Does giving adrenaline during out-of-hospital CPR improve outcomes?

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

Perkins et al NEJM DOI: 10.1056/NEJMoa1806842

“Because maybe you’re gonna be the one that saves me” – Oasis

Summary by Dr Jolyon Cohen

Background

There are only a limited number of interventions available for out of hospital  (OOH) cardiac arrest. The efficacy of early defibrillation and bystander CPR has been proven in previous studies, but evidence for the use of adrenaline has been lacking in quality and equivocal in nature where available. The International Liaison Committee on Resuscitation, therefore called for a placebo control trial to establish whether the use of adrenaline was safe and effective in the management of out of hospital cardiac arrest.

Methods

A double blind randomised control trial comparing adrenaline to placebo in treatment of out of hospital cardiac arrest in 5 UK ambulance trusts.

All adult patients with OOH cardiac arrest assessed for participation. Consent was to be gained retrospectively from either patient or next of kin.

Exclusions:

  • Age less than 16
  • Cardiac arrest due to asthma/anaphylaxis
  • Pregnancy
  • Trauma (in London)
  • Adrenaline given prior to arrival of trial paramedic.

Randomisation carried out by paramedic opening pack of syringes randomised by computer in 1:1 ratio to contain either adrenaline or saline.

Treatment of patients was according to standard advanced life support guidelines.

Outcomes and powering of study

The study aimed to recruit 8000 patients (i.e 4000 to each arm) which based on a predicted OOH cardiac arrest survival rate of 6% would allow calculation of confidence interval (CI) of 0.4 for the risk ratio of adrenaline administration vs placebo. Recruiting more patients would not, it was calculated, narrow the CI sufficiently to make it worthwhile.

  • Primary outcome
    • Survival at 30 days
  • Secondary outcomes
    • Rate of survival until hospital admission
    • Length of stay in the hospital
    • Length of stay in intensive care unit
    • Rates of survival at hospital discharge and at 3 months
    • Neurological outcomes at hospital discharge and at 3 months (a binary outcome with a modified Rankin score of 3 or lower being “good”, and reflecting neurological recovery sufficient to walk without assistance)

Results

A total of 8016 patients were enrolled in the trial, and randomised to one of the two arms. The two groups were similar with no significant difference in any characteristics. A total of 8007 patients were included in the primary analysis.

The study showed a significant improvement in 30 day survival with the use of adrenaline (odds ratio 1.39, CI 1.06-1.82). There was a similarly statistically significant improvement in patients surviving to hospital discharge (odds ratio 1.41, CI 1.07-1.87). Survival rates at 30 days were 3.2% in the treatment arm and 2.4% in the control arm.

Of note, there was no statistically significant difference in the number of patients surviving to discharge with a favourable neurological outcome (odds ratio 1.31, CI 0.94-1.82)

Discussion

Strengths:

  • Large, well powered study
  • Representative of patient population – multiple ambulance trusts
  • Robustly designed with double blinding and randomisation
  • Vast majority of patients followed up to primary outcome
  • Deals with an important clinical question

Limitations:

  • Trial ended at point of admission to hospital with no control over treatment at this point
  • No pre-arrest record of neurological function (although unlikely to be significantly impaired if CPR was commenced)
  • Some loss of patients to followup at 3 months (18% of survivors in each group), and study not powered for secondary outcomes so limits the conclusions we can draw from these.

Although adrenaline improved survival rates overall, there was no evident that it improves the rates of recovery with a favourable neurological outcome, reflecting that there were a number of patients in the adrenaline arm surviving with significant neurological impairment. Of note, the survival rate from OOH cardiac arrest is lower than anticipated (and planned for in the statistical analysis).

The results are interesting, but perhaps of limited applicability to our practice in hospital. The time take to administration of the first dose of adrenaline was 21 minutes – significantly longer than that seen in studies of cardiac arrest in hospital, and obviously the patient population outside hospital may have different causes of cardiac arrest.  Overall, though, this is an important trial that raises some interesting clinical and moral questions, as well as highlighting the continuing importance of early defibrillation and CPR in the management of out of hospital cardiac arrest.

Summary by Dr Jolyon Cohen

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