing obviously better than other models. Similarly, estimates for sensitivity and specificity were highly variable. In the decision analytic modelling, we estimate that in medical inpatients, prophylaxis reduces serious adverse outcomes [fatal PEs, fatal bleeding and non-fatal intracranial haemorrhage (ICH)] from 53 per 10,000 to 42 per 10,000, with a reduction in symptomatic DVTs and non-fatal PEs that is higher than the increase in other bleeds. In the long-term outcomes at 5 years, there is a large reduction in the number of patients experiencing post-thrombotic syndrome (PTS) following prophylaxis from 787 per 10,000 to 385 per 10,000, but minimal difference in overall survival. Modelling showed that thromboprophylaxis for all has a high probability (> 99%) of being the most cost-effective strategy (£20,000 per QALY threshold) based on the performance of existing RAMs in cohorts of medical inpatients. This finding was generally robust under the scenario and sensitivity analyses with one exception; targeting thromboprophylaxis using a Padua score ≥ 3 (84% of cohort) had a 76.6% probability of being the most cost-effective strategy when assuming higher RAM performance (sensitivity 99.9%; specificity 23.7%). The overall expected value of perfect information (EVPI) associated with all parameters included in the probabilistic sensitivity analysis (PSA) when valuing a QALY at £20,000 was £0.06 per patient per year due to the high probability that prophylaxis for all is the optimal strategy. However, the EVPI would be £2.42 per person per year if a more accurate RAM could be developed for medical inpatients. In surgical inpatients, the risk of a serious adverse outcome (as above) is low at 7 per 10,000 but it is increased slightly by prophylaxis to 11 per 10,000 due to the additional risk of fatal bleeding or non-fatal ICH. Although the risk of any symptomatic VTE is reduced form 140 per 10,000 to 41 per 10,000, the risk of any major bleeding is increased from 125 per 10,000 to 370 per 10,000. Prophylaxis still reduces the risk of PTS in surgical inpatients, from 367 per 10,000 to 107 per 10,000, but PTS is less common in the surgical cohort than in the medical cohort. Modelling showed that giving prophylaxis to all surgical inpatients has the highest probability of being cost-effective at £20,000 per QALY, with a 70% likelihood of being optimal, but there is also a 17% likelihood that using a Pannucci score of ≥ 3 would be optimal and a 9% likelihood that using a Pannucci score of ≥ 1 would be optimal. These findings were sensitive to some uncertainties explored in the scenario and sensitivity analyses. In particular, prophylaxis for all may no longer be the optimal strategy for surgical inpatients when the risk of PTS is lower, when using an extended duration of prophylaxis or where a RAM is assumed to have a very high sensitivity. The overall EVPI associated with all parameters included in the PSA when valuing a QALY at £20,000 was £16.35 per person. This does not include the uncertainty of considering which RAM to use as the EVPI and does not include any uncertainty not captured in the PSA, such as uncertainty around the model assumptions or the choice of data sources, or uncertainty around the estimates of sensitivity and specificity. In the analysis of parameter EVPI [expected value of partial perfect information (EVPPI)], the relative risk of VTE for patients having thromboprophylaxis compared to patients not having thromboprophylaxis was the parameter with the largest EVPPI. In specific surgical populations requiring longer durations of prophylaxis, we found that pharmacological prophylaxis for all eligible patients remained optimal in those having elective knee replacement. Offering prophylaxis at a Pannucci score of ≥ 3 (sensitivity of 84% and specificity of 49%) was optimal when prescribing 28 days of low-molecular-weight heparin (LMWH) to patients having elective hip replacement. These conclusions were sensitive to prophylaxis strategy; using direct oral anticoagulants (DOACs) rather than LMWH resulted in prophylaxis for all as the optimal strategy for both hip and knee patients. Workstream 2 The observational cohort study was conducted across all four sites, enrolling 2115 patient hospitalisation episodes, with 2008 eligible for analysis. Medical and surgical cases were evenly balanced, but with more emergency (73.7%) than elective (25.8%) admissions. The sensitivity of routine coding data for detection of HAT and major bleeding events was 62% [95% confidence interval (CI) 54 to 69] and 38% (95% CI 27 to 50), respectively. Local VTE data sets performed better, with sensitivity of 81% (95% CI 75 to 87). The specificity of routine coding data for VTE and bleeding was 98% (95% CI 97 to 99) and 95% (95% CI 94 to 96), respectively, and the specificity of local VTE data sets was 100% (95% CI 99 to 100). We were unable to demonstrate overall feasibility of using efficient outcome measures and did not meet several prespecified criteria. In a smaller subgroup of patients with prospectively collected data, we evaluated potential variation in pharmacological prophylaxis using different RAMs. We identified 543 hospital episodes with VTE risk assessment performed during 2019, with 254 episodes suitable for inclusion, data extraction and comparative analysis. Overall recommendations for pharmacological prophylaxis varied substantially between seven RAMs, ranging from 13% of admitted patients for the IMPROVE associative score (95% CI 9.4 to 17.7) to 91% (95% CI 86.3 to 93.6) for the Department of Health (now Department of Health and Social Care) VTE risk assessment tool. The latter tool resulted in an absolute increase of 28% for prophylaxis recommendation, compared to other RAMs. Within this multicentre cohort of hospitalised inpatients, the HAT event rate was 1.6% (95% CI 1.0 to 2.2) and the major bleeding event rate was 2.5% (95% CI 1.8 to 3.2). Conclusions We updated prior systematic reviews to conclude that that the available evidence has significant methodological limitations and demonstrates current RAMs to have weak predictive accuracy. Decision-analytic modelling showed that the balance of VTE or major bleeding risks, combined with the RAM performance in medical cohorts, means that thromboprophylaxis for all is the optimal strategy within our model for medical inpatients. These findings were robust to multiple scenarios and sensitivity analyses. The optimal strategy for surgical inpatients is to offer thromboprophylaxis to all. However, the scenario analyses for surgical inpatients found that the optimal strategy was sensitive to many of the individual model inputs and assumptions tested. In addition, the optimal strategy for surgical patients receiving extended duration thromboprophylaxis appeared dependent on duration of therapy and prophylaxis strategy. The findings from our cohort study suggest that efficient methods for identifying VTE or major bleeding events during hospital admission or within 90 days of discharge, are not sufficiently sensitive for use in a large data-enabled study. We did not reach several predefined feasibility metrics. We also found limitations in the ability of efficient methods to identify individual risk variables and facilitate RAM comparison in future work. The majority of our sites did not collect contemporaneous data on risk assessment in a digital, or easily accessible format. Implications for policy-makers If, despite drug costs and potential harms, pharmacological prophylaxis for all is the most cost-effective strategy, use of unvalidated RAMs may be suboptimal. Based on our findings, it may be preferable for policy-makers to consider evaluating a new paradigm of ‘opt-out’ VTE prevention, in which all eligible patients are routinely offered pharmacological prophylaxis on hospital admission without complex risk assessment. In this circumstance, patients who are ineligible for pharmacological prophylaxis due to high bleeding risk, specific contraindications or personal choice could opt out, but still utilise evidence-based mechanical thromboprophylaxis strategies. The findings from our cohort study have implications for funders looking to support further work in this area. These data suggest large studies entirely reliant on routine data collection methods for complex time-dependent outcome measures (such as HAT or major bleeding) are likely to be inaccurate. Recommendations for future research Further research should evaluate the following themes in this area of clinical care: Evaluation of routine pharmacological prophylaxis for all eligible medical and surgical patients on hospital admission, compared to current practice of risk assessment using a RAM. Such work would need to be conducted at scale and could not rely on efficient methods for outcome measurement in isolation. Development and validation of RAMs to identify individuals receiving prophylaxis at very low risk of blood clots, who could therefore potentially discontinue pharmacological prophylaxis early during hospital stay. Our analysis was inevitably limited in scope and did not examine the use of RAMs to identify accurate prediction of bleeding risk, the use of mechanical prophylaxis in medical patients with increased bleeding risk (or contraindications to pharmacological prophylaxis) or patients at risk of thromboprophylaxis failure. These issues could be priorities for future research. Study registration This study is registered as Research Registry 5216, PROSPERO CRD42020165778. Funding This award was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127454) and is published in full in Health Technology Assessment; Vol. 28, No. 20. See the NIHR Funding and Awards website for further award information.

