The New England Journal of Medicine August 23, 2018

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

Gavin D. Perkins et al. (PARAMEDIC2 Collaborators)

Bottom Line

In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival and Return of Spontaneous Circulation (ROSC) than placebo, but did not increase the rate of favorable neurologic outcome, leaving more survivors with severe neurologic impairment.

Key Findings

1. Survival at 30 days was significantly higher in the epinephrine group compared to the placebo group (130 of 4,012 patients [3.2%] vs. 94 of 3,995 patients [2.4%]; unadjusted odds ratio 1.39, 95% CI 1.06 to 1.82; p=0.02).

2. The rate of Return of Spontaneous Circulation (ROSC) at the scene or during transport was substantially higher in the epinephrine arm (36.3%) versus the placebo arm (11.7%).

3. There was no significant difference between the groups in survival with a favorable neurologic outcome (modified Rankin Scale score 0 to 3) at hospital discharge (2.2% in the epinephrine group vs. 1.9% in the placebo group; unadjusted OR 1.18, 95% CI 0.86 to 1.61).

4. Among those who survived to hospital discharge, severe neurologic impairment (modified Rankin Scale score 4 or 5) was markedly more frequent in the epinephrine group (39 of 126 [31.0%]) compared to the placebo group (16 of 90 [17.8%]).

Study Design

Design

RCT

Double-Blind

Sample

8,014

Patients

Duration

30 days

Median

Setting

United Kingdom

Population Adult patients (16 years of age or older) with out-of-hospital cardiac arrest for whom advanced life support was provided by trial-trained paramedics. Exclusions included known pregnancy, anaphylaxis, asthma, or epinephrine administration prior to trial paramedic arrival.

Intervention Parenteral epinephrine (1 mg) administered every 3 to 5 minutes via intravenous or intraosseous route, alongside standard care.

Comparator 0.9% saline placebo administered identically, alongside standard care.

Outcome Rate of survival at 30 days.

Study Limitations

• Lack of continuous mechanical data on CPR quality metrics (such as compression depth, rate, and fraction) across the different prehospital systems.

• The median time from the emergency call to the administration of the trial drug was approximately 21 minutes, which reflects real-world EMS challenges but may have missed the optimal physiological window for epinephrine efficacy.

• Patients who achieved ROSC prior to trial drug administration were excluded, which deliberately enriched the cohort with more refractory, difficult-to-resuscitate arrests.

• Post-resuscitation care, such as targeted temperature management and angiography, was left to the discretion of the receiving hospitals, introducing potential variability in post-arrest pathways.

Clinical Significance

PARAMEDIC2 explicitly quantified the clinical trade-off of epinephrine in out-of-hospital cardiac arrest: while its alpha-adrenergic effects successfully restart the heart (tripling ROSC) and improve 30-day survival, its detrimental impact on cerebral microcirculation means it fails to improve neurologically intact survival. Ultimately, the trial demonstrated that the administration of epinephrine results in a higher absolute number of survivors suffering from severe, debilitating neurological impairment, prompting intense ongoing ethical and guideline debates regarding its routine use.

Historical Context

Epinephrine has been a cornerstone of advanced cardiac life support for over 50 years, largely driven by animal models showing it increased aortic diastolic pressure and coronary perfusion pressure, thus facilitating ROSC. Over time, however, observational registry data consistently signaled that while epinephrine increased ROSC, it was associated with worse long-term brain health. The International Liaison Committee on Resuscitation (ILCOR) specifically requested a rigorous, placebo-controlled RCT to settle the debate. PARAMEDIC2 answered this call, becoming the definitive modern trial evaluating the efficacy and safety of epinephrine in cardiac arrest.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How do the alpha-adrenergic and beta-adrenergic effects of epinephrine contribute to its efficacy in achieving ROSC, and how might these same mechanisms theoretically worsen neurologic outcomes after cardiac arrest?

Key Response

Epinephrine's alpha-1 agonism causes peripheral vasoconstriction, increasing aortic diastolic pressure and coronary perfusion pressure, which drives ROSC. However, its beta-1 effects increase myocardial oxygen demand, and intense alpha-1 mediated vasoconstriction can reduce microvascular cerebral blood flow post-resuscitation, potentially worsening hypoxic-ischemic brain injury.

Resident

Given that epinephrine improves 30-day survival but not favorable neurologic outcomes, how should this trial's findings influence your real-time decision-making and communication with family members when running an out-of-hospital cardiac arrest code in the emergency department?

