Adrenaline to improve survival in out-of-hospital cardiac arrest: the PARAMEDIC2 RCT.

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.

Cardiac arrest is a medical emergency that happens when the heart suddenly stops pumping effectively. When cardiac arrest happens, awareness is lost within seconds. If emergency treatment is not started quickly, the person will die. The first treatments of cardiac arrest involve pressing on the chest, giving rescue breaths and defibrillation (electric shocks applied to the heart). If these treatments do not work, ambulance paramedics use a drug called adrenaline to try to restart the heart. Although this treatment has been used for many years, some recent research suggests that it may cause more harm than good. In this research study, we compared the effects of giving adrenaline with the effects of not giving adrenaline to people who had a cardiac arrest in the community. The research showed that adrenaline was effective at restarting the heart, so more people survived long enough to be admitted to hospital. Thirty days later, 130 out of 4012 patients (3.2%) who received adrenaline and 94 out of 3995 (2.4%) who did not receive adrenaline were alive. However, adrenaline did not improve the number of patients who went home from hospital having made a good recovery and were able to care for themselves. The evidence suggests that adrenaline represents a poor use of NHS funds on cost-effectiveness grounds. In a community survey, 95% of people who responded thought that long-term survival with good brain function was more important than just being alive. Further research exploring the opinions of patients and the public will help to understand the results of this research for the NHS.

A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.

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 placebo-controlled 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. (Funded by the U.K. National Institute for Health Research and others; Current Controlled Trials number, ISRCTN73485024 .).

Bypassing nearest hospital for more distant neuroscience care in head-injured adults with suspected traumatic brain injury: findings of the head injury transportation straight to neurosurgery (HITS-NS) pilot cluster randomised trial.

OBJECTIVE: Reconfiguration of trauma services, with direct transport of patients with traumatic brain injury (TBI) to specialist neuroscience centres (SNCs)-bypassing non-specialist acute hospitals (NSAHs), could improve outcomes. However, delays in stabilisation of airway, breathing and circulation (ABC) may worsen outcomes when compared with selective secondary transfer from nearest NSAH to SNC. We conducted a pilot cluster randomised controlled trial to determine the feasibility and plausibility of bypassing suspected patients with TBI -directly into SNCs-producing a measurable effect. SETTING: Two English Ambulance Services. PARTICIPANTS: 74 clusters (ambulance stations) were randomised within pairs after matching for important characteristics. Clusters enrolled head-injured adults-injured nearest to an NSAH-with internationally accepted TBI risk factors and stable ABC. We excluded participants attended by Helicopter Emergency Medical Services or who were injured more than 1 hour by road from nearest SNC. INTERVENTIONS: Intervention cluster participants were transported directly to an SNC bypassing nearest NSAH; control cluster participants were transported to nearest NSAH with selective secondary transfer to SNC. OUTCOMES: Trial recruitment rate (target n=700 per annum) and percentage with TBI on CT scan (target 80%) were the primary feasibility outcomes. 30-day mortality, 6-month Extended Glasgow Outcome Scale and quality of life were secondary outcomes. RESULTS: 56 ambulance station clusters recruited 293 patients in 12 months. The trial arms were similar in terms of age, conscious level and injury severity. Less than 25% of recruited patients had TBI on CT (n=70) with 7% (n=20) requiring neurosurgery. Complete case analysis showed similar 30-day mortality in the two trial arms (control=8.8 (2.7-14.0)% vs intervention=9.4(2.3-14.0)%). CONCLUSION: Bypassing patients with suspected TBI to SNCs gives an overtriage (false positive) ratio of 13:1 for neurosurgical intervention and 4:1 for TBI. A measurable effect from a full trial of early neuroscience care following bypass is therefore unlikely. TRIAL REGISTRATION NUMBER: ISRCTN68087745.

Prehospital randomised assessment of a mechanical compression device in out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised trial and economic evaluation.