Background Guidelines for sepsis recommend treating those at highest risk within 1 hour. The emergency care system can only achieve this if sepsis is recognised and prioritised. Ambulance services can use prehospital early warning scores alongside paramedic diagnostic impression to prioritise patients for treatment or early assessment in the emergency department. Objectives To determine the accuracy, impact and cost-effectiveness of using early warning scores alongside paramedic diagnostic impression to identify sepsis requiring urgent treatment. Design Retrospective diagnostic cohort study and decision-analytic modelling of operational consequences and cost-effectiveness. Setting Two ambulance services and four acute hospitals in England. Participants Adults transported to hospital by emergency ambulance, excluding episodes with injury, mental health problems, cardiac arrest, direct transfer to specialist services, or no vital signs recorded. Interventions Twenty-one early warning scores used alongside paramedic diagnostic impression, categorised as sepsis, infection, non-specific presentation, or other specific presentation. Main outcome measures Proportion of cases prioritised at the four hospitals; diagnostic accuracy for the sepsis-3 definition of sepsis and receiving urgent treatment (primary reference standard); daily number of cases with and without sepsis prioritised at a large and a small hospital; the minimum treatment effect associated with prioritisation at which each strategy would be cost-effective, compared to no prioritisation, assuming willingness to pay £20,000 per quality-adjusted life-year gained. Results Data from 95,022 episodes involving 71,204 patients across four hospitals showed that most early warning scores operating at their pre-specified thresholds would prioritise more than 10% of cases when applied to non-specific attendances or all attendances. Data from 12,870 episodes at one hospital identified 348 (2.7%) with the primary reference standard. The National Early Warning Score, version 2 (NEWS2), had the highest area under the receiver operating characteristic curve when applied only to patients with a paramedic diagnostic impression of sepsis or infection (0.756, 95% confidence interval 0.729 to 0.783) or sepsis alone (0.655, 95% confidence interval 0.63 to 0.68). None of the strategies provided high sensitivity (> 0.8) with acceptable positive predictive value (> 0.15). NEWS2 provided combinations of sensitivity and specificity that were similar or superior to all other early warning scores. Applying NEWS2 to paramedic diagnostic impression of sepsis or infection with thresholds of > 4, > 6 and > 8 respectively provided sensitivities and positive predictive values (95% confidence interval) of 0.522 (0.469 to 0.574) and 0.216 (0.189 to 0.245), 0.447 (0.395 to 0.499) and 0.274 (0.239 to 0.313), and 0.314 (0.268 to 0.365) and 0.333 (confidence interval 0.284 to 0.386). The mortality relative risk reduction from prioritisation at which each strategy would be cost-effective exceeded 0.975 for all strategies analysed. Limitations We estimated accuracy using a sample of older patients at one hospital. Reliable evidence was not available to estimate the effectiveness of prioritisation in the decision-analytic modelling. Conclusions No strategy is ideal but using NEWS2, in patients with a paramedic diagnostic impression of infection or sepsis could identify one-third to half of sepsis cases without prioritising unmanageable numbers. No other score provided clearly superior accuracy to NEWS2. Research is needed to develop better definition, diagnosis and treatments for sepsis. Study registration This study is registered as Research Registry (reference: researchregistry5268). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/136/10) and is published in full in Health Technology Assessment; Vol. 28, No. 16. See the NIHR Funding and Awards website for further award information. Plain language summary Sepsis is a life-threatening condition in which an abnormal response to infection causes heart, lung or kidney failure. People with sepsis need urgent treatment. They need to be prioritised at the emergency department rather than waiting in the queue. Paramedics attempt to identify people with possible sepsis using an early warning score (based on simple measurements, such as blood pressure and heart rate) alongside their impression of the patient’s diagnosis. They can then alert the hospital to assess the patient quickly. However, an inaccurate early warning score might miss cases of sepsis or unnecessarily prioritise people without sepsis. We aimed to measure how accurately early warning scores identified people with sepsis when used alongside paramedic diagnostic impression. We collected data from 71,204 people that two ambulance services transported to four different hospitals in 2019. We recorded paramedic diagnostic impressions and calculated early warning scores for each patient. At one hospital, we linked ambulance records to hospital records and identified who had sepsis. We then calculated the accuracy of using the scores alongside diagnostic impression to diagnose sepsis. Finally, we used modelling to predict how many patients (with and without sepsis) paramedics would prioritise using different strategies based on early warning scores and diagnostic impression. We found that none of the currently available early warning scores were ideal. When they were applied to all patients, they prioritised too many people. When they were only applied to patients whom the paramedics thought had infection, they missed many cases of sepsis. The NEWS2, score, which ambulance services already use, was as good as or better than all the other scores we studied. We found that using the NEWS2, score in people with a paramedic impression of infection could achieve a reasonable balance between prioritising too many patients and avoiding missing patients with sepsis. Scientific summary Background Sepsis is a life-threatening reaction to an infection in which the immune system overreacts to infection and causes organ damage. Early recognition and treatment of sepsis has the potential to reduce mortality. Guidelines for sepsis highlight the importance of early recognition and treatment, with treatment recommended within 1 hour of presentation for those at highest risk. The emergency care system can only achieve this if sepsis is recognised and prioritised. Ambulance services can use prehospital early warning scores to identify people with a high risk of sepsis and then pre-alert the emergency department (ED) or provide the patient with prehospital treatment. However, they need to determine which score to use, the threshold of positivity for the score, and whether to apply the early warning score to all medical cases or just those where the paramedic diagnostic impression suggests sepsis, infection or a non-specific presentation. This requires estimates of the diagnostic accuracy of early warning scores and consideration of the balance between sensitivity (avoiding missing sepsis) and specificity (prioritising too many patients who do not have sepsis). Objectives We aimed to determine the accuracy, impact and cost-effectiveness of prehospital early warning scores for adults with suspected sepsis. Our specific objectives were: to estimate the accuracy of prehospital early warning scores for identifying sepsis requiring time-critical treatment in adults with possible sepsis who are attended by emergency ambulance to estimate the impact of using prehospital early warning scores to guide key prehospital decisions, in terms of the operational consequences, and the cost-effectiveness of alternative strategies. Methods We undertook (1) a retrospective cohort study to estimate the accuracy of prehospital early warning scores alongside paramedic diagnostic impression and (2) decision-analytic modelling of the operational consequences and cost-effectiveness of using prioritisation strategies based on early warning score and diagnostic impression. Retrospective cohort study We used a literature review and expert opinion to identify 21 early warning scores for evaluation. We used routine ambulance service data to identify all episodes in 2019 in which two ambulance services (Yorkshire and West Midlands) transported patients with medical presentations to four acute hospitals (Sheffield Northern General Hospital, Doncaster Royal Infirmary, Rotherham General Hospital, University Hospitals Coventry and Warwickshire). We excluded episodes with injury, mental health problems, cardiac arrest or direct transfer to specialist services, and cases with no vital signs recorded. We calculated early warning scores from the first recorded vital signs on the ambulance service electronic patient-report form and categorised the paramedic diagnostic impression as sepsis, infection, non-specific presentation or other specific presentation. We then determined the number of cases that ambulance services would prioritise at each hospital using each early warning score alongside the categorised paramedic diagnostic impression. We planned to use the National Health Service (NHS) Digital Data Access Request Service to link ambulance service to hospital data but NHS Digital were unable to provide this service. We therefore instituted a rescue plan to link ambulance service to hospital data at one participating hospital (Sheffield) to determine whether patients had a reference standard diagnosis of sepsis, adjudicated by two independent clinicians following hospital record review. The primary reference standard consisted of meeting the sepsis-3 definition [evidence of infection with a change of two or more points in the Sequential (sepsis-related) Organ Failure Assessment (SOFA) score] and receiving treatment for sepsis. The secondary reference standard consisted of meeting the sepsis-3 definition alone. We analysed the ambulance service data descriptively to report the mean daily number of cases that the ambulance service would pre-alert to each hospital for each combination of early warning score and diagnostic impression. For the accuracy analysis, we constructed receiver operating characteristic (ROC) curves to evaluate sensitivity and specificity over the range of each score. We calculated the area under the ROC curve, sensitivities, specificities, and positive and negative predictive values at key cut-points, each with a 95% confidence interval (CI). Reporting of the results highlights sensitivity and positive predictive value as these best indicate under-triage (sensitivity, the proportion of sepsis cases prioritised) and overtriage (positive predictive value, the proportion of prioritised cases with sepsis). To select strategies for the decision-analytic modelling, we calculated the proportion of mean daily ambulance arrivals that would be prioritised at each hospital and excluded strategies that would prioritise a potentially unmanageable proportion (> 10%). We then compared the accuracy of strategies and excluded those with sensitivity and specificity both inferior to another strategy. We also excluded strategies that were not clearly superior to a comparable strategy involving the National Early Warning Score, version 2 (NEWS2) on the basis that NEWS2 is already widely used by NHS ambulance services, whereas other strategies would require additional training and support to implement. Decision-analytic modelling We developed a decision-analytic model to evaluate the consequences to healthcare providers and the cost-effectives for the health services of using 23 different strategies to prioritise patients transported to hospital with possible sepsis. Due to the paucity of data associated with the benefit of early treatment for sepsis and conflicting results from studies where data existed, threshold analyses were independently undertaken to estimate the reduction in mortality, the reduction in general ward length of stay (LoS) and the reduction in intensive care unit LoS that would be required by each strategy in order to be cost-effective compared with a strategy of no prioritisation of patients. We additionally present the number of prehospital alerts associated with each strategy, the number of patients with sepsis who have been correctly prioritised and the number of patients with sepsis who are not prioritised. Results Retrospective cohort study We collected data from 95,022 ambulance episodes involving 71,204 patients with median age 66 years, and included 37,588 (53.0%) women, and 40,045 (94.9%) with white ethnicity. The mean (standard deviation) number of daily attendances meeting the study inclusion criteria was 93.5 (14.7) at Sheffield Northern General Hospital, 59.5 (10.8) at Doncaster Royal Infirmary, 51.3 (8.9) at Rotherham General Hospital and 74 (11) at University Hospitals Coventry and Warwickshire. Most early warning scores operating at their pre-specified thresholds would prioritise fewer than 10% of attendances when applied only to those with a diagnostic impression of sepsis or infection, but would prioritise more than 10% when applied to non-specific attendances or all attendances. The exceptions were qSOFA (threshold > 1), the Screening to Enhance PrehoSpital Identification of Sepsis (SEPSIS) score, the Critical Illness Score (CIS; threshold > 4), the Paramedic Initiated Treatment of Sepsis Targeting Out-of-hospital Patients clinical trial rule, the PRESS score and the sepsis alert criteria. Yorkshire Ambulance Service recorded only one diagnostic impression, whereas West Midlands Ambulance Service recorded multiple unranked impressions, so strategies prioritised a greater proportion of patients transported to University Hospitals Coventry and Warwickshire. Consequently, in the West Midlands most strategies prioritised more than 10% of cases when applied to those with a diagnostic impression of infection or sepsis. We linked 12,870 out of 24,955 (51.6%) cases to the Sheffield Northern General Hospital records at Sheffield and identified 348 (2.7%) with the primary reference standard. The sensitivity and positive predictive value of paramedic diagnostic impression were 0.328 (95% CI 0.28 to 0.379) and 0.285 (95% CI 0.243 to 0.331) for sepsis, 0.572 (95% CI 0.519 to 0.623) and 0.156 (95% CI 0.137 to 0.176) for infection or sepsis, and 0.897 (95% CI 0.86 to 0.924) and 0.053 (95% CI 0.048 to 0.059) for non-specific presentation, infection or sepsis. The early warning scores had a greater area under the ROC curve when applied to all cases rather than alongside diagnostic impression, but the low prevalence of the reference standard meant that thresholds with sensitivity above 0.7 generally had positive predictive value below 0.15, which would prioritise an unmanageable number of cases. When higher thresholds were used to provide acceptable positive predictive value and a manageable number of cases, strategies that applied the early warning score only to those with a diagnostic impression of sepsis or infection tended to have better overall accuracy. NEWS2 had the highest area under the ROC curve when applied only to those with a paramedic diagnostic impression of sepsis or infection (0.756, 95% CI 0.729 to 0.783) or sepsis alone (0.655, 95% CI 0.63 to 0.68). Only the SEPSIS score had a higher area under the ROC curve than NEWS2 when applied to non-specific presentation, infection or sepsis (0.862 vs. 0.858) and all cases (0.882 vs. 0.877). None of the strategies provided high sensitivity (e.g. > 0.8) with acceptable positive predictive value (e.g. > 0.15). NEWS2, using varying thresholds and combinations with diagnostic impression, provided combinations of sensitivity and specificity that were similar or superior to all other early warning scores. We identified strategies reflecting published recommendations for prioritisation that could offer options with varying trade-offs between sensitivity and positive predictive value. Applying NEWS2 only to those with a paramedic diagnostic impression of sepsis or infection respectively provided sensitivities and positive predictive values of 0.522 (95% CI 0.469 to 0.574) and 0.216 (95% CI 0.189 to 0.245) with a threshold > 4, 0.447 (95% CI 0.395 to 0.499) and 0.274 (95% CI 0.239 to 0.313) with a threshold > 6, and 0.314 (95% CI 0.268 to 0.365) and 0.333 (95% CI 0.284 to 0.386) with a threshold > 8. Applying qSOFA > 1 only to those with a paramedic diagnostic impression of sepsis or infection provided sensitivity of 0.305 (95% CI 0.259 to 0.355) and positive predictive value of 0.356 (95% CI 0.304 to 0.412). Decision-analytic modelling The modelling provided estimates for a range of strategies with varying sensitivity and specificity of the number of cases (overall and with sepsis) that would be prioritised in a large and a small hospital. At a large hospital receiving 93.5 eligible cases per day, applying NEWS2 > 4 only to those with a diagnostic impression of infection or sepsis would prioritise 6.10 cases per day, including 1.32 with sepsis, while failing to prioritise 1.21 with sepsis. The corresponding numbers using NEWS2 > 6 were 4.11, 1.13 and 1.40, using NEWS2 > 8 were 2.38, 0.79 and 1.73, and using qSOFA > 1 were 2.17, 0.77 and 1.76. At a small hospital receiving 53.1 eligible cases per day, applying NEWS2 > 4 only to those with a diagnostic impression of infection or sepsis would prioritise 3.35 cases per day, including 0.72 with sepsis, while failing to prioritise 0.66 with sepsis. The corresponding numbers using NEWS2 > 6 were 2.26, 0.62 and 0.77, using NEWS2 > 8 were 1.31, 0.44 and 0.95, and using qSOFA > 1 were 1.19, 0.42 and 0.96. The threshold analysis showed that the relative risk of mortality associated with prioritisation at which each strategy would be cost-effective compared to no prioritisation [assuming willingness to pay £20,000 per quality-adjusted life-year (QALY) gained] ranged from 0.977 applying NEWS2 > 0 only to those with a diagnostic impression of infection or sepsis, to 0.996 applying NEWS2 > 11 only to those with a diagnostic impression of sepsis. The comparable ranges for other measures of effectiveness for these two strategies were: increase in QALYs 0.00056–0.00002; reduction in length of ward stay 3.8–0.7 days; reduction in intensive care LoS 1.2–0.2 days. Conclusions We were unable to identify a strategy that would prioritise a substantial majority of patients with sepsis without prioritising a potentially unmanageable number of patients for the ED. Most early warning scores, used at a recommended threshold, are likely to prioritise an unmanageable number of cases unless they are only used to prioritise cases with a paramedic diagnostic impression of infection or sepsis. However, paramedic diagnostic impression of infection or sepsis only identified 57% of cases with a reference standard diagnosis of sepsis requiring urgent treatment. The NEWS2 provides sensitivity and specificity for identifying sepsis that is generally similar or superior to other scores operating at a comparable threshold. We therefore found no evidence to justify the support and training required to implement an alternative strategy to NEWS2, which is already widely used in NHS ambulance services. National Early Warning Score, version 2, could be used at thresholds of > 4 or > 6 in presentations with a diagnostic impression of infection or sepsis, reflecting the Academy of Medical Royal Colleges clinical decision support framework, or > 8 to provide similar sensitivity and specificity to the use of qSOFA > 1 recommended in the sepsis-3 guidelines. These strategies provide a range of options that ambulance services and hospitals could use, depending upon capacity to manage prioritised cases and what prioritisation involves. Health economic modelling suggests that sensitive strategies for identifying patients with possible sepsis for prioritisation could be cost-effective, if we are convinced that reducing treatment delay reduces mortality and the emergency care system has the capacity to deliver meaningful prioritisation to substantial numbers of cases. Limitations Inability of NHS Digital to link ambulance service to hospital data meant that we were only able to estimate the accuracy of early warning scores at one hospital using data from 51.6% of the eligible population for whom the ambulance service had NHS numbers. The included patients were markedly older than the excluded patients. We were unable to identify reliable evidence to estimate the effectiveness of early treatment for sepsis, so were unable to identify the most cost-effective strategy. Future research Research into prehospital early warning scores for sepsis is limited by our current inability to clinically measure the dysregulated host response that characterises sepsis and uncertain estimates of the benefits of early treatment. We therefore need to prioritise research to develop better ways of defining and diagnosing sepsis, and to develop and evaluate effective early treatment for sepsis. Future research involving routine ambulance service and hospital data requires a system for NHS data management that supports health data science. Study registration This study is registered as Research Registry (reference: researchregistry5268). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/136/10) and is published in full in Health Technology Assessment; Vol. 28, No. 16. See the NIHR Funding and Awards website for further award information.

