Background:The PROTECTeD study sought to develop an evidence-based termination of resuscitation guideline for use within United Kingdom ambulance services. Methods:This mixed-methods study comprised several work packages: Work package 1 - diagnostic test accuracy meta-analysis of termination of resuscitation rules Work package 2 - modelling performance of termination of resuscitation rules using data from the Out of Hospital Cardiac Arrest Outcomes registry Work package 3 - review of ambulance service practices Work package 4 - qualitative interviews with ambulance clinicians, emergency department clinicians and relatives of non-survivors Work package 5 - stakeholder consensus conference to develop a new termination of resuscitation guideline. Results:We described the performance of 42 different termination of resuscitation rules. Our meta-analysis suggests the best performing termination of resuscitation rule is the Universal termination of resuscitation. We modelled the performance of 29 termination of resuscitation rules and found that none would be suitable for implementation within a United Kingdom context. We identified significant variation in how the termination of resuscitation guideline was implemented across the United Kingdom (UK) ambulance services. Ambulance clinicians experience conflict between what the guideline permits them to do and being able to act in the patient's best interest. They felt obliged to follow the guideline. Most emergency department staff believed that paramedics should be empowered to stop resuscitation where appropriate. However, some felt that more senior emergency department clinicians should make these decisions. Relatives needed to be informed about the resuscitation attempt and must feel confident that every effort had been made to save their relative. They also believed that they were able to provide useful information to inform paramedic decision-making. We drafted a new termination of resuscitation guideline in conjunction with clinical experts and multiple stakeholders at a consensus conference. We employed nominal group techniques to determine content and formulate treatment recommendations. Discussion:Termination of resuscitation decisions are complex, requiring consideration of several important aspects, including what is in the patient's best interest. Our work suggests that the current ambulance guideline may restrict the paramedics ability to act in the patient's best interest, increasing the potential for moral injury. Conclusion:Paramedic decision-making is informed by both clinical and best interest considerations. Relatives are confident that paramedics do everything possible to save their loved one, and they are able to provide paramedics with information to guide decision-making. We developed a new evidence-based termination of resuscitation guideline, employing nominal group techniques, in collaboration with multiple stakeholders. Limitations:The evidence comprises observational studies that must be interpreted with caution. We captured the views of multiple stakeholders and patients with personal experience of cardiac arrest. Their insights may not be representative of the wider population who have not had the same experience. Future work:Future research should encompass alternative predictors of poor outcome (e.g. clinical frailty) as well as technology (e.g. ultrasound) to enhance decision-making. Better understanding of how cardiac arrest transport decisions impact system performance and crew safety would be helpful. Little is known about paramedic decision-making in relation to unfavourable neurological outcome rather than fatal outcome. Paramedics may benefit from a decision-making framework. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme as award number 17/99/34.

Introduction: Ambulance services in England attempted resuscitation in over 34,400 cases in 2022. Of these, 58% had the resuscitation attempt terminated at the scene and only 7.8% survived to hospital discharge. The decision to stop resuscitation is informed by a national guideline that is over 20 years old. This study describes the development of a revised termination of resuscitation (TOR) guideline. Methods: This was a mixed-methods study comprising a diagnostic test accuracy meta-analysis of TOR rules, modelling of multiple TOR rules using data from the Out-of-Hospital Cardiac Arrest Outcomes registry, a survey of ambulance services including a review of national policy documents, qualitative interviews with ambulance and emergency department (ED) clinicians, plus interviews with relatives of patients who did not survive a pre-hospital resuscitation attempt. These work packages informed a national consensus meeting with a wide range of stakeholders, employing nominal group techniques, to draft a revised TOR guideline. Results: The systematic review identified very low-certainty evidence from 43 studies, indicating that TOR rules are unlikely to be suitable for implementation in the UK. When we modelled the performance of TOR rules, the three best performing were the Marsden, KOCARC 1 and GOTO1 TOR rules. We identified considerable variation in practice across UK ambulance services; however, there was consistency across services with respect to perceived risks. Paramedics experienced tension when they felt that guidelines restricted them from acting in the patient’s best interests. ED staff felt that paramedics should be empowered to stop resuscitation in some cases. Relatives felt that paramedics did a good job and that they had information that was useful for paramedics. Multiple stakeholders participated in a consensus conference to develop a revised TOR guideline. Conclusion: We iteratively derived updated TOR and verification of death guidelines.