BACKGROUND: Mechanical chest compression devices may help to maintain high-quality cardiopulmonary resuscitation (CPR), but little evidence exists for their effectiveness. We evaluated whether or not the introduction of Lund University Cardiopulmonary Assistance System-2 (LUCAS-2; Jolife AB, Lund, Sweden) mechanical CPR into front-line emergency response vehicles would improve survival from out-of-hospital cardiac arrest (OHCA). OBJECTIVE: Evaluation of the LUCAS-2 device as a routine ambulance service treatment for OHCA. DESIGN: Pragmatic, cluster randomised trial including adults with non-traumatic OHCA. Ambulance dispatch staff and those collecting the primary outcome were blind to treatment allocation. Blinding of the ambulance staff who delivered the interventions and reported initial response to treatment was not possible. We also conducted a health economic evaluation and a systematic review of all trials of out-of-hospital mechanical chest compression. SETTING: Four UK ambulance services (West Midlands, North East England, Wales and South Central), comprising 91 urban and semiurban ambulance stations. Clusters were ambulance service vehicles, which were randomly assigned (approximately 1 : 2) to the LUCAS-2 device or manual CPR. PARTICIPANTS: Patients were included if they were in cardiac arrest in the out-of-hospital environment. Exclusions were patients with cardiac arrest as a result of trauma, with known or clinically apparent pregnancy, or aged < 18 years. INTERVENTIONS: Patients received LUCAS-2 mechanical chest compression or manual chest compressions according to the first trial vehicle to arrive on scene. MAIN OUTCOME MEASURES: Survival at 30 days following cardiac arrest; survival without significant neurological impairment [Cerebral Performance Category (CPC) score of 1 or 2]. RESULTS: We enrolled 4471 eligible patients (1652 assigned to the LUCAS-2 device and 2819 assigned to control) between 15 April 2010 and 10 June 2013. A total of 985 (60%) patients in the LUCAS-2 group received mechanical chest compression and 11 (< 1%) patients in the control group received LUCAS-2. In the intention-to-treat analysis, 30-day survival was similar in the LUCAS-2 (104/1652, 6.3%) and manual CPR groups [193/2819, 6.8%; adjusted odds ratio (OR) 0.86, 95% confidence interval (CI) 0.64 to 1.15]. Survival with a CPC score of 1 or 2 may have been worse in the LUCAS-2 group (adjusted OR 0.72, 95% CI 0.52 to 0.99). No serious adverse events were noted. The systematic review found no evidence of a survival advantage if mechanical chest compression was used. The health economic analysis showed that LUCAS-2 was dominated by manual chest compression. LIMITATIONS: There was substantial non-compliance in the LUCAS-2 arm. For 272 out of 1652 patients (16.5%), mechanical chest compression was not used for reasons that would not occur in clinical practice. We addressed this issue by using complier average causal effect analyses. We attempted to measure CPR quality during the resuscitation attempts of trial participants, but were unable to do so. CONCLUSIONS: There was no evidence of improvement in 30-day survival with LUCAS-2 compared with manual compressions. Our systematic review of recent randomised trials did not suggest that survival or survival without significant disability may be improved by the use of mechanical chest compression. FUTURE WORK: The use of mechanical chest compression for in-hospital cardiac arrest, and in specific circumstances (e.g. transport), has not yet been evaluated. TRIAI REGISTRATION: Current Controlled Trials ISRCTN08233942. 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. 21, No. 11. See the NIHR Journals Library website for further project information.

Pre-hospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug administration In Cardiac arrest (PARAMEDIC-2): Trial protocol.

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).

The Head Injury Transportation Straight to Neurosurgery (HITS-NS) randomised trial: a feasibility study.

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 < 13 in NWAS, GCS score of < 14 in NEAS] and stable ABC, injured nearest to a NSAH were transported either to that hospital (control clusters) or bypassed to the nearest NC (intervention clusters). PRIMARY OUTCOMES: recruitment rate, protocol compliance, selection bias as a result of non-compliance, accuracy of paramedic TBI identification (overtriage of study inclusion criteria) and pathway acceptability to patients, families and staff. 'Open-label' secondary outcomes: 30-day mortality, 6-month Extended Glasgow Outcome Scale (GOSE) and European Quality of Life-5 Dimensions. RESULTS: Overall, 56 clusters recruited 293 (169 intervention, 124 control) patients in 12 months, demonstrating cluster randomised pre-hospital trials as viable for heath service evaluations. Overall compliance was 62%, but 90% was achieved in the control arm and when face-to-face paramedic training was possible. Non-compliance appeared to be driven by proximity of the nearest hospital and perceptions of injury severity and so occurred more frequently in the intervention arm, in which the perceived time to the NC was greater and severity of injury was lower. Fewer than 25% of recruited patients had TBI on computed tomography scan (n = 70), with 7% (n = 20) requiring neurosurgery (craniotomy, craniectomy or intracranial pressure monitoring) but a further 18 requiring admission to an intensive care unit. An intention-to-treat analysis revealed the two trial arms to be equivalent in terms of age, GCS and severity of injury. No significant 30-day mortality differences were found (8.8% vs. 9.1/%; p > 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.