Background Pharmacological prophylaxis to prevent venous thromboembolism is currently recommended for women assessed as being at high risk of venous thromboembolism during pregnancy or in the 6 weeks after delivery (the puerperium). The decision to provide thromboprophylaxis involves weighing the benefits, harms and costs, which vary according to the individual’s venous thromboembolism risk. It is unclear whether the United Kingdom’s current risk stratification approach could be improved by further research. Objectives To quantify the current decision uncertainty associated with selecting women who are pregnant or in the puerperium for thromboprophylaxis and to estimate the value of one or more potential future studies that would reduce that uncertainty, while being feasible and acceptable to patients and clinicians. Methods A decision-analytic model was developed which was informed by a systematic review of risk assessment models to predict venous thromboembolism in women who are pregnant or in the puerperium. Expected value of perfect information analysis was used to determine which factors are associated with high decision uncertainty and should be the target of future research. To find out whether future studies would be acceptable and feasible, we held workshops with women who have experienced a blood clot or have been offered blood-thinning drugs and surveyed healthcare professionals. Expected value of sample information analysis was used to estimate the value of potential future research studies. Results The systematic review included 17 studies, comprising 19 unique externally validated risk assessment models and 1 internally validated model. Estimates of sensitivity and specificity were highly variable ranging from 0% to 100% and 5% to 100%, respectively. Most studies had unclear or high risk of bias and applicability concerns. The decision analysis found that there is substantial decision uncertainty regarding the use of risk assessment models to select high-risk women for antepartum prophylaxis and obese postpartum women for postpartum prophylaxis. The main source of decision uncertainty was uncertainty around the effectiveness of thromboprophylaxis for preventing venous thromboembolism in women who are pregnant or in the puerperium. We found that a randomised controlled trial of thromboprophylaxis in obese postpartum women is likely to have substantial value and is more likely to be acceptable and feasible than a trial recruiting women who have had a previous venous thromboembolism. In unselected postpartum women and women following caesarean section, the poor performance of risk assessment models meant that offering prophylaxis based on these models had less favourable cost effectiveness with lower decision uncertainty. Limitations The performance of the risk assessment model for obese postpartum women has not been externally validated. Conclusions Future research should focus on estimating the efficacy of pharmacological thromboprophylaxis in pregnancy and the puerperium, and clinical trials would be more acceptable in women who have not had a previous venous thromboembolism. Study registration This study is registered as PROSPERO CRD42020221094. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR131021) and is published in full in Health Technology Assessment; Vol. 28, No. 9. See the NIHR Funding and Awards website for further award information. Plain language summary Women who are pregnant or who have given birth in the previous 6 weeks are at increased risk of developing blood clots that can cause serious illness or death. Small doses of blood thinners given by injection are safe in pregnancy and can reduce the risk of blood clots, but they can slightly increase the risk of bleeding. Healthcare professionals use risk assessment tools to decide if a woman is at high risk of blood clots and should be offered blood thinners. We wanted to find out what research would be useful to help them make better decisions. We reviewed previous research to establish which risk assessment tools are best at predicting who will have a blood clot. We then created a mathematical model to predict what would happen when using different risk assessment tools to decide who should be offered blood thinners, both during pregnancy and after giving birth. We found that there was a lot of uncertainty about which women should be offered blood thinners. This was mainly because there have only been a few small studies comparing blood thinners to no treatment in pregnant women or women who have recently given birth. We estimated the value of future studies comparing blood thinners to no treatment, in groups of women with different risk factors, by predicting what information we would gain and how this would be used to improve decisions about using blood thinners. To find out whether these studies would be acceptable and feasible, we held workshops with women who have experienced a blood clot or have been offered blood thinners and surveyed healthcare professionals. We found that a study in obese women who have recently given birth would have substantial value and may be more acceptable than a study in pregnant women with a previous blood clot. Scientific summary Background Pharmacological prophylaxis to prevent venous thromboembolism (VTE) is currently recommended for women who are deemed to be at high risk of VTE during pregnancy or in the 6 weeks after delivery (the puerperium). The decision to provide prophylaxis involves weighing the benefits, harms and costs, which will vary according to the individual’s VTE risk. It is unclear whether the current risk stratification approach could be improved by further research. Aims and objectives The aim of this research was to determine whether further primary research is worthwhile to inform NHS practice on the use of risk assessment models (RAMs) for the prediction of VTE and appropriate provision of thromboprophylaxis for women in pregnancy and in the puerperium. The specific objectives were: to estimate the expected costs and health benefits of providing thromboprophylaxis using current and alternative RAMs and quantify decision uncertainty to determine which factors are the most important drivers of uncertainty when trying to determine the optimal risk-based thromboprophylaxis strategy to identify one or more potential future studies that would reduce the current decision uncertainty, while being feasible and acceptable to patients and clinicians to evaluate the value of future research studies in terms of the net health benefits to patients and the cost of the research. Methods To identify all relevant RAMs and their predictive performance, we undertook a systematic review in accordance with the preferred reporting items for systematic review and meta-analysis (PRISMA) statement. Systematic searches were performed across five electronic databases, including MEDLINE, EMBASE and the Cochrane Library, from inception to February 2021. We included all primary validation studies that examined the comparative accuracy of a multivariable RAM (or scoring system) for predicting the risk of developing VTE in women who are pregnant or in the puerperium. Two or more reviewers independently undertook study selection, data extraction and risk of bias assessments using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). We used narrative synthesis to summarise the findings. A decision-analytic model was used to estimate lifetime expected costs and quality-adjusted life-years (QALYs) under alternative thromboprophylaxis strategies. The decision-analytic modelling focused on the following subgroups for which data were available on the performance of RAMs: high-risk antepartum women (e.g. prior VTE or known thrombophilia) unselected postpartum women obese postpartum women postpartum women following caesarean section. In the analysis for high-risk antepartum women, the strategies compared were: antepartum and postpartum prophylaxis for all (from booking to 6 weeks postpartum) antepartum prophylaxis according to a RAM followed by 6 weeks postpartum prophylaxis for all six weeks postpartum prophylaxis for all no prophylaxis. In the analyses for postpartum women, the strategies compared were: postpartum prophylaxis for all (10 days) postpartum prophylaxis according to a RAM (10 days) no prophylaxis. In all cases, the thromboprophylaxis agent was assumed to be low-molecular-weight heparin (LMWH). In high-risk antepartum women, the RAMs compared were the Lyon RAM and the Efficacy of Thromboprophylaxis as an Intervention during Gravidity (EThIG) RAM. For the unselected postpartum population, the RAMs compared were Royal College of Obstetricians and Gynaecologists (RCOG), Swedish Society of Obstetrics and Gynecology (SFOG), Caprini and the novel Sultan RAM. In the subgroup of obese postpartum women, the only RAM included was the novel Ellis-Kahana RAM. In the subgroup of postpartum women following caesarean section, the RAMs compared were RCOG and the novel Binstock RAM. We also conducted an analysis assuming that a RAM was available for the post-caesarean section population with performance similar to the Sultan RAM in the unselected postpartum population. The model takes a United Kingdom (UK) NHS and Personal Social Services perspective with future costs and QALYs discounted at 3.5% per annum. Costs are reported in Great British pounds based on 2020 prices. Short-term outcomes are captured in a decision-tree phase and long-term outcomes in a lifetime state-transition model. The decision tree is used to estimate for each strategy: the number of women receiving thromboprophylaxis; the impact of thromboprophylaxis on VTE outcomes (fatal and non-fatal pulmonary embolisms and deep-vein thromboses); and the incidence of major bleeds during either thromboprophylaxis or VTE treatment with anticoagulants and wound haematoma. Major bleeds are separated into fatal bleeds, non-fatal intracerebral haemorrhages (ICH) and other major bleeds. Symptomatic VTEs are assumed to result in 3 months of anticoagulant treatment which should be continued until at least 6 weeks post delivery. Outcomes captured in the long-term model include post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension. These are in addition to the long-term model capturing the QALY losses from fatalities and ongoing morbidity from ICH. For women being assessed for postpartum prophylaxis, a single decision tree captures the short-term outcomes. For women being assessed for antepartum prophylaxis, the decision-tree phase of the model is repeated to capture the antepartum and postpartum periods separately. Those patients who have experienced a symptomatic VTE or a non-fatal ICH in the antepartum model are assumed to remain in the same health state in the postpartum phase; all other patients remain at risk of VTE and progress to the postpartum decision tree. All model parameters were based on published literature or clinical opinion where published evidence was lacking. Sources specific to the target population were identified for the following parameters: data related to population characteristics [age, body mass index (BMI) and life expectancy]; absolute risks of VTE, bleeding and PTS; costs of prophylaxis and VTE treatment. There is a paucity of data on the efficacy of thromboprophylaxis during pregnancy and in the puerperium. Based on the clinical expert’s understanding of the mechanism of action of prophylaxis, their personal experience and the prothrombotic physiologic changes during pregnancy, it was decided that the relative risk (RR) for VTE should be based on a single small pilot trial in antepartum women with prior VTE, while the RR for bleeding should be extrapolated from studies in medical inpatients. Other data were generally based on sources used in a published cost-effectiveness analysis of thromboprophylaxis in hospitalised patients (who are not pregnant or in the puerperium), with costs updated to reflect changes in prices. Parameter uncertainty was incorporated using probabilistic sensitivity analysis and structural uncertainty was explored using deterministic scenario analysis. Expected value of perfect information (EVPI) analysis was used to identify the key drivers of decision uncertainty that could be reduced by future studies. We held workshops with women with a prior VTE or who had been offered thromboprophylaxis during pregnancy, and undertook a survey of healthcare professionals, to understand whether potential future trials would be acceptable to the individuals who would be invited to take part. Expected value of sample information (EVSI) analysis was then used to estimate the value of these potential future research studies. Results Our systematic review of RAMs included 17 studies, comprising 19 unique externally validated RAMs and 1 internally validated model (Ellis-Kahana). Estimates of sensitivity were highly variable ranging from 0% to 100% for RAMs that were applied to antepartum women and 0% to 100% for RAMs applied to postpartum women. Specificity estimates were similarly diverse ranging from 28% to 98% and 5% to 100%, respectively. Most studies had unclear or high risk of bias and applicability concerns, mainly due to limitations in participant selection and statistical analysis. In the decision analysis for high-risk antepartum women, using the EThIG RAM to select patients for antepartum prophylaxis had a 42% probability of having an incremental cost-effectiveness ratio (ICER) under £30,000 per QALY compared to a strategy of offering only postpartum prophylaxis. This led to considerable decision uncertainty, with an overall EVPI of £1454 per patient for high-risk antepartum women, equivalent to £21.8 million over 5 years of births. A high proportion of this (94%) was related to uncertainty in the effectiveness of LWMH to reduce VTE risk compared to no prophylaxis. The EVSI analysis found that a randomised controlled trial (RCT) of 30 patients per arm comparing LMWH with no prophylaxis would have a value of £13.1 million over 5 years of births, rising to £19.7 million for a RCT of 500 patients per arm. Small trials such as these would have substantial value compared to the typical cost of trials in these populations (£1.1–2.0 million), assuming decision-makers are willing to use the estimates of efficacy obtained, to make better informed decisions about prophylaxis in this population, without requiring them to meet a formal hypothesis test. In the decision analysis for unselected postpartum women, the poor performance of the available RAMs (including RCOG, SFOG and Sultan), combined with the relatively low absolute risk of VTE, meant that a strategy of offering no prophylaxis had an 89% probability of being optimal, when valuing a QALY at £30,000. This was reflected in an EVPI of £0.68 per person; £2.0 million over 5 years of births. No EVSI was conducted for this population due to the low EVPI estimates. In the decision analysis for obese postpartum women, there was substantial decision uncertainty, with the Ellis-Kahana RAM having a 64% probability of being the optimal strategy when valuing a QALY at £30,000, despite the fact that on average it had lower QALYs and higher costs than a strategy of offering no prophylaxis. The overall EVPI was £22.35 per patient, or £13.4 million across 5 years of births, with a high proportion (99%) being related to the RR of VTE. The EVSI analysis found that a RCT of LMWH versus no prophylaxis in obese postpartum women would have a value of £2.8 million, over 5 years of births, if it enrolled 300 patients per arm, rising to £11.6 million if enrolling 10,000 patients per arm. In the decision analysis for postpartum women following caesarean section, neither of the RAMs that had been specifically validated in women following caesarean section (RCOG and Binstock) performed sufficiently well to have an ICER under £30,000 per QALY compared to a strategy of offering no prophylaxis. Offering no prophylaxis had the highest probability of being the optimal strategy (when valuing a QALY at £30,000) even when assuming that a RAM could be identified for the post-caesarean section group which performed similarly to the Sultan RAM in the unselected cohort. In this scenario, the EVPI was £7.74 per patient, equivalent to £5.6 million over 5 years of births and 68% of the overall EVPI was related to the RR of VTE. In the post-caesarean section group, a RCT of 5000 patients per arm would be needed to generate an EVSI of £2.2 million over 5 years of births, when assuming that a RAM is available which performs similarly to the Sultan RAM. The only RAM validated in an unselected antepartum population had poor performance; therefore, analysis in this group was limited to an exploratory analysis which suggested that for a RAM to be cost-effective for use in an unselected antepartum population, it would need to have high specificity (90–95% for a sensitivity of 100–53%). Exploratory analyses were also conducted for women with three antepartum risk factors. This found that offering antepartum prophylaxis from 28 weeks to women with three antepartum risk factors (excluding prior VTE) as per current RCOG guidance is unlikely to have an ICER under £30,000 per QALY. However, a formal analysis of EVPI could not be conducted as the absolute risk in this group is not well quantified. The workshops indicated that a study randomising women to LMWH or placebo would be less acceptable to women who have had a prior VTE or thrombophilia than for other groups of women. Surveyed healthcare professionals reported lower clinical equipoise for women with prior VTE, thrombophilia or BMI > 40 kg/m2. The survey also suggests that healthcare professionals have greater clinical equipoise for a study determining the effectiveness of thromboprophylaxis in antepartum women with three clinical risk factors (other than prior VTE or thrombophilia) who are currently eligible for prophylaxis from 28 weeks. The survey results also suggest that in postpartum women there is greater clinical equipoise in women whose risk factors are an elective caesarean section combined with either age over 35 years or obesity, and women whose only clinical risk factors are age and a BMI between 30 and 40 kg/m2. Workshop participants reported receiving limited information about VTE or risks and benefits of thromboprophylaxis during pregnancy and the puerperium and those without prior VTE often did not understand why they had received treatment. However, women with experience of a prior VTE felt that it would not be ethical to randomise women to placebo given the perceived risk of VTE and the perceived effectiveness of LMWH in this group. Although the workshop participants generally favoured cluster randomisation over individual randomisation, clinicians felt individual randomisation was more acceptable. Conclusions The benefits of thromboprophylaxis clearly outweigh the risks in those with the highest risk of VTE, such as women with a prior VTE, but the balance of benefits and harms is less clear in lower-risk groups. There is substantial decision uncertainty regarding the use of RAMs to select high-risk women for antepartum prophylaxis and obese postpartum women for postpartum prophylaxis. The main source of decision uncertainty was related to the RR reduction of thromboprophylaxis for preventing VTE due to a lack of RCTs in pregnancy and the puerperium. This uncertainty is reflected in the widely variant strategies and guidelines for use of thromboprophylaxis in obstetric populations in different countries, notably the USA and UK. The expected benefits of conducting further trials to reduce this uncertainty are highly relative to typical research costs, but in the UK, clinical trials are more likely to be acceptable and feasible in the group of women who have not had a previous VTE. In unselected postpartum women and women following caesarean section, the poor performance of available RAMs (including RCOG) meant that RAM-based prophylaxis strategies had less favourable cost-effectiveness with lower decision uncertainty. Recommendations for future research Future research should focus on estimating the efficacy of thromboprophylaxis in preventing VTE in pregnancy and the puerperium. Clinical trials comparing LMWH with no prophylaxis would be more acceptable to both healthcare professionals and the public, in women who have not had a previous VTE, but who have other risk factors, such as obesity. Study registration This study is registered as PROSPERO CRD42020221094. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR131021) and is published in full in Health Technology Assessment; Vol. 28, No. 9. See the NIHR Funding and Awards website for further award information.

ObjectivesTo evaluate the diagnostic accuracy of the aortic dissection detection risk score (ADD-RS) used alone or in combination with D-dimer for detecting acute aortic syndrome (AAS) in patients presenting with symptoms suggestive of AAS.MethodsWe searched MEDLINE, EMBASE, and the Cochrane Library from inception to February 2024. Additionally, the reference lists of included studies and other systematic reviews were thoroughly searched. All diagnostic accuracy studies that assessed the use of ADD-RS alone or with D-Dimer for diagnosing AAS compared with a reference standard test (e.g. computer tomographic angiography (CTA), ECG-gated CTA, echocardiography, magnetic resonance angiography, operation, or autopsy) were included. Two reviewers independently selected and extracted data. Risk of bias was appraised using QUADAS-2 tool. Data were synthesised using hierarchical meta-analysis models.ResultsWe selected 13 studies from the 2017 citations identified, including six studies evaluating combinations of ADD-RS alongside D-dimer>500ng/L. Summary sensitivities and specificities (95% credible interval) were: ADD-RS>0 94.6% (90%, 97.5%) and 34.7% (20.7%, 51.2%), ADD-RS>1 43.4% (31.2%, 57.1%) and 89.3% (80.4%, 94.8%); ADD RS>0 or D-Dimer>500ng/L 99.8% (98.7%, 100%) and 21.8% (12.1%, 32.6%); ADD RS>1 or D-Dimer>500ng/L 98.3% (94.9%, 99.5%) and 51.4% (38.7%, 64.1%); ADD RS>1 or ADD RS = 1 with D-dimer>500ng/L 93.1% (87.1%, 96.3%) and 67.1% (54.4%, 77.7%).ConclusionsCombinations of ADD-RS and D-dimer can be used to select patients with suspected AAS for imaging with a range of trade-offs between sensitivity (93.1% to 99.8%) and specificity (21.8% to 67.1%).

Abstract Background The majority of patients with suspected acute coronary syndrome presenting to the emergency department will be discharged once myocardial infarction has been ruled out, although a proportion will have unrecognised coronary artery disease. In this setting, high-sensitivity cardiac troponin identifies those at increased risk of future cardiac events. In patients with intermediate cardiac troponin concentrations in whom myocardial infarction has been ruled out, this trial aims to investigate whether outpatient computed tomography coronary angiography (CTCA) reduces subsequent myocardial infarction or cardiac death. Methods TARGET-CTCA is a multicentre prospective randomised open label with blinded endpoint parallel group event driven trial. After myocardial infarction and clear alternative diagnoses have been ruled out, participants with intermediate cardiac troponin concentrations (5 ng/L to 99th centile upper reference limit) will be randomised 1:1 to outpatient CTCA plus standard of care or standard of care alone. The primary endpoint is myocardial infarction or cardiac death. Secondary endpoints include clinical, patient-centred, process and cost-effectiveness. Recruitment of 2270 patients will give 90% power with a two-sided P value of 0.05 to detect a 40% relative risk reduction in the primary endpoint. Follow-up will continue until 97 primary outcome events have been accrued in the standard care arm with an estimated median follow-up of 36 months. Discussion This randomised controlled trial will determine whether high-sensitivity cardiac troponin-guided CTCA can improve outcomes and reduce subsequent major adverse cardiac events in patients presenting to the emergency department who do not have myocardial infarction. Trial registration ClinicalTrials.gov Identifier: NCT03952351. Registered on May 16, 2019.

COVID-19 infection rates remain high in South Africa. Clinical prediction models may be helpful for rapid triage, and supporting clinical decision making, for patients with suspected COVID-19 infection. The Western Cape, South Africa, has integrated electronic health care data facilitating large-scale linked routine datasets. The aim of this study was to develop a machine learning model to predict adverse outcome in patients presenting with suspected COVID-19 suitable for use in a middle-income setting. A retrospective cohort study was conducted using linked, routine data, from patients presenting with suspected COVID-19 infection to public-sector emergency departments (EDs) in the Western Cape, South Africa between 27th August 2020 and 31st October 2021. The primary outcome was death or critical care admission at 30 days. An XGBoost machine learning model was trained and internally tested using split-sample validation. External validation was performed in 3 test cohorts: Western Cape patients presenting during the Omicron COVID-19 wave, a UK cohort during the ancestral COVID-19 wave, and a Sudanese cohort during ancestral and Eta waves. A total of 282,051 cases were included in a complete case training dataset. The prevalence of 30-day adverse outcome was 4.0%. The most important features for predicting adverse outcome were the requirement for supplemental oxygen, peripheral oxygen saturations, level of consciousness and age. Internal validation using split-sample test data revealed excellent discrimination (C-statistic 0.91, 95% CI 0.90 to 0.91) and calibration (CITL of 1.05). The model achieved C-statistics of 0.84 (95% CI 0.84 to 0.85), 0.72 (95% CI 0.71 to 0.73), and 0.62, (95% CI 0.59 to 0.65) in the Omicron, UK, and Sudanese test cohorts. Results were materially unchanged in sensitivity analyses examining missing data. An XGBoost machine learning model achieved good discrimination and calibration in prediction of adverse outcome in patients presenting with suspected COVID19 to Western Cape EDs. Performance was reduced in temporal and geographical external validation.