Background:Ambulance services treat over 32,000 patients sustaining an out-of-hospital cardiac arrest annually, receiving over 90,000 calls. The definitive treatment for out-of-hospital cardiac arrest is defibrillation. Prompt treatment with an automated external defibrillator can improve survival significantly. However, their location in the community limits opportunity for their use. There is a requirement to identify the optimal location for an automated external defibrillator to improve out-of-hospital cardiac arrest coverage, to improve the chances of survival. Methods:This was a secondary analysis of data collected by the Out-of-Hospital Cardiac Arrest Outcomes registry on historical out-of-hospital cardiac arrests, data held on the location of automated external defibrillators registered with ambulance services, and locations of points of interest. Walking distance was calculated between out-of-hospital cardiac arrests, registered automated external defibrillators and points of interest designated as potential sites for an automated external defibrillator. An out-of-hospital cardiac arrest was deemed to be covered if it occurred within 500 m of a registered automated external defibrillator or points of interest. For the optimisation analysis, mathematical models focused on the maximal covering location problem were adapted. A de novo decision-analytic model was developed for the cost-effectiveness analysis and used as a vehicle for assessing the costs and benefits (in terms of quality-adjusted life-years) of deployment strategies. A meeting of stakeholders was held to discuss and review the results of the study. Results:Historical out-of-hospital cardiac arrests occurred in more deprived areas and automated external defibrillators were placed in more affluent areas. The median out-of-hospital cardiac arrest - automated external defibrillator distance was 638 m and 38.9% of out-of-hospital cardiac arrests occurred within 500 m of an automated external defibrillator. If an automated external defibrillator was placed in all points of interests, the proportion of out-of-hospital cardiac arrests covered varied greatly. The greatest coverage was achieved with cash machines. Coverage loss, assuming an automated external defibrillator was not available outside working hours, varied between points of interest and was greatest for schools. Dividing the country up into 1 km2 grids and placing an automated external defibrillator in the centre increased coverage significantly to 78.8%. The optimisation model showed that if automated external defibrillators were placed in each points-of-interest location out-of-hospital cardiac arrest coverage levels would improve above the current situation significantly, but it would not reach that of optimisation-based placement (based on grids). The coverage efficiency provided by the optimised grid points was unmatched by any points of interest in any region. An economic evaluation determined that all alternative placements were associated with higher quality-adjusted life-years and costs compared to current placement, resulting in incremental cost-effectiveness ratios over £30,000 per additional quality-adjusted life-year. The most appealing strategy was automated external defibrillator placement in halls and community centres, resulting in an additional 0.007 quality-adjusted life-year (non-parametric 95% confidence interval 0.004 to 0.011), an additional expected cost of £223 (non-parametric 95% confidence interval £148 to £330) and an incremental cost-effectiveness ratio of £32,418 per quality-adjusted life-year. The stakeholder meeting agreed that the current distribution of registered publicly accessible automated external defibrillators was suboptimal, and that there was a disparity in their location in respect of deprivation and other health inequalities. Conclusions:We have developed a data-driven framework to support decisions about public-access automated external defibrillator locations, using optimisation and statistical models. Optimising automated external defibrillator locations can result in substantial improvement in coverage. Comparison between placement based on points of interest and current placement showed that the former improves coverage but is associated with higher costs and incremental cost-effectiveness ratio values over £30,000 per additional quality-adjusted life-year. Study registration:This study is registered as researchregistry5121. 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: NIHR127368) and is published in full in Health and Social Care Delivery Research; Vol. 13, No. 5. See the NIHR Funding and Awards website for further award information.