Mechanical versus manual chest compression for out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised controlled trial.

BACKGROUND: Mechanical chest compression devices have the potential to help maintain high-quality cardiopulmonary resuscitation (CPR), but despite their increasing use, little evidence exists for their effectiveness. We aimed to study whether the introduction of LUCAS-2 mechanical CPR into front-line emergency response vehicles would improve survival from out-of-hospital cardiac arrest. METHODS: The pre-hospital randomised assessment of a mechanical compression device in cardiac arrest (PARAMEDIC) trial was a pragmatic, cluster-randomised open-label trial including adults with non-traumatic, out-of-hospital cardiac arrest from four UK Ambulance Services (West Midlands, North East England, Wales, South Central). 91 urban and semi-urban ambulance stations were selected for participation. Clusters were ambulance service vehicles, which were randomly assigned (1:2) to LUCAS-2 or manual CPR. Patients received LUCAS-2 mechanical chest compression or manual chest compressions according to the first trial vehicle to arrive on scene. The primary outcome was survival at 30 days following cardiac arrest and was analysed by intention to treat. Ambulance dispatch staff and those collecting the primary outcome were masked to treatment allocation. Masking of the ambulance staff who delivered the interventions and reported initial response to treatment was not possible. The study is registered with Current Controlled Trials, number ISRCTN08233942. FINDINGS: We enrolled 4471 eligible patients (1652 assigned to the LUCAS-2 group, 2819 assigned to the control group) between April 15, 2010 and June 10, 2013. 985 (60%) patients in the LUCAS-2 group received mechanical chest compression, and 11 (<1%) patients in the control group received LUCAS-2. In the intention-to-treat analysis, 30 day survival was similar in the LUCAS-2 group (104 [6%] of 1652 patients) and in the manual CPR group (193 [7%] of 2819 patients; adjusted odds ratio [OR] 0·86, 95% CI 0·64-1·15). No serious adverse events were noted. Seven clinical adverse events were reported in the LUCAS-2 group (three patients with chest bruising, two with chest lacerations, and two with blood in mouth). 15 device incidents occurred during operational use. No adverse or serious adverse events were reported in the manual group. INTERPRETATION: We noted no evidence of improvement in 30 day survival with LUCAS-2 compared with manual compressions. On the basis of ours and other recent randomised trials, widespread adoption of mechanical CPR devices for routine use does not improve survival. FUNDING: National Institute for Health Research HTA - 07/37/69.

Trauma systems: the potential impact of a trauma divert policy on a regional ambulance service.

INTRODUCTION: Recent initiatives in the Care of the Trauma patient in the UK have led to the establishment of Major Trauma Centres (MTCs), supporting a Trauma Network. It is envisaged that any person suffering from major trauma will be taken directly to one of these centres, with an expectant increase in survivability and decrease in morbidity. This will have an impact on the Ambulance Service in terms of journey times, and the MTCs in terms of bed days. Whilst these are not 'new' patients to the NHS, they may require a redistribution of funds. Most of the modelling into the effects of this has been carried out in London, which may not be applicable to more rural areas. We therefore determined to gain data on how a similar policy would affect trauma services in our rural region. METHOD: A retrospective study of all trauma patients conveyed by a regional ambulance service. The London Trauma Divert Criteria were applied to the patient report forms, and the number of patients who may have transported directly (or by secondary transfer) to MTCs identified. RESULTS: We found that between 28 and 58 additional patients a month would be transferred. CONCLUSION: As this is more than 1 patient a day, there may be considerable strain on the MTCs and Ambulance Services. We believe service commissioners in rural areas need to consider the funding and organisational arrangements for major trauma in light of this.