Abstract Background Approximately 75,000 people fracture a hip each year in the UK. This painful injury can be devastating—with a high associated mortality rate—and survivors likely to be more dependent and less mobile. Pain relief at the scene of injury is known to be inadequate. Intravenous morphine is usually given by paramedics, but opioids are less effective for dynamic pain and can cause serious side effects, including nausea, constipation, delirium and respiratory depression. These may delay surgery, require further treatment and worsen patient outcomes. We completed a feasibility study of paramedic-provided fascia iliaca compartment block (FICB), testing the intervention, trial methods and data collection. The study (RAPID) demonstrated that a full trial was feasible. In this subsequent study, we aim to test safety, clinical and cost-effectiveness of paramedic-provided FICB as pain relief to patients with suspected hip fracture in the prehospital environment. Methods We will conduct a pragmatic multi-centre individually randomised parallel-group trial, with a 1:1 allocation between usual care (control) and FICB (intervention). Hospital clinicians in five sites (paired ambulance services and receiving hospitals) in England and Wales will train 220 paramedics to administer FICB. The primary outcome is change in pain score from pre-randomisation to arrival at the emergency department. One thousand four hundred patients are required to find a clinically important difference between trial arms in the primary outcome (standardised statistical effect ~ 0.2; 90% power, 5% significance). We will use NHS Digital (England) and the SAIL (Secure Anonymised Information Linkage) databank (Wales) to follow up patient outcomes using routine anonymised linked data in an efficient study design, and questionnaires to capture patient-reported outcomes at 1 and 4 months. Secondary outcomes include mortality, length of hospital stay, job cycle time, prehospital medications including morphine, presence of hip fracture, satisfaction, mobility, and NHS costs. We will assess safety by monitoring serious adverse events (SAEs). Discussion The trial will help to determine whether paramedic administered FICB is a safe, clinically and cost-effective treatment for suspected hip fracture in the pre-hospital setting. Impact will be shown if and when clinical guidelines either recommend or reject the use of FICB in routine practice in this context. Trial registration ISRCTN15831813 . Registered on 22 September 2021.

Introduction Injuries are a major public health problem which can lead to disability or death. However, little is known about the incidence, presentation, management and outcomes of emergency care for patients with injuries among people from ethnic minorities in the UK. The aim of this study is to investigate what may differ for people from ethnic minorities compared with white British people when presenting with injury to ambulance and Emergency Departments (EDs).Methods and analysis This mixed methods study covers eight services, four ambulance services (three in England and one in Scotland) and four hospital EDs, located within each ambulance service. The study has five Work Packages (WP): (WP1) scoping review comparing mortality by ethnicity of people presenting with injury to emergency services; (WP2) retrospective analysis of linked NHS routine data from patients who present to ambulances or EDs with injury over 5 years (2016–2021); (WP3) postal questionnaire survey of 2000 patients (1000 patients from ethnic minorities and 1000 white British patients) who present with injury to ambulances or EDs including self-reported outcomes (measured by Quality of Care Monitor and Health Related Quality of Life measured by SF-12); (WP4) qualitative interviews with patients from ethnic minorities (n=40) and focus groups—four with asylum seekers and refugees and four with care providers and (WP5) a synthesis of quantitative and qualitative findings.Ethics and dissemination This study received a favourable opinion by the Wales Research Ethics Committee (305391). The Health Research Authority has approved the study and, on advice from the Confidentiality Advisory Group, has supported the use of confidential patient information without consent for anonymised data. Results will be shared with ambulance and ED services, government bodies and third-sector organisations through direct communications summarising scientific conference proceedings and publications.

Introduction Diagnosing underlying arrhythmia in emergency department (ED) syncope patients is difficult. There is a evidence that diagnostic yield for detecting underlying arrhythmia is highest when cardiac monitoring devices are applied early, ideally at the index visit. This strategy has the potential to change current syncope management from low diagnostic yield Holter to higher yield ambulatory monitoring, reduce episodes of syncope, reduce risk of recurrence and its potential serious consequences, reduce hospital admissions, reduce overall health costs and increase quality of life by allowing earlier diagnosis, treatment and exclusion of clinically important arrhythmias.Methods and analyses This is a UK open prospective parallel group multicentre randomised controlled trial of an immediate 14-day ambulatory patch heart monitor vs standard care in 2234 patients presenting acutely with unexplained syncope. Our patient focused primary endpoint will be number of episodes of syncope at 1 year. Health economic evaluation will estimate the incremental cost per syncope episode avoided and quality-adjusted life year gained.Ethics and dissemination Informed consent for participation will be sought. The ASPIRED trial received a favourable ethical opinion from South East Scotland Research Ethics Committee 01 (21/SS/0073). Results will be disseminated via scientific publication, lay summary and visual abstract.Trial registration number ISRCTN 10278811.

Objectives We evaluated the accuracy of using routine health service data to identify hospital-acquired thrombosis (HAT) and major bleeding events (MBE) compared with a reference standard of case note review.Design A multicentre observational cohort study.Setting Four acute hospitals in the UK.Participants A consecutive unselective cohort of general medical and surgical patients requiring hospitalisation for a period of >24 hours during the calendar year 2021. We excluded paediatric, obstetric and critical care patients due to differential risk profiles.Interventions We compared preidentified sources of routinely collected information (using hospital coding data and local contractually mandated thrombosis datasets) to data extracted from case notes using a predesigned workflow methodology.Primary and secondary outcome measures We defined HAT as objectively confirmed venous thromboembolism occurring during hospital stay or within 90 days of discharge and MBE as per international consensus.Results We were able to source all necessary routinely collected outcome data for 87% of 2008 case episodes reviewed. The sensitivity of hospital coding data (International Classification of Diseases 10th Revision, ICD-10) for the diagnosis of HAT and MBE was 62% (95% CI, 54 to 69) and 38% (95% CI, 27 to 50), respectively. Sensitivity improved to 81% (95% CI, 75 to 87) when using local thrombosis data sets.Conclusions Using routinely collected data appeared to miss a substantial proportion of outcome events, when compared with case note review. Our study suggests that currently available routine data collection methods in the UK are inadequate to support efficient study designs in venous thromboembolism research.Trial registration number NIHR127454.

BackgroundUneven vaccination and less resilient health care systems mean hospitals in LMICs are at risk of being overwhelmed during periods of increased COVID-19 infection. Risk-scores proposed for rapid triage of need for admission from the emergency department (ED) have been developed in higher-income settings during initial waves of the pandemic.MethodsRoutinely collected data for public hospitals in the Western Cape, South Africa from the 27th August 2020 to 11th March 2022 were used to derive a cohort of 446,084 ED patients with suspected COVID-19. The primary outcome was death or ICU admission at 30 days. The cohort was divided into derivation and Omicron variant validation sets. We developed the LMIC-PRIEST score based on the coefficients from multivariable analysis in the derivation cohort and existing triage practices. We externally validated accuracy in the Omicron period and a UK cohort.ResultsWe analysed 305,564 derivation, 140,520 Omicron and 12,610 UK validation cases. Over 100 events per predictor parameter were modelled. Multivariable analyses identified eight predictor variables retained across models. We used these findings and clinical judgement to develop a score based on South African Triage Early Warning Scores and also included age, sex, oxygen saturation, inspired oxygen, diabetes and heart disease. The LMIC-PRIEST score achieved C-statistics: 0.82 (95% CI: 0.82 to 0.83) development cohort; 0.79 (95% CI: 0.78 to 0.80) Omicron cohort; and 0.79 (95% CI: 0.79 to 0.80) UK cohort. Differences in prevalence of outcomes led to imperfect calibration in external validation. However, use of the score at thresholds of three or less would allow identification of very low-risk patients (NPV ≥0.99) who could be rapidly discharged using information collected at initial assessment.ConclusionThe LMIC-PRIEST score shows good discrimination and high sensitivity at lower thresholds and can be used to rapidly identify low-risk patients in LMIC ED settings.

Abstract Background Many health care systems triage injured patients to major trauma centres (MTCs) or local hospitals by using triage tools and paramedic judgement. Triage tools are typically assessed by whether patients with an Injury Severity Score (ISS) ≥ 16 go to an MTC and whether patients with an ISS

Objectives To assess the comparative accuracy of risk assessment models (RAMs) to identify women during pregnancy and the early postnatal period who are at increased risk of venous thromboembolism (VTE).Design Systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Data sources MEDLINE, Embase, Cochrane Library and two research registers were searched until February 2021.Eligibility criteria All validation studies that examined the accuracy of a multivariable RAM (or scoring system) for predicting the risk of developing VTE in women who are pregnant or in the puerperium (within 6 weeks post-delivery).Data extraction and synthesis Two authors independently selected and extracted data. Risk of bias was appraised using PROBAST (Prediction model Risk Of Bias ASsessment Tool). Data were synthesised without meta-analysis.Results Seventeen studies, comprising 19 externally validated RAMs and 1 internally validated model, met the inclusion criteria. The most widely evaluated RAMs were the Royal College of Obstetricians and Gynaecologists guidelines (six studies), American College of Obstetricians and Gynecologists guidelines (two studies), Swedish Society of Obstetrics and Gynecology guidelines (two studies) and the Lyon score (two studies). In general, estimates of sensitivity and specificity were highly variable with sensitivity estimates ranging from 0% to 100% for RAMs that were applied to antepartum women to predict antepartum or postpartum VTE and 0% to 100% for RAMs applied postpartum to predict postpartum VTE. Specificity estimates were similarly diverse ranging from 28% to 98% and 5% to 100%, respectively.Conclusions Available data suggest that external validation studies have weak designs and limited generalisability, so estimates of prognostic accuracy are very uncertain.PROSPERO registration number CRD42020221094.

Background: Acute coronary syndrome is a common medical emergency. The optimal strategy to investigate patients who are at intermediate risk of acute coronary syndrome has not been fully determined. Objective: To investigate the role of early computed tomography coronary angiography in the investigation and treatment of adults presenting with suspected acute coronary syndrome. Design: A prospective, multicentre, open, parallel-group randomised controlled trial with blinded end-point adjudication. Setting: Thirty-seven hospitals in the UK. Participants: Adults (aged ≥ 18 years) presenting to the emergency department, acute medicine services or cardiology department with suspected or provisionally diagnosed acute coronary syndrome and at least one of the following: (1) a prior history of coronary artery disease, (2) a cardiac troponin level > 99th centile and (3) an abnormal 12-lead electrocardiogram. Interventions: Early computed tomography coronary angiography in addition to standard care was compared with standard care alone. Participants were followed up for 1 year. Main outcome measure: One-year all-cause death or subsequent type 1 (spontaneous) or type 4b (stent thrombosis) myocardial infarction, measured as the time to such event adjudicated by two cardiologists blinded to the computerised tomography coronary angiography (CTCA) arm. Cost-effectiveness was estimated as the lifetime incremental cost per quality-adjusted life-year gained. Results: Between 23 March 2015 and 27 June 2019, 1748 participants [mean age 62 years (standard deviation 13 years), 64% male, mean Global Registry Of Acute Coronary Events score 115 (standard deviation 35)] were randomised to receive early computed tomography coronary angiography (n = 877) or standard care alone (n = 871). The primary end point occurred in 51 (5.8%) participants randomised to receive computed tomography coronary angiography and 53 (6.1%) participants randomised to receive standard care (adjusted hazard ratio 0.91, 95% confidence interval 0.62 to 1.35; p = 0.65). Computed tomography coronary angiography was associated with a reduced use of invasive coronary angiography (adjusted hazard ratio 0.81, 95% confidence interval 0.72 to 0.92; p = 0.001) but no change in coronary revascularisation (adjusted hazard ratio 1.03, 95% confidence interval 0.87 to 1.21; p = 0.76), acute coronary syndrome therapies (adjusted odds ratio 1.06, 95% confidence interval 0.85 to 1.32; p = 0.63) or preventative therapies on discharge (adjusted odds ratio 1.07, 95% confidence interval 0.87 to 1.32; p = 0.52). Early computed tomography coronary angiography was associated with longer hospitalisations (median increase 0.21 days, 95% confidence interval 0.05 to 0.40 days) and higher mean total health-care costs over 1 year (£561 more per patient) than standard care. Limitations: The principal limitation of the trial was the slower than anticipated recruitment, leading to a revised sample size, and the requirement to compromise and accept a larger relative effect size estimate for the trial intervention. Future work: The potential role of computed tomography coronary angiography in selected patients with a low probability of obstructive coronary artery disease (intermediate or mildly elevated level of troponin) or who have limited access to invasive cardiac catheterisation facilities needs further prospective evaluation. Conclusions: In patients with suspected or provisionally diagnosed acute coronary syndrome, computed tomography coronary angiography did not alter overall coronary therapeutic interventions or 1-year clinical outcomes, but it did increase the length of hospital stay and health-care costs. These findings do not support the routine use of early computed tomography coronary angiography in intermediate-risk patients with acute chest pain. Trial registration: This trial is registered as ISRCTN19102565 and Clinical Trials NCT02284191. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 37. See the NIHR Journals Library website for further project information.

Objectives Settings in identifying need for emergency care amongst those with suspected COVID-19 infection and identify factors which affect triage accuracy. Approach An observational cohort study of adults who contacted the NHS 111 telephone triage service provided by Yorkshire Ambulance Service between March and June 2020 with symptoms indicating possible COVID-19 infection. Patient-level data encompassing triage call, primary care, hospital care and death registration records relating to 40,261 adults were linked. The accuracy of triage outcome (self-care/non-urgent assessment versus ambulance/urgent assessment) was assessed for death or organ support 30 days from first contact. Multivariable logistic regression was used to identify factors associated with risk of false negative or false positive triage. Results Callers had a 3% (1,200/40,261) risk of serious adverse outcomes. Telephone triage recommended self-care or non-urgent assessment for 60% (24,335/40,261), with a 1.3% (310/24,335) risk of adverse outcomes 30 days from first contact. Telephone triage had 74.2% sensitivity (95% CI: 71.6 to 76.6%) and 61.5% specificity (61% to 62%) for the primary outcome. Analysis suggested respiratory comorbidities may be over-appreciated and diabetes under-appreciated as predictors of deterioration. Repeat contact with triage service appears to be an important under-recognised predictor of deterioration. Conclusion Patients advised to self-care or receive non-urgent clinical assessment had a small but non-negligible risk of serious clinical deterioration. Repeat contact with telephone services needs recognition as an important predictor of subsequent adverse outcomes.

Abstract Background Standard prehospital management for Acute respiratory failure (ARF) involves controlled oxygen therapy. Continuous positive airway pressure (CPAP) is a potentially beneficial alternative treatment, however, it is uncertain whether this could improve outcomes and provide value for money. This study aimed to evaluate the cost-effectiveness of prehospital CPAP in ARF. Methods A cost-utility economic evaluation was performed using a probabilistic decision tree model synthesising available evidence. The model consisted of a hypothetical cohort of patients in a representative ambulance service with undifferentiated ARF, receiving standard oxygen therapy or prehospital CPAP. Costs and quality adjusted life years (QALYs) were estimated using methods recommended by NICE. Results In the base case analysis, using CPAP effectiveness estimates form the ACUTE trial, the mean expected costs of standard care and prehospital CPAP were £15,201 and £14,850 respectively and the corresponding mean expected QALYs were 1.190 and 1.128, respectively. The mean ICER estimated as standard oxygen therapy compared to prehospital CPAP was £5685 per QALY which indicated that standard oxygen therapy strategy was likely to be cost-effective at a threshold of £20,000 per QALY (67% probability). The scenario analysis, using effectiveness estimates from an updated meta-analysis, suggested that prehospital CPAP was more effective (mean incremental QALYs of 0.157), but also more expensive (mean incremental costs of £1522), than standard care. The mean ICER, estimated as prehospital CPAP compared to standard care, was £9712 per QALY. At the £20,000 per QALY prehospital CPAP was highly likely to be the most cost-effective strategy (94%). Conclusions Cost-effectiveness of prehospital CPAP depends upon the estimate of effectiveness. When based on a small pragmatic feasibility trial, standard oxygen therapy is cost-effective. When based on meta-analysis of heterogeneous trials, CPAP is cost-effective. Value of information analyses support commissioning of a large pragmatic effectiveness trial, providing feasibility and plausibility conditions are met.