Aims: The PARAMEDIC-3 trial evaluates the clinical and cost-effectiveness of an intraosseous first strategy, compared with an intravenous first strategy, for drug administration in adults who have sustained an out-of-hospital cardiac arrest. Methods: PARAMEDIC-3 is a pragmatic, allocation concealed, open-label, multi-centre, superiority randomised controlled trial. It will recruit 15,000 patients across English and Welsh ambulance services. Adults who have sustained an out-of-hospital cardiac arrest are individually randomised to an intraosseous access first strategy or intravenous access first strategy in a 1:1 ratio through an opaque, sealed envelope system. The randomised allocation determines the route used for the first two attempts at vascular access. Participants are initially enrolled under a deferred consent model.The primary clinical-effectiveness outcome is survival at 30-days. Secondary outcomes include return of spontaneous circulation, neurological functional outcome, and health-related quality of life. Participants are followed-up to six-months following cardiac arrest. The primary health economic outcome is incremental cost per quality-adjusted life year gained. Conclusion: The PARAMEDIC-3 trial will provide key information on the clinical and cost-effectiveness of drug route in out-of-hospital cardiac arrest.Trial registration: ISRCTN14223494, registered 16/08/2021, prospectively registered.

BACKGROUND:Adrenaline has been used as a treatment for cardiac arrest for many years, despite uncertainty about its effects on long-term outcomes and concerns that it may cause worse neurological outcomes. OBJECTIVES:The objectives were to evaluate the effects of adrenaline on survival and neurological outcomes, and to assess the cost-effectiveness of adrenaline use. DESIGN:This was a pragmatic, randomised, allocation-concealed, placebo-controlled, parallel-group superiority trial and economic evaluation. Costs are expressed in Great British pounds and reported in 2016/17 prices. SETTING:This trial was set in five NHS ambulance services in England and Wales. PARTICIPANTS:Adults treated for an out-of-hospital cardiac arrest were included. Patients were ineligible if they were pregnant, if they were aged < 16 years, if the cardiac arrest had been caused by anaphylaxis or life-threatening asthma, or if adrenaline had already been given. INTERVENTIONS:Participants were randomised to either adrenaline (1 mg) or placebo in a 1 : 1 allocation ratio by the opening of allocation-concealed treatment packs. MAIN OUTCOME MEASURES:The primary outcome was survival to 30 days. The secondary outcomes were survival to hospital admission, survival to hospital discharge, survival at 3, 6 and 12 months, neurological outcomes and health-related quality of life through to 6 months. The economic evaluation assessed the incremental cost per quality-adjusted life-year gained from the perspective of the NHS and Personal Social Services. Participants, clinical teams and those assessing patient outcomes were masked to the treatment allocation. RESULTS:From December 2014 to October 2017, 8014 participants were assigned to the adrenaline (n = 4015) or to the placebo (n = 3999) arm. At 30 days, 130 out of 4012 participants (3.2%) in the adrenaline arm and 94 out of 3995 (2.4%) in the placebo arm were alive (adjusted odds ratio for survival 1.47, 95% confidence interval 1.09 to 1.97). For secondary outcomes, survival to hospital admission was higher for those receiving adrenaline than for those receiving placebo (23.6% vs. 8.0%; adjusted odds ratio 3.83, 95% confidence interval 3.30 to 4.43). The rate of favourable neurological outcome at hospital discharge was not significantly different between the arms (2.2% vs. 1.9%; adjusted odds ratio 1.19, 95% confidence interval 0.85 to 1.68). The pattern of improved survival but no significant improvement in neurological outcomes continued through to 6 months. By 12 months, survival in the adrenaline arm was 2.7%, compared with 2.0% in the placebo arm (adjusted odds ratio 1.38, 95% confidence interval 1.00 to 1.92). An adjusted subgroup analysis did not identify significant interactions. The incremental cost-effectiveness ratio for adrenaline was estimated at £1,693,003 per quality-adjusted life-year gained over the first 6 months after the cardiac arrest event and £81,070 per quality-adjusted life-year gained over the lifetime of survivors. Additional economic analyses estimated incremental cost-effectiveness ratios for adrenaline at £982,880 per percentage point increase in overall survival and £377,232 per percentage point increase in neurological outcomes over the first 6 months after the cardiac arrest. LIMITATIONS:The estimate for survival with a favourable neurological outcome is imprecise because of the small numbers of patients surviving with a good outcome. CONCLUSIONS:Adrenaline improved long-term survival, but there was no evidence that it significantly improved neurological outcomes. The incremental cost-effectiveness ratio per quality-adjusted life-year exceeds the threshold of £20,000-30,000 per quality-adjusted life-year usually supported by the NHS. FUTURE WORK:Further research is required to better understand patients' preferences in relation to survival and neurological outcomes after out-of-hospital cardiac arrest and to aid interpretation of the trial findings from a patient and public perspective. TRIAL REGISTRATION:Current Controlled Trials ISRCTN73485024 and EudraCT 2014-000792-11. 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. 25. See the NIHR Journals Library website for further project information.

