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Foundational Trials

PARAMEDIC2

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Ampoule of adrenaline being lifted from a drug tray

Publication

  • Title: A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest
  • Acronym: PARAMEDIC-2
  • Year: 2018
  • Journal published in: The New England Journal of Medicine
  • Citation: Perkins GD, Ji C, Deakin CD, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med 2018;379:711–721

Context & Rationale

  • Background
    Adrenaline (epinephrine) has long been a core component of advanced life support for out-of-hospital cardiac arrest because of its physiologic ability to increase coronary perfusion pressure. However, prior evidence largely suggested improved short-term outcomes (ROSC, hospital admission) without clear improvement in survival with good neurologic outcome, leaving persistent uncertainty about overall patient-centred benefit.
  • Research Question/Hypothesis
    Does standard-dose adrenaline during prehospital resuscitation improve 30-day survival compared with placebo, and if so, does it also improve neurologic outcomes among survivors?

Design & Methods

  • Research Question: In adults with out-of-hospital cardiac arrest, does adrenaline compared with saline placebo improve survival at 30 days?
  • Study Type: Randomised, multicentre, double-blind, placebo-controlled prehospital trial.
  • Population: Adults with out-of-hospital cardiac arrest treated by paramedics in five UK National Health Service ambulance services; eligibility and procedures were prespecified in trial documents and registration.1
  • Intervention: Parenteral adrenaline (standard advanced life support dosing) administered by paramedics during resuscitation.
  • Comparison: Saline placebo administered in an identical manner.
  • Blinding: Double-blind, with identical trial packs and masking of clinicians and outcome assessors as prespecified.1
  • Statistics: Primary analysis and key secondary outcomes were prespecified, including adjustment framework for odds ratios.1
  • Follow-up: Primary endpoint at 30 days (with additional secondary outcomes through 3 months).

Key Results

This trial was not stopped early.

Outcome Epinephrine Placebo Effect p value / 95% CI Notes
Survival at 30 days 130/4012 (3.2%) 94/3995 (2.4%) OR 1.39 p=0.02; 95% CI 1.06–1.82 Primary outcome (unadjusted OR)
Survival until hospital admission 947/3973 (23.8%) 319/3982 (8.0%) OR 3.59 95% CI 3.14–4.12 Defined as sustained ROSC until admission (“survived event”)
Survival until hospital discharge 128/4009 (3.2%) 91/3995 (2.3%) OR 1.41 95% CI 1.08–1.86 Secondary outcome (unadjusted OR)
Favorable neurologic outcome at hospital discharge 87/4007 (2.2%) 74/3994 (1.9%) OR 1.18 95% CI 0.86–1.61 mRS 0–3
Favorable neurologic outcome at 3 months 82/3986 (2.1%) 63/3979 (1.6%) OR 1.31 95% CI 0.94–1.82 mRS 0–3
  • 30-day survival was higher with adrenaline (3.2% vs 2.4%; OR 1.39; p=0.02); the reported number needed to treat to prevent one death at 30 days was 112.
  • Survival to hospital admission (“survived event”) was substantially higher with adrenaline (23.8% vs 8.0%).
  • There was no statistically significant difference in favorable neurologic outcome at discharge (2.2% vs 1.9%) or at 3 months (2.1% vs 1.6%).
  • Among survivors at hospital discharge, severe neurologic impairment (mRS 4–5) occurred more often in the adrenaline group than the placebo group.

Internal Validity

  • Randomisation and allocation: Randomised allocation with concealment via identical trial packs; operational methods prespecified in trial documentation and registration.1
  • Performance/detection bias: Double-blind placebo design; primary endpoint (30-day survival) is objective.
  • Statistical rigour: Prespecified primary analysis with very high completeness of primary outcome ascertainment; adjusted analyses reported alongside unadjusted estimates.