Abstract Background More than half of deaths in low- and middle-income countries (LMICs) result from conditions that could be treated with emergency care - an integral component of universal health coverage (UHC) - through timely access to lifesaving interventions. Methods The World Health Organization (WHO) aims to extend UHC to a further 1 billion people by 2023, yet evidence supporting improved emergency care coverage is lacking. In this article, we explore four phases of a research prioritisation setting (RPS) exercise conducted by researchers and stakeholders from South Africa, Egypt, Nepal, Jamaica, Tanzania, Trinidad and Tobago, Tunisia, Colombia, Ethiopia, Iran, Jordan, Malaysia, South Korea and Phillipines, USA and UK as a key step in gathering evidence required by policy makers and practitioners for the strengthening of emergency care systems in limited-resource settings. Results The RPS proposed seven priority research questions addressing: identification of context-relevant emergency care indicators, barriers to effective emergency care; accuracy and impact of triage tools; potential quality improvement via registries; characteristics of people seeking emergency care; best practices for staff training and retention; and cost effectiveness of critical care – all within LMICs. Conclusions Convened by WHO and facilitated by the University of Sheffield, the Global Emergency Care Research Network project (GEM-CARN) brought together a coalition of 16 countries to identify research priorities for strengthening emergency care in LMICs. Our article further assesses the quality of the RPS exercise and reviews the current evidence supporting the identified priorities.

Abstract Background Opioids, such as heroin, kill more people worldwide by overdose than any other type of drug, and death rates associated with opioid poisoning in the UK are at record levels (World Drug Report 2018 [Internet]. [cited 2019 Nov 19]. Available from: http://www.unodc.org/wdr2018/ ; Deaths related to drug poisoning in England and Wales - Office for National Statistics [Internet]. [cited 2019 Nov 19]. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsrelatedtodrugpoisoninginenglandandwales/2018registrations ). Naloxone is an opioid antagonist which can be distributed in ‘kits’ for administration by witnesses in an overdose emergency. This intervention is known as take-home naloxone (THN). We know that THN can save lives on an individual level, but there is currently limited evidence about the effectiveness of THN distribution on an aggregate level, in specialist drug service settings or in emergency service settings. Notably, we do not know whether THN kits reduce deaths from opioid overdose in at-risk populations, if there are unforeseen harms associated with THN distribution or if THN is cost-effective. In order to address this research gap, we aim to determine the feasibility of a fully powered cluster randomised controlled trial (RCT) of THN distribution in emergency settings. Methods We will carry out a feasibility study for a RCT of THN distributed in emergency settings at four sites, clustered by Emergency Department (ED) and catchment area within its associated ambulance service. THN is a peer-administered intervention. At two intervention sites, emergency ambulance paramedics and ED clinical staff will distribute THN to adult patients who are at risk of opioid overdose. At two control sites, practice will carry on as usual. We will develop a method of identifying a population to include in an evaluation, comprising people at risk of fatal opioid overdose, who may potentially receive naloxone included in a THN kit. We will gather anonymised outcomes up to 1 year following a 12-month ‘live’ trial period for patients at risk of death from opioid poisoning. We expect approximately 100 patients at risk of opioid overdose to be in contact with each service during the 1-year recruitment period. Our outcomes will include deaths, emergency admissions, intensive care admissions, and ED attendances. We will collect numbers of eligible patients attended by participating in emergency ambulance paramedics and attending ED, THN kits issued, and NHS resource usage. We will determine whether to progress to a fully powered trial based on pre-specified progression criteria: sign-up of sites (n = 4), staff trained (≥ 50%), eligible participants identified (≥ 50%), THN provided to eligible participants (≥ 50%), people at risk of death from opioid overdose identified for inclusion in follow-up (≥ 75% of overdose deaths), outcomes retrieved for high-risk individuals (≥ 75%), and adverse event rate (< 10% difference between study arms). Discussion This feasibility study is the first randomised, methodologically robust investigation of THN distribution in emergency settings. The study addresses an evidence gap related to the effectiveness of THN distribution in emergency settings. As this study is being carried out in emergency settings, obtaining informed consent on behalf of participants is not feasible. We therefore employ novel methods for identifying participants and capturing follow-up data, with effectiveness dependent on the quality of the available routine data. Trial registration ISRCTN13232859 (Registered 16/02/2018)

Abstract Background With millions of pounds spent annually on medical research in the UK, it is important that studies are spending funds wisely. Internal pilots offer the chance to stop a trial early if it becomes apparent that the study will not be able to recruit enough patients to show whether an intervention is clinically effective. This study aims to assess the use of internal pilots in individually randomised controlled trials funded by the Health Technology Assessment (HTA) programme and to summarise the progression criteria chosen in these trials. Methods Studies were identified from reports of the HTA committees’ funding decisions from 2012 to 2016. In total, 242 trials were identified of which 134 were eligible to be included in the audit. Protocols for the eligible studies were located on the NIHR Journals website, and if protocols were not available online then study managers were contacted to provide information. Results Over two-thirds (72.4%) of studies said in their protocol that they would include an internal pilot phase for their study and 37.8% of studies without an internal pilot had done an external pilot study to assess the feasibility of the full study. A typical study with an internal pilot has a target sample size of 510 over 24 months and aims to recruit one-fifth of their total target sample size within the first one-third of their recruitment time. There has been an increase in studies adopting a three-tiered structure for their progression rules in recent years, with 61.5% (16/26) of studies using the system in 2016 compared to just 11.8% (2/17) in 2015. There was also a rise in the number of studies giving a target recruitment rate in their progression criteria: 42.3% (11/26) in 2016 compared to 35.3% (6/17) in 2015. Conclusions Progression criteria for an internal pilot are usually well specified but targets vary widely. For the actual criteria, red/amber/green systems have increased in popularity in recent years. Trials should justify the targets they have set, especially where targets are low.

Abstract Background Delirium affects > 15% of hospitalised patients but is grossly underdetected, contributing to poor care. The 4 ‘A’s Test (4AT, www.the4AT.com) is a short delirium assessment tool designed for routine use without special training. The primary objective was to assess the accuracy of the 4AT for delirium detection. The secondary objective was to compare the 4AT with another commonly used delirium assessment tool, the Confusion Assessment Method (CAM). Methods This was a prospective diagnostic test accuracy study set in emergency departments or acute medical wards involving acute medical patients aged ≥ 70. All those without acutely life-threatening illness or coma were eligible. Patients underwent (1) reference standard delirium assessment based on DSM-IV criteria and (2) were randomised to either the index test (4AT, scores 0–12; prespecified score of > 3 considered positive) or the comparator (CAM; scored positive or negative), in a random order, using computer-generated pseudo-random numbers, stratified by study site, with block allocation. Reference standard and 4AT or CAM assessments were performed by pairs of independent raters blinded to the results of the other assessment. Results Eight hundred forty-three individuals were randomised: 21 withdrew, 3 lost contact, 32 indeterminate diagnosis, 2 missing outcome, and 785 were included in the analysis. Mean age was 81.4 (SD 6.4) years. 12.1% (95/785) had delirium by reference standard assessment, 14.3% (56/392) by 4AT, and 4.7% (18/384) by CAM. The 4AT had an area under the receiver operating characteristic curve of 0.90 (95% CI 0.84–0.96). The 4AT had a sensitivity of 76% (95% CI 61–87%) and a specificity of 94% (95% CI 92–97%). The CAM had a sensitivity of 40% (95% CI 26–57%) and a specificity of 100% (95% CI 98–100%). Conclusions The 4AT is a short, pragmatic tool which can help improving detection rates of delirium in routine clinical care. Trial registration International standard randomised controlled trial number (ISRCTN) 53388093. Date applied 30/05/2014; date assigned 02/06/2014.

Background: Acute respiratory failure is a life-threatening emergency. Standard prehospital management involves controlled oxygen therapy. Continuous positive airway pressure is a potentially beneficial alternative treatment; however, it is uncertain whether or not this treatment could improve outcomes in NHS ambulance services. Objectives: To assess the feasibility of a large-scale pragmatic trial and to update an existing economic model to determine cost-effectiveness and the value of further research. Design: (1) An open-label, individual patient randomised controlled external pilot trial. (2) Cost-effectiveness and value-of-information analyses, updating an existing economic model. (3) Ancillary substudies, comprising an acute respiratory failure incidence study, an acute respiratory failure diagnostic agreement study, clinicians perceptions of a continuous positive airway pressure mixed-methods study and an investigation of allocation concealment. Setting: Four West Midlands Ambulance Service hubs, recruiting between August 2017 and July 2018. Participants: Adults with respiratory distress and peripheral oxygen saturations below the British Thoracic Society’s target levels were included. Patients with limited potential to benefit from, or with contraindications to, continuous positive airway pressure were excluded. Interventions: Prehospital continuous positive airway pressure (O-Two system, O-Two Medical Technologies Inc., Brampton, ON, Canada) was compared with standard oxygen therapy, titrated to the British Thoracic Society’s peripheral oxygen saturation targets. Interventions were provided in identical sealed boxes. Main outcome measures: Feasibility objectives estimated the incidence of eligible patients, the proportion recruited and allocated to treatment appropriately, adherence to allocated treatment, and retention and data completeness. The primary clinical end point was 30-day mortality. Results: Seventy-seven patients were enrolled (target 120 patients), including seven patients with a diagnosis for which continuous positive airway pressure could be ineffective or harmful. Continuous positive airway pressure was fully delivered to 74% of participants (target 75%). There were no major protocol violations/non-compliances. Full data were available for all key outcomes (target ≥ 90%). Thirty-day mortality was 27.3%. Of the 21 deceased participants, 14 (68%) either did not have a respiratory condition or had ceiling-of-treatment decision implemented that excluded hospital non-invasive ventilation and critical care. The base-case economic evaluation indicated that standard oxygen therapy was probably cost-effective (incremental cost-effectiveness ratio £5685 per quality-adjusted life-year), but there was considerable uncertainty (population expected value of perfect information of £16.5M). Expected value of partial perfect information analyses indicated that effectiveness of prehospital continuous positive airway pressure was the only important variable. The incidence rate of acute respiratory failure was 17.4 (95% confidence interval 16.3 to 18.5) per 100,000 persons per year. There was moderate agreement between the primary prehospital and final hospital diagnoses (Gwet’s AC1 coefficient 0.56, 95% confidence interval 0.43 to 0.69). Lack of hospital awareness of the Ambulance continuous positive airway pressure (CPAP): Use, Treatment Effect and economics (ACUTE) trial, limited time to complete trial training and a desire to provide continuous positive airway pressure treatment were highlighted as key challenges by participating clinicians. Limitations: During week 10 of recruitment, the continuous positive airway pressure arm equipment boxes developed a ‘rattle’. After repackaging and redistribution, no further concerns were noted. A total of 41.4% of ambulance service clinicians not participating in the ACUTE trial indicated a difference between the control and the intervention arm trial boxes (115/278); of these clinician 70.4% correctly identified box contents. Conclusions: Recruitment rate was below target and feasibility was not demonstrated. The economic evaluation results suggested that a definitive trial could represent value for money. However, limited compliance with continuous positive airway pressure and difficulty in identifying patients who could benefit from continuous positive airway pressure indicate that prehospital continuous positive airway pressure is unlikely to materially reduce mortality. Future work: A definitive clinical effectiveness trial of continuous positive airway pressure in the NHS is not recommended. Trial registration: Current Controlled Trials ISRCTN12048261. 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. 25, No. 7. See the NIHR Journals Library website for further project information.

ObjectivesWe aimed to derive and validate a triage tool, based on clinical assessment alone, for predicting adverse outcome in acutely ill adults with suspected COVID-19 infection.MethodsWe undertook a mixed prospective and retrospective observational cohort study in 70 emergency departments across the United Kingdom (UK). We collected presenting data from 22445 people attending with suspected COVID-19 between 26 March 2020 and 28 May 2020. The primary outcome was death or organ support (respiratory, cardiovascular, or renal) by record review at 30 days. We split the cohort into derivation and validation sets, developed a clinical score based on the coefficients from multivariable analysis using the derivation set, and the estimated discriminant performance using the validation set.ResultsWe analysed 11773 derivation and 9118 validation cases. Multivariable analysis identified that age, sex, respiratory rate, systolic blood pressure, oxygen saturation/inspired oxygen ratio, performance status, consciousness, history of renal impairment, and respiratory distress were retained in analyses restricted to the ten or fewer predictors. We used findings from multivariable analysis and clinical judgement to develop a score based on the NEWS2 score, age, sex, and performance status. This had a c-statistic of 0.80 (95% confidence interval 0.79-0.81) in the validation cohort and predicted adverse outcome with sensitivity 0.98 (0.97-0.98) and specificity 0.34 (0.34-0.35) for scores above four points.ConclusionA clinical score based on NEWS2, age, sex, and performance status predicts adverse outcome with good discrimination in adults with suspected COVID-19 and can be used to support decision-making in emergency care.RegistrationISRCTN registry, ISRCTN28342533, http://www.isrctn.com/ISRCTN28342533.

Background: No seizure first aid training intervention exists for people with epilepsy who regularly attend emergency departments and their significant others, despite such an intervention’s potential to reduce clinically unnecessary and costly visits. Objectives: The objectives were to (1) develop Seizure first Aid training For Epilepsy (SAFE) by adapting a broader intervention and (2) determine the feasibility and optimal design of a definitive randomised controlled trial to test SAFE’s efficacy. Design: The study involved (1) the development of an intervention informed by a co-design approach with qualitative feedback and (2) a pilot randomised controlled trial with follow-ups at 3, 6 and 12 months and assessments of treatment fidelity and the cost of SAFE’s delivery. Setting: The setting was (1) third-sector patient support groups and professional health-care organisations and (2) three NHS emergency departments in England. Participants: Participants were (1) people with epilepsy who had visited emergency departments in the prior 2 years, their significant others and emergency department, paramedic, general practice, commissioning, neurology and nursing representatives and (2) people with epilepsy aged ≥ 16 years who had been diagnosed for ≥ 1 year and who had made two or more emergency department visits in the prior 12 months, and one of their significant others. Emergency departments identified ostensibly eligible people with epilepsy from attendance records and patients confirmed their eligibility. Interventions: Participants in the pilot randomised controlled trial were randomly allocated 1 : 1 to SAFE plus treatment as usual or to treatment as usual only. Main outcome measures: Consent rate and availability of routine data on emergency department use at 12 months were the main outcome measures. Other measures of interest included eligibility rate, ease with which people with epilepsy could be identified and routine data secured, availability of self-reported emergency department data, self-reported emergency department data’s comparability with routine data, SAFE’s effect on emergency department use, and emergency department use in the treatment as usual arm, which could be used in sample size calculations. Results: (1) Nine health-care professionals and 23 service users provided feedback that generated an intervention considered to be NHS feasible and well positioned to achieve its purpose. (2) The consent rate was 12.5%, with 53 people with epilepsy and 38 significant others recruited. The eligibility rate was 10.6%. Identifying people with epilepsy from attendance records was resource intensive for emergency department staff. Those recruited felt more stigmatised because of epilepsy than the wider epilepsy population. Routine data on emergency department use at 12 months were secured for 94.1% of people with epilepsy, but the application process took 8.5 months. Self-reported emergency department data were available for 66.7% of people with epilepsy, and people with epilepsy self-reported more emergency department visits than were captured in routine data. Most participants (76.9%) randomised to SAFE received the intervention. The intervention was delivered with high fidelity. No related serious adverse events occurred. Emergency department use at 12 months was lower in the SAFE plus treatment as usual arm than in the treatment as usual only arm, but not significantly so. Calculations indicated that a definitive trial would need ≈ 674 people with epilepsy and ≈ 39 emergency department sites. Limitations: Contrary to patient statements on recruitment, routine data secured at the pilot trial’s end indicated that ≈ 40% may not have satisfied the inclusion criterion of two or more emergency department visits. Conclusions: An intervention was successfully developed, a pilot randomised controlled trial conducted and outcome data secured for most participants. The consent rate did not satisfy a predetermined ‘stop/go’ level of ≥ 20%. The time that emergency department staff needed to identify eligible people with epilepsy is unlikely to be replicable. A definitive trial is currently not feasible. Future work: Research to more easily identify and recruit people from the target population is required. Trial registration: Current Controlled Trials ISRCTN13871327. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 39. See the NIHR Journals Library website for further project information.