Background We recently reported early outcomes in patients enrolled in a randomised trial of adrenaline in out-of-hospital cardiac arrest: the PARAMEDIC-2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest) trial. The purpose of the present paper is to report long-term survival, quality of life, functional and cognitive outcomes in cardiac arrest patients who survived. Methods PARAMEDIC-2 was a pragmatic, individually randomised, double blind, controlled trial and economic evaluation. Patients were randomised to either adrenaline or placebo. The 12-months survival post randomisation was checked. The 3- and 6-months outcomes included the modified Rankin Scale (0–3 defined as favourable neurological outcome), Two Simple Questions, the Mini Mental State Examination, the Informant Questionnaire on Cognitive Decline Evaluation for Cardiac Arrest, Hospital Anxiety and Depression Scale, the Post Traumatic Stress Disorder Checklist - Civilian Version and general health-related quality of life (HRQoL) assessed with both the Short-Form 12-item Health Survey and the EuroQoL EQ-5D-5L. Results 8,014 patients were randomised with confirmed trial drug administration. Adrenaline survivors had marginally better 12-months survival (adjusted odds ratio: 1.385, 95% confidence interval: [1.000, 1.917], p=0.050). There was no significant treatment difference in favourable neurological outcome at both follow-ups. Similarly, no significant difference was found in other outcomes. Moderate to large effect sizes are reported in both arms when survivors were compared to the UK general population regarding general HRQoL and physical health. Conclusions Adrenaline had a short to long-term effect on survival to 12-months post OHCA, compared to placebo, but more survivors in the adrenaline arm had poor functional, cognitive and HRQoL. A large proportion of the survivors experienced significant cognitive impairment and an important reduction in mental and physical wellbeing over the initial 6-months when compared to the general population.

Cardiac arrest effectiveness trials have traditionally reported outcomes that focus on survival. A lack of consistency in outcome reporting between trials limits the opportunities to pool results for meta-analysis. The COSCA initiative (Core Outcome Set for Cardiac Arrest), a partnership between patients, their partners, clinicians, research scientists, and the International Liaison Committee on Resuscitation, sought to develop a consensus core outcome set for cardiac arrest for effectiveness trials. Core outcome sets are primarily intended for large, randomized clinical effectiveness trials (sometimes referred to as pragmatic trials or phase III/IV trials ) rather than for pilot or efficacy studies. A systematic review of the literature combined with qualitative interviews among cardiac arrest survivors was used to generate a list of potential outcome domains. This list was prioritized through a Delphi process, which involved clinicians, patients, and their relatives/partners. An international advisory panel narrowed these down to 3 core domains by debate that led to consensus. The writing group refined recommendations for when these outcomes should be measured and further characterized relevant measurement tools. Consensus emerged that a core outcome set for reporting on effectiveness studies of cardiac arrest (COSCA) in adults should include survival, neurological function, and health-related quality of life. This should be reported as survival status and modified Rankin scale score at hospital discharge, at 30 days, or both. Health-related quality of life should be measured with ≥1 tools from Health Utilities Index version 3, Short-Form 36-Item Health Survey, and EuroQol 5D-5L at 90 days and at periodic intervals up to 1 year after cardiac arrest, if resources allow.