Conclusion on Internal Validity: Internal validity is strong for the primary survival endpoint and key secondary survival outcomes, supported by randomisation, masking, and objective outcome measurement.1

External Validity

  • Population representativeness: Large, pragmatic UK EMS population (five ambulance services) with real-world out-of-hospital resuscitation practice.
  • Applicability: Highly applicable to EMS systems using standard advanced life support algorithms with IV/IO access and vasopressor administration.

Conclusion on External Validity: Generalisability is high to comparable prehospital systems; absolute effects may vary with baseline survival, response times, and timing of drug delivery.

Strengths & Limitations

  • Strengths: Very large sample size, double-blind placebo control, pragmatic EMS setting, objective primary endpoint, and inclusion of neurologic outcome measures.
  • Limitations: Neurologic outcomes can be influenced by post–cardiac arrest in-hospital care; time to trial-drug administration reflects real-world constraints and may affect observed benefit; survival gains were small in absolute terms.

Interpretation & Why It Matters

  • Small Survival Benefit
    Adrenaline increased the likelihood of survival to 30 days and markedly increased short-term outcomes (ROSC sustained to hospital admission), demonstrating clear physiologic effectiveness at achieving return of circulation.
  • Trade-off: Survival vs Neurologic Outcome
    Despite improved survival, there was no statistically significant improvement in favorable neurologic outcome; the adrenaline group had a higher proportion of survivors with severe neurologic impairment, sharpening the focus on patient-centred endpoints and the importance of post-arrest care.3

Controversies & Subsequent Evidence

  • Short-term benefit vs patient-centred outcomes
    • PARAMEDIC-2 reinforced that adrenaline improves ROSC/survival to admission, but uncertainty remains about improving neurologically favorable survival at the population level, as reflected in subsequent systematic reviews and network meta-analyses.34
  • Timing and heterogeneity of effect
    • Observational data and post hoc analyses suggest timing (earlier administration, especially in non-shockable rhythms) may influence outcomes, supporting guideline emphasis on early dosing for non-shockable rhythms.56
  • Guideline convergence
    • Major resuscitation guidelines continue to recommend standard-dose epinephrine during adult cardiac arrest, with emphasis on early administration in non-shockable rhythms and after defibrillation attempts in shockable rhythms.78
  • Long-term outcomes
    • Longer-term follow-up of PARAMEDIC-2 participants has been published, extending outcomes beyond the initial trial timepoints.9

Summary

  • Adrenaline increased 30-day survival versus placebo (3.2% vs 2.4%; OR 1.39; p=0.02).
  • Adrenaline markedly increased survival to hospital admission (“survived event”) (23.8% vs 8.0%).
  • No statistically significant improvement in favorable neurologic outcome at discharge or 3 months.
  • Subsequent reviews and guidelines continue to support epinephrine use during adult cardiac arrest while emphasizing patient-centred outcomes and early administration in non-shockable rhythms.378

Further Reading

Other Trials

Systematic Review & Meta Analysis

Observational Studies

Notes

  • Observational associations can be distorted by resuscitation time bias and confounding by indication.
  • Placebo-controlled RCT evidence remains the most reliable basis for estimating patient-centred benefit vs harm.
  • Outcomes after ROSC are strongly influenced by post–cardiac arrest care, which can modify neurologic endpoints.

Guidelines

Overall Takeaway

In a large, double-blind, placebo-controlled UK EMS trial, adrenaline increased 30-day survival after out-of-hospital cardiac arrest and markedly increased survival to hospital admission, but did not demonstrate a statistically significant improvement in favorable neurologic outcomes—highlighting the central trade-off between achieving ROSC and meaningful neurologic recovery. 3 7 8

Overall Summary

  • Higher 30-day survival with adrenaline (3.2% vs 2.4%; OR 1.39; p=0.02).
  • Much higher survival to hospital admission (“survived event”) with adrenaline (23.8% vs 8.0%).
  • No statistically significant improvement in favorable neurologic outcome at discharge or 3 months; more survivors had severe neurologic impairment. 3 7