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

Research output: Contribution to journalArticlepeer-review

Authors

  • Gavin D Perkins
  • Chen Ji
  • Felix Achana
  • John Jm Black
  • Karl Charlton
  • James Crawford
  • Adam de Paeztron
  • Charles Deakin
  • Mark Docherty
  • Judith Finn
  • Rachael T Fothergill
  • Imogen Gunson
  • Kyee Han
  • Susie Hennings
  • Jessica Horton
  • Kamran Khan
  • Sarah Lamb
  • John Long
  • Joshua Miller
  • Fionna Moore
  • Jerry Nolan
  • Lyndsey O'Shea
  • Stavros Petrou
  • Helen Pocock
  • Tom Quinn
  • Nigel Rees
  • Scott Regan
  • Andy Rosser
  • Charlotte Scomparin
  • Anne Slowther
  • Ranjit Lall

Colleges, School and Institutes

External organisations

  • North East Ambulance Service NHS Foundation Trust, Newcastle upon Tyne, NE15 8NY, UK.
  • West Midlands Ambulance Service University NHS Foundation Trust, Brierley Hill, West Midlands, DY5 1LX, UK.
  • Curtin University
  • London Ambulance Service NHS Trust, 8-20 Pocock Street, London, SE1 0BW, UK.
  • South East Coast Ambulance Service NHS Foundation Trust
  • Welsh Ambulance Service NHS Trust
  • The University of Warwick
  • University Hospitals Birmingham NHS Foundation Trust
  • University Hospital Southampton NHS Foundation Trust
  • South Central Ambulance Service NHS Foundation Trust
  • Kingston University and St George's, University of London

Abstract

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.

Details

Original languageEnglish
Pages (from-to)1-166
Number of pages166
JournalHealth Technology Assessment
Volume25
Issue number25
Publication statusPublished - 30 Apr 2021