Please cite this article as: Couper Keith, Kimani Peter K, Gale Chris P, Quinn Tom, Squire Iain B, Marshall Andrea, Black John JM, Cooke Matthew W, Ewings Bob, Long John, Perkins Gavin D.Patient, health service factors and variation in mortality following resuscitated out-of-hospital cardiac arrest in acute coronary syndrome: analysis of the Myocardial Ischaemia National Audit Project.Resuscitation https://doi.org/10.1016/j.resuscitation.2018.01.011

Background Each year, approximately 30,000 people have an out-of-hospital cardiac arrest (OHCA) that is treated by UK ambulance services. Across all cases of OHCA, survival to hospital discharge is less than 10%. Acute coronary syndrome (ACS) is a common cause of OHCA. Objectives To explore factors that influence survival in patients who initially survive an OHCA attributable to ACS. Data source Data collected by the Myocardial Ischaemia National Audit Project (MINAP) between 2003 and 2015. Participants Adult patients who had a first OHCA attributable to ACS and who were successfully resuscitated and admitted to hospital. Main outcome measures Hospital mortality, neurological outcome at hospital discharge, and time to all-cause mortality. Methods We undertook a cohort study using data from the MINAP registry. MINAP is a national audit that collects data on patients admitted to English, Welsh and Northern Irish hospitals with myocardial ischaemia. From the data set, we identified patients who had an OHCA. We used imputation to address data missingness across the data set. We analysed data using multilevel logistic regression to identify modifiable and non-modifiable factors that affect outcome. Results Between 2003 and 2015, 1,127,140 patient cases were included in the MINAP data set. Of these, 17,604 OHCA cases met the study inclusion criteria. Overall hospital survival was 71.3%. Across hospitals with at least 60 cases, hospital survival ranged from 34% to 89% (median 71.4%, interquartile range 60.7–76.9%). Modelling, which adjusted for patient and treatment characteristics, could account for only 36.1% of this variability. For the primary outcome, the key modifiable factors associated with reduced mortality were reperfusion treatment [primary percutaneous coronary intervention (pPCI) or thrombolysis] and admission under a cardiologist. Admission to a high-volume cardiac arrest hospital did not influence survival. Sensitivity analyses showed that reperfusion was associated with reduced mortality among patients with a ST elevation myocardial infarction (STEMI), but there was no evidence of a reduction in mortality in patients who did not present with a STEMI. Limitations This was an observational study, such that unmeasured confounders may have influenced study findings. Differences in case identification processes at hospitals may contribute to an ascertainment bias. Conclusions In OHCA patients who have had a cardiac arrest attributable to ACS, there is evidence of variability in survival between hospitals, which cannot be fully explained by variables captured in the MINAP data set. Our findings provide some support for the current practice of transferring resuscitated patients with a STEMI to a hospital that can deliver pPCI. In contrast, it may be reasonable to transfer patients without a STEMI to the nearest appropriate hospital. Future work There is a need for clinical trials to examine the clinical effectiveness and cost-effectiveness of invasive reperfusion strategies in resuscitated OHCA patients of cardiac cause who have not had a STEMI. Funding The National Institute for Health Research Health Services and Delivery Research programme.

