Elsevier

Resuscitation

Volume 140, July 2019, Pages 55-63
Resuscitation

Clinical paper
The effects of adrenaline in out of hospital cardiac arrest with shockable and non-shockable rhythms: Findings from the PACA and PARAMEDIC-2 randomised controlled trials

https://doi.org/10.1016/j.resuscitation.2019.05.007Get rights and content

Abstract

Introduction

Previous research suggests there may be differences in the effects of adrenaline related to the initial cardiac arrest rhythm. The aim of this study was to assess the effect of adrenaline compared with placebo according to whether the initial cardiac arrest rhythm was shockable or non-shockable.

Methods

Return of spontaneous circulation (ROSC), survival and neurological outcomes according to the initial arrest rhythm were compared amongst patients enrolled in the PARAMEDIC-2 randomised, placebo controlled trial. The results of the PARAMEDIC-2 and PACA out of hospital cardiac arrest trials were combined and meta-analysed.

Results

The initial rhythm was known for 3929 (98.2%) in the placebo arm and 3919 (97.6%) in the adrenaline arm. The effect on the rate of ROSC of adrenaline relative to placebo was greater in patients with non-shockable cardiac rhythms (1002/3003 (33.4%) versus 222/3005 (7.4%), adjusted OR: 6.5, (95% CI 5.6–7.6)) compared with shockable rhythms 349/716 (48.7%) versus (208/702 (29.6%), adjusted OR: 2.3, 95%CI: 1.9–2.9)). The adjusted odds ratio for survival at discharge for non-shockable rhythms was 2.5 (1.3, 4.8) and 1.3 (0.9, 1.8) for shockable rhythms (P value for interaction 0.065) and 1.8 (0.8–4.1) and 1.1 (0.8–1.6) respectively for neurological outcome at discharge (P value for interaction 0.295). Meta-analysis found similar results.

Conclusion

Relative to placebo, the effects of adrenaline ROSC are greater for patients with an initially non-shockable rhythm than those with a shockable rhythms. Similar patterns are observed for longer term survival outcomes and favourable neurological outcomes, although the differences in effects are less pronounced. ISRCTN73485024.

Introduction

Adrenaline has been used as a treatment for cardiac arrest for many years.1, 2, 3 Despite its widespread use, until recently there has been limited evidence from randomised, placebo controlled trials about its safety and effectiveness.4, 5 The Cochrane systematic review and meta-analysis identified two randomised controlled trials which enrolled patients before admission to hospital and allocated them to adrenaline (1 mg aliquots) or placebo.4 The Pre-hospital Adrenaline for Cardiac Arrest (PACA) trial6 and Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest (PARAMEDIC-2)7 enrolled 8534 patients with out of hospital cardiac arrest (OHCA) and allocated them to receive adrenaline (1 mg every 3–5 min) or placebo. Meta-analysis of the trial results showed that adrenaline increased the rate of return of spontaneous circulation (ROSC) and survival to hospital discharge, but did not find evidence of improved neurological outcomes.4

Observational studies suggest that there may be differences in the effects of adrenaline according to the initial cardiac arrest heart rhythm. Administration of adrenaline in patients with initially shockable rhythms may be less effective8 or potentially harmful.9, 10 Although overall outcomes are generally poorer in patients with non-shockable rhythms, the incremental effectiveness of adrenaline by contrast appears to be greater.8, 9, 10, 11 Although informative, observational studies are limited by the risk of bias due to un-measured confounding factors. This includes the potential association between adrenaline being given later in patients with initially shockable rhythms, which might introduce resuscitation time bias.12

The aim of this study was (i) to assess the effect of initial arrest rhythm (i.e. shockable vs non-shockable) on primary and secondary outcomes in the PARAMEDIC-2 trial7 (ii) to provide a meta-analysis to assess the effect of initial rhythm on a set of outcomes that were common to the PARAMEDIC-2 and PACA trial.6

Section snippets

PARAMEDIC-2 trial (2018)

The background to the trial, methods and baseline characteristics of the randomised patients have been previously reported.7, 13 In brief, PARAMEDIC-2 was a multicentre double-blinded placebo-controlled trial conducted by five National Health Service ambulance services in the United Kingdom from December 2014 to October 2017 inclusive. Patients treated by ambulance paramedics for OHCA who were not successfully resuscitated by means of defibrillation or cardiopulmonary resuscitation (CPR), and

PARAMEDIC-2 study

Of 8014 patients enrolled in the study those with known treatment allocation consisted of 3999 in the placebo and 4015 in the adrenaline arm. Removal of cases where initial cardiac rhythm was unknown (166 in total), reduced the numbers to 3929 (98.25%) and 3919 (97.61%) respectively. These cases were analysed with the exception of those lost to follow up. A CONSORT diagram demonstrates the number of patients in each group (after excluding those where the initial arrest rhythm was not recorded)

Discussion

This paper reports that, relative to placebo, the effects of adrenaline on any ROSC and sustained ROSC appear to be greater for patients with an initially non-shockable arrest rhythm than those with shockable rhythms. Similar patterns are observed for longer term survival outcomes and favourable neurological outcomes, although the differences in effect are less pronounced.

The findings of the present study are consistent with previous research. Olasveengen et al. examined the effect of

Contributions

Conception or design of the work: GDP, CK, CJ, CD, JN, TQ, JF, SG, RL; acquisition of data: RF, IG, HP, NR, KC, JF; Analysis CK, CJ, RL and interpretation CK, CJ, RL, SG, GDP, CD, JN, TQ, JF.

Drafting the work CK, CJ, RL, GDP, critical revision – all authors. Final approval – all authors.

Statement of GCP compliance

All authors.

Acknowledgements

This project was funded by the NIHR HTA Programme (ref 12/127/126). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The research team would like to acknowledge the contribution of patients and staff from London, North East, South Central, Welsh and West Midlands Ambulance Services, the NIHR Comprehensive Research Network, Health Care Wales, Warwick Clinical Trials Unit, Intensive Care Foundation and Out of

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