Key Response

Residents must grapple with the tension between algorithmic ACLS compliance and the reality of the outcomes. Communication should reflect that while epinephrine might restart the heart, the brain may not recover, highlighting the importance of early defibrillation and high-quality CPR over medications alone, and guiding realistic prognostic discussions.

Fellow

Does the timing of epinephrine administration or the initial arrest rhythm (shockable versus non-shockable) modify the treatment effect observed in this trial, and how might we individualize resuscitation pharmacology based on these variables?

Key Response

Fellows should appreciate that epinephrine is generally more beneficial in non-shockable rhythms (PEA/asystole) where it is given earlier. In shockable rhythms (VF/pVT), early epinephrine might be harmful or distract from defibrillation. Nuanced resuscitation involves tailoring epinephrine timing based on the rhythm phase rather than a blind one-size-fits-all protocol.

Attending

How does the PARAMEDIC2 trial challenge our historical definition of 'success' in resuscitation, and how can attendings use these data to shift the departmental culture from prioritizing ROSC to optimizing intact neurologic survival?

Key Response

The trial highlights the 'ROSC-to-discharge gap' and the ethical dilemma of creating severe neurologic morbidity. Attendings can use this to teach teams that true success is neurologically intact survival, emphasizing meticulous post-arrest care, targeted temperature management, and avoiding hyperoxia, rather than just celebrating the return of a pulse.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The trial utilized deferred consent and a primary outcome of 30-day survival rather than neurologically intact survival. How do these methodological choices impact the statistical power and ethical validity of the study, and what alternative composite endpoints could future resuscitation trials employ?

Key Response

Survival is a hard, objective endpoint requiring smaller sample sizes for power, but neurologic status (e.g., modified Rankin Scale) is more patient-centered. Deferred consent is necessary in OHCA but raises ethical debates, especially when an intervention increases severe morbidity. Future trials might use hierarchical endpoints or utility-weighted mRS to capture the true burden of the outcome.

Journal Editor

As a peer reviewer analyzing the PARAMEDIC2 manuscript, what potential threats to external validity and protocol adherence would you flag regarding the administration of open-label epinephrine or differences in post-resuscitation care across the participating EMS agencies?

Key Response

A rigorous review would scrutinize the rate of protocol deviations, such as paramedics giving open-label epinephrine if they suspected the patient was receiving placebo, the time to drug administration, and whether variations in post-arrest ICU care between hospitals could have confounded the neurologic outcome data.

Guideline Committee

How should the AHA and ERC weigh the conflicting outcomes of increased survival but unimproved neurologic status from PARAMEDIC2 when grading the recommendation for routine epinephrine use in OHCA, and should guidelines introduce a maximum dose or rhythm-specific dosing strategy?

Key Response

Current AHA guidelines recommend epinephrine for OHCA (Class 2a or 2b depending on rhythm) because survival is valued, but acknowledge the neurologic trade-off. The committee must balance the ethical weight of severe brain injury against the finality of death, potentially leaning toward weaker recommendations for shockable rhythms or emphasizing caps on the total number of doses.

Clinical Landscape

Noteworthy Related Trials

2011

PACA Trial

n = 534 · Resuscitation

Tested

Epinephrine 1mg IV

Population

Adults with out-of-hospital cardiac arrest

Comparator

Placebo

Endpoint

Survival to hospital discharge

Key result: Epinephrine significantly increased prehospital return of spontaneous circulation but did not significantly improve survival to hospital discharge.

2013

TTM Trial

n = 939 · NEJM

Tested

Targeted temperature management at 33 degrees Celsius

Population

Unconscious adults admitted to the hospital after out-of-hospital cardiac arrest

Comparator

Targeted temperature management at 36 degrees Celsius

Endpoint

All-cause mortality

Key result: There was no significant difference in all-cause mortality or poor neurologic outcomes between targeting 33 degrees Celsius and 36 degrees Celsius.

2016

ALPS Trial

n = 3,026 · NEJM

Tested

Amiodarone or lidocaine

Population

Patients with OHCA and shock-refractory ventricular fibrillation or pulseless ventricular tachycardia

Comparator

Placebo

Endpoint

Survival to hospital discharge

Key result: Neither amiodarone nor lidocaine resulted in a significantly higher rate of overall survival to hospital discharge compared to placebo, though survival was improved in bystander-witnessed arrests.

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