AIMS:To determine patient and health service factors associated with variation in hospital mortality among resuscitated cases of out-of-hospital cardiac arrest (OHCA) with acute coronary syndrome (ACS).METHODS:In this cohort study, we used the Myocardial Ischaemia National Audit Project database to study outcomes in patients hospitalised with resuscitated OHCA due to ACS between 2003 and 2015 in the United Kingdom. We analysed variation in inter-hospital mortality and used hierarchical multivariable regression models to examine the association between patient and health service factors with hospital mortality.RESULTS:We included 17604 patients across 239 hospitals. Overall hospital mortality was 28.7%. In 94 hospitals that contributed at least 60 cases, mortality by hospital ranged from 10.7% to 66.3% (median 28.6%, IQR 23.2% to 39.1%)). Patient and health service factors explained 36.1% of this variation. After adjustment for covariates, factors associated with higher hospital mortality included increasing serum glucose, ST-Elevation myocardial infarction (STEMI) diagnosis, and initial admission to a primary percutaneous coronary intervention (pPCI) capable hospital. Hospital OHCA volume was not associated with mortality. The key modifiable factor associated with lower mortality was early reperfusion therapy in STEMI patients.CONCLUSION:There was wide variation in inter-hospital mortality following resuscitated OHCA due to ACS that was only partially explained by patient and health service factors. Hospital OHCA volume and pPCI capability were not associated with lower mortality. Early reperfusion therapy was associated with lower mortality in STEMI patients.

BACKGROUND Concern about the use of epinephrine as a treatment for out-of-hospital cardiac arrest led the International Liaison Committee on Resuscitation to call for a placebocontrolled trial to determine whether the use of epinephrine is safe and effective in such patients. METHODS In a randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest in the United Kingdom, paramedics at five National Health Service ambulance services administered either parenteral epinephrine (4015 patients) or saline placebo (3999 patients), along with standard care. The primary outcome was the rate of survival at 30 days. Secondary outcomes included the rate of survival until hospital discharge with a favorable neurologic outcome, as indicated by a score of 3 or less on the modified Rankin scale (which ranges from 0 [no symptoms] to 6 [death]). RESULTS At 30 days, 130 patients (3.2%) in the epinephrine group and 94 (2.4%) in the placebo group were alive (unadjusted odds ratio for survival, 1.39; 95% confidence interval [CI], 1.06 to 1.82; P = 0.02). There was no evidence of a significant difference in the proportion of patients who survived until hospital discharge with a favorable neurologic outcome (87 of 4007 patients [2.2%] vs. 74 of 3994 patients [1.9%]; unadjusted odds ratio, 1.18; 95% CI, 0.86 to 1.61). At the time of hospital discharge, severe neurologic impairment (a score of 4 or 5 on the modified Rankin scale) had occurred in more of the survivors in the epinephrine group than in the placebo group (39 of 126 patients [31.0%] vs. 16 of 90 patients [17.8%]). CONCLUSIONS In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.

Despite its use since the 1960s, the safety or effectiveness of adrenaline as a treatment for cardiac arrest has never been comprehensively evaluated in a clinical trial. Although most studies have found that adrenaline increases the chance of return of spontaneous circulation for short periods, many studies found harmful effects on the brain and raise concern that adrenaline may reduce overall survival and/or good neurological outcome. The PARAMEDIC-2 trial seeks to determine if adrenaline is safe and effective in out-of-hospital cardiac arrest.This is a pragmatic, individually randomised, double blind, controlled trial with a parallel economic evaluation. Participants will be eligible if they are in cardiac arrest in the out-of-hospital environment and advanced life support is initiated. Exclusions are cardiac arrest as a result of anaphylaxis or life threatening asthma, and patient known or appearing to be under 16 or pregnant.8000 participants treated by 5 UK ambulance services will be randomised between December 2014 and August 2017 to adrenaline (intervention) or placebo (control) through opening pre-randomised drug packs. Clinical outcomes are survival to 30 days (primary outcome), hospital discharge, 3, 6 and 12 months, health related quality of life, and neurological and cognitive outcomes (secondary outcomes).Trial registration (ISRCTN73485024).