Objectives To determine the feasibility of a large-scale definitive multicentre trial of prehospital continuous positive airway pressure (CPAP) in acute respiratory failure.Design A single-centre, open-label, individual patient randomised, controlled, external pilot trial.Setting A single UK Ambulance Service, between August 2017 and July 2018.Participants Adults with respiratory distress and peripheral oxygen saturations below British Thoracic Society target levels despite controlled oxygen treatment.Interventions Patients were randomised to prehospital CPAP (O-Two system) versus standard oxygen therapy in a 1:1 ratio using simple randomisation.Primary and secondary outcome measures Feasibility outcomes comprised recruitment rate, adherence to allocated treatment, retention and data completeness. The primary clinical outcome was 30-day mortality.Results 77 patients were enrolled (target 120), including 7 cases with a diagnosis where CPAP could be ineffective or harmful. CPAP was fully delivered in 74% (target 75%). There were no major protocol violations. Full data were available for all key outcomes (targets ≥90%). Overall 30-day mortality was 27.3%. Of these deceased patients, 14/21 (68%) either did not have a respiratory condition or had ceiling of treatment decisions implemented excluding hospital non-invasive ventilation and critical care.Conclusions Recruitment rate was below target and feasibility was not demonstrated. Limited compliance with CPAP, and difficulty in identifying patients who could benefit from CPAP, indicate that prehospital CPAP is unlikely to materially reduce mortality. A definitive effectiveness trial of CPAP is therefore not recommended.Trial registration number ISRCTN12048261; Post-results.

Background: Front-line health-care services are under increased demand when acute alcohol intoxication is most common, which is in night-time environments. Cities have implemented alcohol intoxication management services to divert the intoxicated away from emergency care. Objectives: To evaluate the effectiveness, cost-effectiveness and acceptability to patients and staff of alcohol intoxication management services and undertake an ethnographic study capturing front-line staff’s views on the impact of acute alcohol intoxication on their professional lives. Methods: This was a controlled mixed-methods longitudinal observational study with an ethnographic evaluation in parallel. Six cities with alcohol intoxication management services were compared with six matched control cities to determine effects on key performance indicators (e.g. number of patients in the emergency department and ambulance response times). Surveys captured the impact of alcohol intoxication management services on the quality of care for patients in six alcohol intoxication management services, six emergency departments with local alcohol intoxication management services and six emergency departments without local alcohol intoxication management services. The ethnographic study considered front-line staff perceptions in two cities with alcohol intoxication management services and one city without alcohol intoxication management services. Results: Alcohol intoxication management services typically operated in cities in which the incidence of acute alcohol intoxication was greatest. The per-session average number of attendances across all alcohol intoxication management services was low (mean 7.3, average minimum 2.8, average maximum 11.8) compared with the average number of emergency department attendances per alcohol intoxication management services session (mean 78.8), and the number of patients diverted away from emergency departments, per session, required for services to be considered cost-neutral was 8.7, falling to 3.5 when ambulance costs were included. Alcohol intoxication management services varied, from volunteer-led first aid to more clinically focused nurse practitioner services, with only the latter providing evidence for diversion from emergency departments. Qualitative and ethnographic data indicated that alcohol intoxication management services are acceptable to practitioners and patients and that they address unmet need. There was evidence that alcohol intoxication management services improve ambulance response times and reduce emergency department attendance. Effects are uncertain owing to the variation in service delivery. Limitations: The evaluation focused on health service outcomes, yet evidence arose suggesting that alcohol intoxication management services provide broader societal benefits. There was no nationally agreed standard operating procedure for alcohol intoxication management services, undermining the evaluation. Routine health data outcomes exhibited considerable variance, undermining opportunities to provide an accurate appraisal of the heterogenous collection of alcohol intoxication management services. Conclusions: Alcohol intoxication management services are varied, multipartner endeavours and would benefit from agreed national standards. Alcohol intoxication management services are popular with and benefit front-line staff and serve as a hub facilitating partnership working. They are popular with alcohol intoxication management services patients and capture previously unmet need in night-time environments. However, acute alcohol intoxication in emergency departments remains an issue and opportunities for diversion have not been entirely realised. The nurse-led model was the most expensive service evaluated but was also the most likely to divert patients away from emergency departments, suggesting that greater clinical involvement and alignment with emergency departments is necessary. Alcohol intoxication management services should be regarded as fledgling services that require further work to realise benefit. Future work: Research could be undertaken to determine if a standardised model of alcohol intoxication management services, based on the nurse practitioner model, can be developed and implemented in different settings. Future evaluations should go beyond the health service and consider outcomes more generally, especially for the police. Future work on the management of acute alcohol intoxication in night-time environments could recognise the partnership between health-care, police and ambulance services and third-sector organisations in managing acute alcohol intoxication. Trial registration: Current Controlled Trials ISRCTN63096364. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 24. See the NIHR Journals Library website for further project information.

Background: There is widespread concern about the pressure on emergency and urgent services in the UK, particularly emergency ambulances, emergency departments and same-day general practitioner appointments. A mismatch between supply and demand has led to interest in what can be termed ‘clinically unnecessary’ use of services. This is defined by the research team in this study as ‘patients attending services with problems that are classified as suitable for treatment by a lower urgency service or self-care’. This is a challenging issue to consider because patients may face difficulties when deciding the best action to take, and different staff may make different judgements about what constitutes a legitimate reason for service use. Objectives: To identify the drivers of ‘clinically unnecessary’ use of emergency ambulances, emergency departments and same-day general practitioner appointments from patient and population perspectives. Design: This was a sequential mixed-methods study with three components: a realist review; qualitative interviews (n = 48) and focus groups (n = 3) with patients considered ‘clinically unnecessary’ users of these services, focusing on parents of young children, young adults and people in areas of social deprivation; and a population survey (n = 2906) to explore attitudes towards seeking care for unexpected, non-life-threatening health problems and to identify the characteristics of someone with a tendency for ‘clinically unnecessary’ help-seeking. Results: From the results of the three study components, we found that multiple, interacting drivers influenced individuals’ decision-making. Drivers could be grouped into symptom related, patient related and health service related. Symptom-related drivers were anxiety or need for reassurance, which were caused by uncertainty about the meaning or seriousness of symptoms; concern about the impact of symptoms on daily activities/functioning; and a need for immediate relief of intolerable symptoms, particularly pain. Patient-related drivers were reduced coping capacity as a result of illness, stress or limited resources; fear of consequences when responsible for another person’s health, particularly a child; and the influence of social networks. Health service-related drivers were perceptions or previous experiences of services, particularly the attractions of emergency departments; a lack of timely access to an appropriate general practitioner appointment; and compliance with health service staff’s advice. Limitations: Difficulty recruiting patients who had used the ambulance service to the interviews and focus groups meant that we were not able to add as much as we had anticipated to the limited evidence base regarding this service. Conclusions: Patients use emergency ambulances, emergency departments and same-day general practitioner appointments when they may not need the level of clinical care provided by these services for a multitude of inter-related reasons that sometimes differ by population subgroup. Some of these reasons relate to health services, in terms of difficulty accessing general practice leading to use of emergency departments, and to population-learnt behaviour concerning the positive attributes of emergency departments, rather than to patient characteristics. Social circumstances, such as complex and stressful lives, influence help-seeking for all three services. Demand may be ‘clinically unnecessary’ but completely understandable when service accessibility and patients’ social circumstances are considered. Future work: There is a need to evaluate interventions, including changing service configuration, strengthening general practice and addressing the stressors that have an impact on people’s coping capacity. Different subgroups may require different interventions. Study registration: This study is registered as PROSPERO CRD42017056273. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 15. See the NIHR Journals Library website for further project information.

BackgroundHospital emergency departments play a crucial role in the initial assessment and management of suspected COVID-19 infection. This needs to be guided by studies of people presenting with suspected COVID-19, including those admitted and discharged, and those who do not ultimately have COVID-19 confirmed. We aimed to characterise patients attending emergency departments with suspected COVID-19, including subgroups based on sex, ethnicity and COVID-19 test results.Methods and findingsWe undertook a mixed prospective and retrospective observational cohort study in 70 emergency departments across the United Kingdom (UK). We collected presenting data from 22445 people attending with suspected COVID-19 between 26 March 2020 and 28 May 2020. Outcomes were admission to hospital, COVID-19 result, organ support (respiratory, cardiovascular or renal), and death, by record review at 30 days. Mean age was 58.4 years, 11200 (50.4%) were female and 11034 (49.6%) male. Adults (age >16 years) were acutely unwell (median NEWS2 score of 4), frequently had limited performance status (46.9%) and had high rates of admission (67.1%), COVID-19 positivity (31.2%), organ support (9.8%) and death (15.5%). Children had much lower rates of admission (27.4%), COVID-19 positivity (1.2%), organ support (1.4%) and death (0.3%). Similar numbers of men and women presented to the ED, but men were more likely to be admitted (72.9% v 61.4%), require organ support (12.2% v 7.7%) and die (18.2% v 13.0%). Black or Asian adults tended to be younger than White adults (median age 54, 50 and 67 years), were less likely to have impaired performance status (43.1%, 26.8% and 51.6%), be admitted to hospital (60.8%, 57.3%, 69.6%) or die (11.6%, 11.2%, 16.4%), but were more likely to require organ support (15.9%, 14.3%, 8.9%) or have a positive COVID-19 test (40.8%, 42.1%, 30.0%). Adults admitted with suspected and confirmed COVID-19 had similar age, performance status and comorbidities (except chronic lung disease) to those who did not have COVID-19 confirmed, but were much more likely to need organ support (22.2% v 8.9%) or die (32.1% v 15.5%).ConclusionsImportant differences exist between patient groups presenting to the emergency department with suspected COVID-19. Adults and children differ markedly and require different approaches to emergency triage. Admission and adverse outcome rates among adults suggest that policies to avoid unnecessary ED attendance achieved their aim. Subsequent COVID-19 confirmation confers a worse prognosis and greater need for organ support.RegistrationISRCTN registry, ISRCTN56149622, http://www.isrctn.com/ISRCTN28342533.

Background: Thromboprophylaxis can reduce the risk of venous thromboembolism (VTE) during lower-limb immobilisation, but it is unclear whether or not this translates into meaningful health benefit, justifies the risk of bleeding or is cost-effective. Risk assessment models (RAMs) could select higher-risk individuals for thromboprophylaxis. Objectives: To determine the clinical effectiveness and cost-effectiveness of different strategies for providing thromboprophylaxis to people with lower-limb immobilisation caused by injury and to identify priorities for future research. Data sources: Ten electronic databases and research registers (MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Review of Effects, the Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluation Database, Science Citation Index Expanded, ClinicalTrials.gov and the International Clinical Trials Registry Platform) were searched from inception to May 2017, and this was supplemented by hand-searching reference lists and contacting experts in the field. Review methods: Systematic reviews were undertaken to determine the effectiveness of pharmacological thromboprophylaxis in lower-limb immobilisation and to identify any study of risk factors or RAMs for VTE in lower-limb immobilisation. Study quality was assessed using appropriate tools. A network meta-analysis was undertaken for each outcome in the effectiveness review and the results of risk-prediction studies were presented descriptively. A modified Delphi survey was undertaken to identify risk predictors supported by expert consensus. Decision-analytic modelling was used to estimate the incremental cost per quality-adjusted life-year (QALY) gained of different thromboprophylaxis strategies from the perspectives of the NHS and Personal Social Services. Results: Data from 6857 participants across 13 trials were included in the meta-analysis. Thromboprophylaxis with low-molecular-weight heparin reduced the risk of any VTE [odds ratio (OR) 0.52, 95% credible interval (CrI) 0.37 to 0.71], clinically detected deep-vein thrombosis (DVT) (OR 0.40, 95% CrI 0.12 to 0.99) and pulmonary embolism (PE) (OR 0.17, 95% CrI 0.01 to 0.88). Thromboprophylaxis with fondaparinux (Arixtra®, Aspen Pharma Trading Ltd, Dublin, Ireland) reduced the risk of any VTE (OR 0.13, 95% CrI 0.05 to 0.30) and clinically detected DVT (OR 0.10, 95% CrI 0.01 to 0.94), but the effect on PE was inconclusive (OR 0.47, 95% CrI 0.01 to 9.54). Estimates of the risk of major bleeding with thromboprophylaxis were inconclusive owing to the small numbers of events. Fifteen studies of risk factors were identified, but only age (ORs 1.05 to 3.48), and injury type were consistently associated with VTE. Six studies of RAMs were identified, but only two reported prognostic accuracy data for VTE, based on small numbers of patients. Expert consensus was achieved for 13 risk predictors in lower-limb immobilisation due to injury. Modelling showed that thromboprophylaxis for all is effective (0.015 QALY gain, 95% CrI 0.004 to 0.029 QALYs) with a cost-effectiveness of £13,524 per QALY, compared with thromboprophylaxis for none. If risk-based strategies are included, it is potentially more cost-effective to limit thromboprophylaxis to patients with a Leiden thrombosis risk in plaster (cast) [L-TRiP(cast)] score of ≥ 9 (£20,000 per QALY threshold) or ≥ 8 (£30,000 per QALY threshold). An optimal threshold on the L-TRiP(cast) receiver operating characteristic curve would have sensitivity of 84–89% and specificity of 46–55%. Limitations: Estimates of RAM prognostic accuracy are based on weak evidence. People at risk of bleeding were excluded from trials and, by implication, from modelling. Conclusions: Thromboprophylaxis for lower-limb immobilisation due to injury is clinically effective and cost-effective compared with no thromboprophylaxis. Risk-based thromboprophylaxis is potentially optimal but the prognostic accuracy of existing RAMs is uncertain. Future work: Research is required to determine whether or not an appropriate RAM can accurately select higher-risk patients for thromboprophylaxis. Study registration: This study is registered as PROSPERO CRD42017058688. Funding: The National Institute for Health Research Health Technology Assessment programme.

