Adrenaline to improve survival in out-of-hospital cardiac arrest: the PARAMEDIC2 RCT
Authors: Perkins Gavin D , Ji Chen , Achana Felix , Black John JM , Charlton Karl , Crawford James , de Paeztron Adam , Deakin Charles , Docherty Mark , Finn Judith , Fothergill Rachael T , Gates Simon , Gunson Imogen , Han Kyee , Hennings Susie , Horton Jessica , Khan Kamran , Lamb Sarah , Long John , Miller Joshua , Moore Fionna , Nolan Jerry , O’Shea Lyndsey , Petrou Stavros , Pocock Helen , Quinn Tom , Rees Nigel , Regan Scott , Rosser Andy , Scomparin Charlotte , Slowther Anne , Lall Ranjit 
Published: April 2021

BackgroundAdrenaline 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.ObjectivesThe objectives were to evaluate the effects of adrenaline on survival and neurological outcomes, and to assess the cost-effectiveness of adrenaline use.DesignThis 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.SettingThis trial was set in five NHS ambulance services in England and Wales.ParticipantsAdults 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.InterventionsParticipants 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 measuresThe 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.ResultsFrom 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.LimitationsThe estimate for survival with a favourable neurological outcome is imprecise because of the small numbers of patients surviving with a good outcome.ConclusionsAdrenaline 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 workFurther 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 registrationCurrent Controlled Trials ISRCTN73485024 and EudraCT 2014-000792-11.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 25, No. 25. See the NIHR Journals Library website for further project information.