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.

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.