Abstract Background Acute respiratory failure (ARF) is a common and life-threatening medical emergency. Standard prehospital management involves controlled oxygen therapy and disease-specific ancillary treatments. Continuous positive airway pressure (CPAP) is a potentially beneficial alternative treatment that could be delivered by emergency medical services. However, it is uncertain whether this treatment could work effectively in United Kingdom National Health Service (NHS) ambulance services and if it represents value for money. Methods An individual patient randomised controlled external pilot trial will be conducted comparing prehospital CPAP to standard oxygen therapy for ARF. Adults presenting to ambulance service clinicians will be eligible if they have respiratory distress with peripheral oxygen saturation below British Thoracic Society (BTS) target levels, despite titrated supplemental oxygen. Enrolled patients will be allocated (1:1 simple randomisation) to prehospital CPAP (O_two system) or standard oxygen therapy using identical sealed boxes. Feasibility outcomes will include incidence of recruited eligible patients, number of erroneously recruited patients and proportion of cases adhering to allocation schedule and treatment, followed up at 30 days and with complete data collection. Effectiveness outcomes will comprise survival at 30 days (definitive trial primary end point), endotracheal intubation, admission to critical care, length of hospital stay, visual analogue scale (VAS) dyspnoea score, EQ-5D-5L and health care resource use at 30 days. The cost-effectiveness of CPAP, and of conducting a definitive trial, will be evaluated by updating an existing economic model. The trial aims to recruit 120 patients over 12 months from four regional ambulance hubs within the West Midlands Ambulance Service (WMAS). This sample size will allow estimation of feasibility outcomes with a precision of

Background: Delirium is a common and serious neuropsychiatric syndrome, usually triggered by illness or drugs. It remains underdetected. One reason for this is a lack of brief, pragmatic assessment tools. The 4 ‘A’s test (Arousal, Attention, Abbreviated Mental Test – 4, Acute change) (4AT) is a screening tool designed for routine use. This project evaluated its usability, diagnostic accuracy and cost. Methods: Phase 1 – the usability of the 4AT in routine practice was measured with two surveys and two qualitative studies of health-care professionals, and a review of current clinical use of the 4AT as well as its presence in guidelines and reports. Phase 2 – the 4AT’s diagnostic accuracy was assessed in newly admitted acute medical patients aged ≥ 70 years. Its performance was compared with that of the Confusion Assessment Method (CAM; a longer screening tool). The performance of individual 4AT test items was related to cognitive status, length of stay, new institutionalisation, mortality at 12 weeks and outcomes. The method used was a prospective, double-blind diagnostic test accuracy study in emergency departments or in acute general medical wards in three UK sites. Each patient underwent a reference standard delirium assessment and was also randomised to receive an assessment with either the 4AT (n = 421) or the CAM (n = 420). A health economics analysis was also conducted. Results: Phase 1 found evidence that delirium awareness is increasing, but also that there is a need for education on delirium in general and on the 4AT in particular. Most users reported that the 4AT was useful, and it was in widespread use both in the UK and beyond. No changes to the 4AT were considered necessary. Phase 2 involved 785 individuals who had data for analysis; their mean age was 81.4 (standard deviation 6.4) years, 45% were male, 99% were white and 9% had a known dementia diagnosis. The 4AT (n = 392) had an area under the receiver operating characteristic curve of 0.90. A positive 4AT score (> 3) had a specificity of 95% [95% confidence interval (CI) 92% to 97%] and a sensitivity of 76% (95% CI 61% to 87%) for reference standard delirium. The CAM (n = 382) had a specificity of 100% (95% CI 98% to 100%) and a sensitivity of 40% (95% CI 26% to 57%) in the subset of participants whom it was possible to assess using this. Patients with positive 4AT scores had longer lengths of stay (median 5 days, interquartile range 2.0–14.0 days) than did those with negative 4AT scores (median 2 days, interquartile range 1.0–6.0 days), and they had a higher 12-week mortality rate (16.1% and 9.2%, respectively). The estimated 12-week costs of an initial inpatient stay for patients with delirium were more than double the costs of an inpatient stay for patients without delirium (e.g. in Scotland, £7559, 95% CI £7362 to £7755, vs. £4215, 95% CI £4175 to £4254). The estimated cost of false-positive cases was £4653, of false-negative cases was £8956, and of a missed diagnosis was £2067. Limitations: Patients were aged ≥ 70 years and were assessed soon after they were admitted, limiting generalisability. The treatment of patients in accordance with reference standard diagnosis limited the ability to assess comparative cost-effectiveness. Conclusions: These findings support the use of the 4AT as a rapid delirium assessment instrument. The 4AT has acceptable diagnostic accuracy for acute older patients aged > 70 years. Future work: Further research should address the real-world implementation of delirium assessment. The 4AT should be tested in other populations. Trial registration: Current Controlled Trials ISRCTN53388093. 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. 23, No. 40. See the NIHR Journals Library website for further project information. The funder specified that any new delirium assessment tool should be compared against the CAM, but had no other role in the study design or conduct of the study.

Background: Ambulance service quality measures have focused on response times and a small number of emergency conditions, such as cardiac arrest. These quality measures do not reflect the care for the wide range of problems that ambulance services respond to and the Prehospital Outcomes for Evidence Based Evaluation (PhOEBE) programme sought to address this. Objectives: The aim was to develop new ways of measuring the impact of ambulance service care by reviewing and synthesising literature on prehospital ambulance outcome measures and using consensus methods to identify measures for further development; creating a data set linking routinely collected ambulance service, hospital and mortality data; and using the linked data to explore the development of case-mix adjustment models to assess differences or changes in processes and outcomes resulting from ambulance service care. Design: A mixed-methods study using a systematic review and synthesis of performance and outcome measures reported in policy and research literature; qualitative interviews with ambulance service users; a three-stage consensus process to identify candidate indicators; the creation of a data set linking ambulance, hospital and mortality data; and statistical modelling of the linked data set to produce novel case-mix adjustment measures of ambulance service quality. Setting: East Midlands and Yorkshire, England. Participants: Ambulance services, patients, public, emergency care clinical academics, commissioners and policy-makers between 2011 and 2015. Interventions: None. Main outcome measures: Ambulance performance and quality measures. Data sources: Ambulance call-and-dispatch and electronic patient report forms, Hospital Episode Statistics, accident and emergency and inpatient data, and Office for National Statistics mortality data. Results: Seventy-two candidate measures were generated from systematic reviews in four categories: (1) ambulance service operations (n = 14), (2) clinical management of patients (n = 20), (3) impact of care on patients (n = 9) and (4) time measures (n = 29). The most common operations measures were call triage accuracy; clinical management was adherence to care protocols, and for patient outcome it was survival measures. Excluding time measures, nine measures were highly prioritised by participants taking part in the consensus event, including measures relating to pain, patient experience, accuracy of dispatch decisions and patient safety. Twenty experts participated in two Delphi rounds to refine and prioritise measures and 20 measures scored ≥ 8/9 points, which indicated good consensus. Eighteen patient and public representatives attending a consensus workshop identified six measures as important: time to definitive care, response time, reduction in pain score, calls correctly prioritised to appropriate levels of response, proportion of patients with a specific condition who are treated in accordance with established guidelines, and survival to hospital discharge for treatable emergency conditions. From this we developed six new potential indicators using the linked data set, of which five were constructed using case-mix-adjusted predictive models: (1) mean change in pain score; (2) proportion of serious emergency conditions correctly identified at the time of the 999 call; (3) response time (unadjusted); (4) proportion of decisions to leave a patient at scene that were potentially inappropriate; (5) proportion of patients transported to the emergency department by 999 emergency ambulance who did not require treatment or investigation(s); and (6) proportion of ambulance patients with a serious emergency condition who survive to admission, and to 7 days post admission. Two indicators (pain score and response times) did not need case-mix adjustment. Among the four adjusted indicators, we found that accuracy of call triage was 61%, rate of potentially inappropriate decisions to leave at home was 5–10%, unnecessary transport to hospital was 1.7–19.2% and survival to hospital admission was 89.5–96.4% depending on Clinical Commissioning Group area. We were unable to complete a fourth objective to test the indicators in use because of delays in obtaining data. An economic analysis using indicators (4) and (5) showed that incorrect decisions resulted in higher costs. Limitations: Creation of a linked data set was complex and time-consuming and data quality was variable. Construction of the indicators was also complex and revealed the effects of other services on outcome, which limits comparisons between services. Conclusions: We identified and prioritised, through consensus processes, a set of potential ambulance service quality measures that reflected preferences of services and users. Together, these encompass a broad range of domains relevant to the population using the emergency ambulance service. The quality measures can be used to compare ambulance services or regions or measure performance over time if there are improvements in mechanisms for linking data across services. Future work: The new measures can be used to assess different dimensions of ambulance service delivery but current data challenges prohibit routine use. There are opportunities to improve data linkage processes and to further develop, validate and simplify these measures. Funding: The National Institute for Health Research Programme Grants for Applied Research programme.

Purpose. To measure fidelity with which a group seizure first aid training intervention was delivered within a pilot randomized controlled trial underway in the UK for adults with epilepsy who visit emergency departments (ED) and informal carers. Estimates of its effects, including on ED use, will be produced by the trial. Whilst hardly ever reported for trials of epilepsy interventions—only one publication on this topic exists—this study provides the information on treatment fidelity necessary to allow the trial’s estimates to be accurately interpreted. This rare worked example of how fidelity can be assessed could also provide guidance sought by neurology trialists on how to assess fidelity. Methods. 53 patients who had visited ED on ≥2 occasions in prior year were recruited for the trial; 26 were randomized to the intervention. 7 intervention courses were delivered for them by one facilitator. Using audio recordings, treatment “adherence” and “competence” were assessed. Adherence was assessed by a checklist of the items comprising the intervention. Using computer software, competence was measured by calculating facilitator speech during the intervention (didacticism). Interrater reliability was evaluated by two independent raters assessing each course using the measures and their ratings being compared. Results. The fidelity measures were found to be reliable. For the adherence instrument, raters agreed 96% of the time, PABAK-OS kappa 0.91. For didacticism, raters’ scores had an intraclass coefficient of 0.96. In terms of treatment fidelity, not only were courses found to have been delivered with excellent adherence (88% of its items were fully delivered) but also as intended they were highly interactive, with the facilitator speaking for, on average, 55% of course time. Conclusions. The fidelity measures used were reliable and showed that the intervention was delivered as attended. Therefore, any estimates of intervention effect will not be influenced by poor implementation fidelity.

Background: Ankle sprains are very common injuries. Although recovery can occur within weeks, around one-third of patients have longer-term problems. Objectives: To develop and externally validate a prognostic model for identifying people at increased risk of poor outcome after an acute ankle sprain. Design: Development of a prognostic model in a clinical trial cohort data set and external validation in a prospective cohort study. Setting: Emergency departments (EDs) in the UK. Participants: Adults with an acute ankle sprain (within 7 days of injury). Sample size: There were 584 clinical trial participants in the development data set and 682 recruited for the external validation study. Predictors: Candidate predictor variables were chosen based on availability in the clinical data set, clinical consensus, face validity, a systematic review of the literature, data quality and plausibility of predictiveness of the outcomes. Main outcome measures: Models were developed to predict two composite outcomes representing poor outcome. Outcome 1 was the presence of at least one of the following symptoms at 9 months after injury: persistent pain, functional difficulty or lack of confidence. Outcome 2 included the same symptoms as outcome 1, with the addition of recurrence of injury. Rates of poor outcome in the external data set were lower than in the development data set, 7% versus 20% for outcome 1 and 16% versus 24% for outcome 2. Analysis: Multiple imputation was used to handle missing data. Logistic regression models, together with multivariable fractional polynomials, were used to select variables and identify transformations of continuous predictors that best predicted the outcome based on a nominal alpha of 0.157, chosen to minimise overfitting. Predictive accuracy was evaluated by assessing model discrimination (c-statistic) and calibration (flexible calibration plot). Results: (1) Performance of the prognostic models in development data set – the combined c-statistic for the outcome 1 model across the 50 imputed data sets was 0.74 [95% confidence interval (CI) 0.70 to 0.79], with good model calibration across the imputed data sets. The combined c-statistic for the outcome 2 model across the 50 imputed data sets was 0.70 (95% CI 0.65 to 0.74), with good model calibration across the imputed data sets. Updating these models, which used baseline data collected at the ED, with an additional variable at 4 weeks post injury (pain when bearing weight on the ankle) improved the discriminatory ability (c-statistic 0.77, 95% CI 0.73 to 0.82, for outcome 1 and 0.75, 95% CI 0.71 to 0.80, for outcome 2) and calibration of both models. (2) Performance of the models in the external data set – the combined c-statistic for the outcome 1 model across the 50 imputed data sets was 0.73 (95% CI 0.66 to 0.79), with a calibration plot intercept of –0.91 (95% CI –0.98 to 0.44) and slope of 1.13 (95% CI 0.76 to 1.50). The combined c-statistic for the outcome 2 model across the 50 imputed data sets was 0.63 (95% CI 0.58 to 0.69), with a calibration plot intercept of –0.25 (95% CI –0.27 to 0.11) and slope of 1.03 (95% CI 0.65 to 1.42). The updated models with the additional pain variable at 4 weeks had improved discriminatory ability over the baseline models but not better calibration. Conclusions: The SPRAINED (Synthesising a clinical Prognostic Rule for Ankle Injuries in the Emergency Department) prognostic models performed reasonably well, and showed benefit compared with not using any model; therefore, the models may assist clinical decision-making when managing and advising ankle sprain patients in the ED setting. The models use predictors that are simple to obtain. Limitations: The data used were from a randomised controlled trial and so were not originally intended to fulfil the aim of developing prognostic models. However, the data set was the best available, including data on the symptoms and clinical events of interest. Future work: Further model refinement, including recalibration or identifying additional predictors, may be required. The effect of implementing and using either model in clinical practice, in terms of acceptability and uptake by clinicians and on patient outcomes, should be investigated. Trial registration: Current Controlled Trials ISRCTN12726986. 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. 22, No. 64. See the NIHR Journals Library website for further project information. Funding was also recieved from the NIHR Collaboration for Leadership in Applied Health Research, Care Oxford at Oxford Health NHS Foundation Trust, NIHR Biomedical Research Centre, Oxford, and the NIHR Fellowship programme.

Background: Pulmonary embolism (PE) is a leading cause of death in pregnancy and post partum, but the symptoms of PE are common in normal pregnancy. Simple diagnostic tests are needed to select women for diagnostic imaging. Objective: To estimate the accuracy, effectiveness and cost-effectiveness of clinical features, decision rules and biomarkers for selecting pregnant or postpartum women with a suspected PE for imaging. Design: An expert consensus study to develop new clinical decision rules, a case–control study of women with a diagnosed PE or a suspected PE, a biomarker study of women with a suspected PE or diagnosed deep-vein thrombosis (DVT) and decision-analysis modelling. Setting: Emergency departments and consultant-led maternity units. Participants: Pregnant/postpartum women with a diagnosed PE from any hospital reporting to the UK Obstetric Surveillance System research platform and pregnant/postpartum women with a suspected PE or diagnosed DVT at 11 prospectively recruiting sites. Interventions: Clinical features, decision rules and biomarkers. Main outcome measures: Sensitivity, specificity, area under receiver operating characteristic (AUROC) curve, quality-adjusted life-years (QALYs) and health-care costs. Results: The primary analysis involved 181 women with PE and 259 women without PE in the case–control study and 18 women with DVT, 18 with PE and 247 women without either in the biomarker study. Most clinical features showed no association with PE. The AUROC curves for the clinical decision rules were as follows: primary consensus, 0.626; sensitive consensus, 0.620; specific consensus, 0.589; PE rule-out criteria, 0.621; simplified Geneva score, 0.579; Wells’s PE criteria (permissive), 0.577; and Wells’s PE criteria (strict), 0.732. The sensitivities and specificities of the D-dimer measurement were 88.4% and 8.8%, respectively, using a standard threshold, and 69.8% and 32.8%, respectively, using a pregnancy-specific threshold. Previous venous thromboembolism, long-haul travel, multiple pregnancy, oxygen saturation, recent surgery, temperature and PE-related chest radiograph abnormality were predictors of PE on multivariable analysis. We were unable to derive a rule through multivariable analysis or recursive partitioning with adequate accuracy. The AUROC curves for the biomarkers were as follows: activated partial thromboplastin time – 0.669, B-type natriuretic peptide – 0.549, C-reactive protein – 0.542, Clauss fibrinogen – 0.589, enzyme-linked immunosorbent assay D-dimer – 0.668, Innovance D-dimer (Siemens Healthcare Diagnostics Products GmbH, distributed by Sysmex UK Ltd, Milton Keynes, UK) – 0.651, mid-regional pro-atrial natriuretic peptide (MRproANP) – 0.524, prothrombin fragment 1 + 2 – 0.562, plasmin-antiplasmin – 0.639, Prothombin time – 0.613, thrombin generation lag time – 0.702, thrombin generation endogenous potential – 0.559, thrombin generation peak – 0.596, thrombin generation time to peak – 0.655, tissue factor – 0.531 and troponin – 0.597. The repeat analysis excluding women who had received anticoagulation was limited by the small number of women with PE (n = 4). The health economic analysis showed that a strategy of scanning all women with a suspected PE accrued more QALYs and incurred fewer costs than any selective strategy based on a clinical decision rule and was therefore the dominant strategy. Limitations: The findings apply specifically to the diagnostic assessment of women with a suspected PE in secondary care. Conclusions: Clinical features, decision rules and biomarkers do not accurately, effectively or cost-effectively select pregnant or postpartum women with a suspected PE for diagnostic imaging. Future work: New diagnostic technologies need to be developed to detect PE in pregnancy. Trial registration: Current Controlled Trials ISRCTN21245595. Funding details: 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. 22, No. 47. See the NIHR Journals Library website for further project information.

Background: Reconfiguration of trauma services, with direct transport of traumatic brain injury (TBI) patients to neuroscience centres (NCs), bypassing non-specialist acute hospitals (NSAHs), could potentially improve outcomes. However, delays in stabilisation of airway, breathing and circulation (ABC) and the difficulties in reliably identifying TBI at scene may make this practice deleterious compared with selective secondary transfer from nearest NSAH to NC. National Institute for Health and Care Excellence guidance and systematic reviews suggested equipoise and poor-quality evidence – with regard to ‘early neurosurgery’ in this cohort – which we sought to address. Methods: Pilot cluster randomised controlled trial of bypass to NC conducted in two ambulance services with the ambulance station (n = 74) as unit of cluster [Lancashire/Cumbria in the North West Ambulance Service (NWAS) and the North East Ambulance Service (NEAS)]. Adult patients with signs of isolated TBI [Glasgow Coma Scale (GCS) score of 0.05) in the 273 (159/113) patients with data available. There were no apparent differences in staff and patient preferences for either pathway, with satisfaction high with both. Very low responses to invitations to consent for follow-up in the large number of mild head injury-enrolled patients meant that only 20% of patients had 6-month outcomes. The trial-based economic evaluation could not focus on early neurosurgery because of these low numbers but instead investigated the comparative cost-effectiveness of bypass compared with selective secondary transfer for eligible patients at the scene of injury. Conclusions: Current NHS England practice of bypassing patients with suspected TBI to neuroscience centres gives overtriage ratios of 13 : 1 for neurosurgery and 4 : 1 for TBI. This important finding makes studying the impact of bypass to facilitate early neurosurgery not plausible using this study design. Future research should explore an efficient comparative effectiveness design for evaluating ‘early neurosurgery through bypass’ and address the challenge of reliable TBI diagnosis at the scene of injury. Trial registration: Current Controlled Trials ISRCTN68087745. 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. 20, No. 1. See the NIHR Journals Library website for further project information.

Background: Non-invasive ventilation (NIV), in the form of continuous positive airway pressure (CPAP) or bilevel inspiratory positive airway pressure (BiPAP), is used in hospital to treat patients with acute respiratory failure. Pre-hospital NIV may be more effective than in-hospital NIV but requires additional ambulance service resources. Objectives: We aimed to determine the clinical effectiveness and cost-effectiveness of pre-hospital NIV compared with usual care for adults presenting to the emergency services with acute respiratory failure and to identify priorities for future research. Data sources: Fourteen electronic databases and research registers (including MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, and Cumulative Index to Nursing and Allied Health Literature) were searched from inception to August 2013, supplemented by hand-searching reference lists and contacting experts in the field. Review methods: We included all randomised or quasi-randomised controlled trials of pre-hospital NIV in patients with acute respiratory failure. Methodological quality was assessed according to established criteria. An aggregate data network meta-analysis (NMA) of mortality and intubation was used to jointly estimate intervention effects relative to usual care. A NMA, using individual patient-level data (IPD) and aggregate data where IPD were not available, was carried out to assess whether or not covariates were treatment effect modifiers. A de novo economic model was developed to explore the costs and health outcomes when pre-hospital NIV (specifically CPAP provided by paramedics) and standard care (in-hospital NIV) were applied to a hypothetical cohort of patients with acute respiratory failure. Results: The literature searches identified 2284 citations. Of the 10 studies that met the inclusion criteria, eight were randomised controlled trials and two were quasi-randomised trials (six CPAP; four BiPAP; sample sizes 23–207 participants). IPD were available from seven trials (650 patients). The aggregate data NMA suggested that CPAP was the most effective treatment in terms of mortality (probability = 0.989) and intubation rate (probability = 0.639), and reduced both mortality [odds ratio (OR) 0.41, 95% credible interval (CrI) 0.20 to 0.77] and intubation rate (OR 0.32, 95% CrI 0.17 to 0.62) compared with standard care. The effect of BiPAP on mortality (OR 1.94, 95% CrI 0.65 to 6.14) and intubation rate (OR 0.40, 95% CrI 0.14 to 1.16) compared with standard care was uncertain. The combined IPD and aggregate data NMA suggested that sex was a statistically significant treatment effect modifier for mortality. The economic analysis showed that pre-hospital CPAP was more effective and more expensive than standard care, with an incremental cost-effectiveness ratio of £20,514 per quality-adjusted life-year (QALY) and a 49.5% probability of being cost-effective at the £20,000-per-QALY threshold. Variation in the incidence of eligible patients had a marked impact on cost-effectiveness and the expected value of sample information for a future randomised trial. Limitations: The meta-analysis lacked power to detect potentially important differences in outcome (particularly for BiPAP), the intervention was not always compared with the best alternative care (in-hospital NIV) in the primary studies and findings may not be generalisable. Conclusions: Pre-hospital CPAP can reduce mortality and intubation rates, but cost-effectiveness is uncertain and the value of further randomised evaluation depends on the incidence of suitable patients. A feasibility study is required to determine if a large pragmatic trial of clinical effectiveness and cost-effectiveness is appropriate. Study registration: The study is registered as PROSPERO CRD42012002933. Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Research needs to be undertaken rapidly in the event of an influenza pandemic to develop and evaluate triage methods for people presenting to the emergency department with suspected pandemic influenza. Objectives: We aimed to pilot a research study to be undertaken in a pandemic to identify the most accurate triage method for patients presenting to the emergency department with suspected pandemic influenza. The objectives of the pilot study were to develop a standardised clinical assessment form and secure online database; test both using data from patients with seasonal influenza; seek clinician views on the usability of the form; and obtain all regulatory approvals required for the main study. Design: Study methods were piloted using an observational cohort study and clinician views were sought using qualitative, semistructured interviews. Setting: Six acute hospital emergency departments. Participants: Patients attending the emergency department with suspected seasonal influenza during winter 2012–13 and clinicians working in the emergency departments. Main outcome measures: Adverse events up to 30 days were identified, but analysis of the pilot data was limited to descriptive reporting of patient flow, data completeness and patient characteristics. Results: Some 165 patients were identified, of whom 10 withdrew their data, leaving 155 (94%) for analysis. Follow-up data were available for 129 of 155 (83%), with 50 of 129 (39%) being admitted to hospital. Three cases (2%) were recorded as having suffered an adverse outcome. There appeared to be variation between the hospitals, allowing for small numbers. Three of the hospitals identified 150 of 165 (91%) of the patients, and all 10 withdrawing patients were at the same hospital. The proportion with missing follow-up data varied from 8% to 31%, and the proportion admitted varied from 4% to 85% across the three hospitals with meaningful numbers of cases. All of the deaths were at one hospital. There was less variation between hospitals in rates of missing data, and for most key variables missing rates were between 5% and 30%. Higher missing rates were recorded for blood pressure (39%), inspired oxygen (43%), capillary refill (36%) and Glasgow Coma Scale score (43%). Chest radiography was performed in 51 of 118 cases, and electrocardiography in 40 of 111 cases with details recorded. Blood test results were available for 32 of 155 cases. The qualitative interviews revealed generally positive views towards the standardised assessment form. Concerns about lack of space for free text were raised but counterbalanced by appreciation that it fitted on to one A4 page. A number of amendments were suggested but only three of these were suggested by more than one participant, and no suggestions were made by more than two participants. Conclusions: A standardised assessment form is acceptable to clinicians and could be used to collect research data in an influenza pandemic, but analysis may be limited by missing data. Future work: An observational cohort study to identify the most accurate triage method for predicting severe illness in emergency department attendees with suspected pandemic influenza is set up and ready to activate if, or when, a pandemic occurs. Trial registration: Current Controlled Trials ISRCTN56149622. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 3. See the NIHR Journals Library website for further project information.

Background: Recent increases in emergency admission rates have caused concern. Some emergency admissions may be avoidable if services in the emergency and urgent care system are available and accessible. A set of 14 conditions, likely to be rich in avoidable emergency admissions, was identified by expert consensus. Objective: We aimed to understand variation in avoidable emergency admissions between different emergency and urgent care systems in England. Methods: The design was a sequential mixed-methods study in three phases. In phase 1 we calculated an age- and sex-adjusted avoidable admission rate for 2008–11. We located routine data on characteristics of emergency and urgent care systems and used linear regression to explain variation in avoidable admissions rates in 150 systems. In phase 2 we undertook in-depth case studies in six systems to identify further factors. A key part of these case studies was interviews with commissioners, service providers and patient representatives, totalling 82 interviews. In phase 3 we returned to the linear regression to test further factors identified in the case studies. Results: The 14 conditions accounted for 3,273,395 admissions in 2008–11 (22% of all emergency admissions). The mean age- and sex-adjusted admission rate was 2258 per year per 100,000 population, with a 3.4-fold variation between systems (1268–4359). Characteristics of the population explained the majority of variation: deprivation explained 72% of variation, with urban/rural status explaining 3% more. Systems serving populations with high levels of deprivation and in urban areas had high rates of potentially avoidable admissions. Interviewees described the complexity of deprivation, representing high levels of morbidity, low awareness of alternative services to emergency departments and high expressed need for immediate access to urgent care. Factors related to emergency departments (EDs), hospitals, emergency ambulance services and general practice explained a further 10% of variation in avoidable admissions. Systems with high, potentially avoidable, admission rates had high rates of acute beds (suggesting supply-induced demand), high rates of attendance at EDs (which have been associated with poor perceived access to general practice), high rates of conversion from ED attendances to admissions, and low rates of non-transport to emergency departments by emergency ambulances. The six case studies revealed further possible explanations of variation: there was variation in how hospitals coded admissions; some systems focused proactively on admission avoidance whereas others were more interested in hospital discharge, for example use of multidisciplinary teams based at acute trusts; there were different levels of integration between different services such as health and social care, and acute and community trusts; and some systems faced more challenging problems around geographical boundaries operating for different services in the system. Interviewees often described admission as the easy or safe option. Conclusions: Deprivation explained most of the variation in avoidable admission rates. Research is needed to understand the complex relationship between deprivation and avoidable admission, and to develop interventions tailored to avoid admissions from deprived communities. Standardisation of coding of admissions would reduce variation. Funding: The National Institute for Health Research Health Service and Research Delivery programme.

Background: Magnesium sulphate, administered by the intravenous (i.v.) or inhaled (nebulised) route, has been proposed as a treatment for adults with acute severe asthma. Existing trials show mixed results and uncertain evidence of benefit. Objectives: We aimed to determine whether i.v. or nebulised magnesium sulphate improves symptoms of breathlessness and reduces the need for hospital admission in adults with acute severe asthma. Design: Multicentre, double-blind, placebo-controlled, three-arm, randomised trial. Setting: The emergency departments of 34 acute hospitals in the UK. Participants: We recruited 1109 adults (age > 16 years) with acute severe asthma [peak expiratory flow rate (PEFR) 25 breaths per minute, heart rate > 110 beats per minute or inability to complete sentences in one breath]. Patients with life-threatening features or a contraindication to either nebulised or intravenous magnesium sulphate were excluded. Interventions: Participants were randomly allocated to i.v. magnesium sulphate (2 g over 20 minutes) or nebulised magnesium sulphate (3 × 500 mg over 1 hour) or standard therapy alone. Main outcome measures: The primary outcome was the proportion of patients admitted to hospital (either after emergency department treatment or at any time over the subsequent 7 days) and breathlessness measured on a 100-mm visual analogue scale (VAS) over 2 hours after initiation of treatment. Results: We randomised 406 patients to i.v. magnesium sulphate, 339 to nebulised magnesium sulphate and 364 to placebo. Hospital admission was recorded for 394, 332 and 358 patients, respectively, and VAS breathlessness for 357, 296 and 323 patients respectively. Mean age was 36.1 years and 763 out of 1084 (70%) patients were female. Intravenous magnesium sulphate was associated with an odds ratio (OR) of 0.73 [95% confidence interval (CI) 0.51 to 1.04; p = 0.083] for hospital admission, an improvement in VAS breathlessness that was 2.6 mm (95% CI –1.6 to 6.8 mm; p = 0.231) greater than that associated with placebo and an improvement in PEFR that was 2.4 l/minute (95% CI –8.8 to 13.6 l/minute; p = 0.680) greater than that associated with placebo. Nebulised magnesium sulphate was associated with an OR of 0.96 (95% CI 0.65 to 1.40; p = 0.819) for hospital admission, an improvement in VAS breathlessness that was 2.6 mm (95% CI –1.8 mm to 7.0 mm; p = 0.253) less than that associated with placebo and an improvement in PEFR that was 2.6 l/minute (95% CI –9.2 to 14.5 l/minute; p = 0.644) less than that associated with placebo. There were no significant differences between i.v. or nebulised magnesium sulphate and placebo for any other outcomes. The number (%) of patients reporting any side effect was 61 (15.5%) in the i.v. group, 52 (15.7%) in the nebuliser group and 36 (10.1%) in the placebo group. The ORs for suffering any side effect were 1.68 (95% CI 1.07 to 2.63; p = 0.025) for i.v. compared with placebo and 1.67 (95% CI 1.05 to 2.66; p = 0.031) for nebuliser compared with placebo. Conclusions: We were unable to demonstrate a clinically worthwhile benefit from magnesium sulphate in acute severe asthma. There was some weak evidence of an effect of i.v. magnesium sulphate on hospital admission, but no evidence of an effect on VAS breathlessness or PEFR compared with placebo. We found no evidence that nebulised magnesium sulphate was more effective than placebo. Trial registration: Current Controlled Trials ISRCTN04417063. Source of funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 22. See the NIHR Journals Library programme website for further project information.