Epinephrine is widely used during cardiac arrest because it increases vascular tone, blood pressure, and heart rate, improving the likelihood of return of spontaneous circulation (ROSC). Yet its role remains contested. Evidence from the PARAMEDIC2 trial and later analyses showed that although epinephrine improves ROSC rates, it does not lead to better neurologic recovery and may adversely affect cerebral microcirculation while promoting platelet aggregation. These findings have sharpened clinical and ethical debate over whether improved short-term survival justifies potential harm to neurologic outcomes.

PARAMEDIC2 Findings

The PARAMEDIC2 randomized, placebo-controlled trial enrolled 8014 patients with out-of-hospital cardiac arrests across five UK emergency medical service regions. Patients were randomly assigned to receive 1 mg epinephrine every 3 to 5 minutes or a saline placebo administered via intravenous or intraosseous access after initial defibrillation failed. The study drug was visually indistinguishable from saline to preserve blinding. Exclusion criteria, including trauma, anaphylaxis, and asthma, were applied to reduce confounding.

The primary endpoint was 0-day survival; secondary endpoints included ROSC and neurologic outcome. The latter was evaluated using the modified Rankin Scale at hospital discharge.

Epinephrine significantly increased ROSC compared with placebo (36.3% vs 11.7%). Thirty-day survival was also higher in the epinephrine group, although absolute survival remained low. Among survivors, severe neurologic impairment (modified Rankin Scale, 4-5) was more frequent in the epinephrine group (31.0%) compared with the placebo group (17.8%). Favorable neurologic outcome (modified Rankin Scale, 0-3) did not differ significantly between groups (2.2% vs 1.9%).

Many individuals achieve ROSC after treatment with epinephrine but survive with severe neurologic impairment, including permanent dependence on care or a vegetative state. With the statistical number needed to treat of 112 individuals to achieve one additional survivor at 30 days, pharmacologic intervention offers a far smaller survival benefit than basic measures such as immediate bystander cardiopulmonary resuscitation.

Subsequent analyses, including findings from the ADRE-TIME-LINE study, have raised additional concerns regarding dosing intervals. Patients who received epinephrine strictly at 3- to 5-minute intervals had the lowest rates of ROSC and favorable neurologic outcome compared with those receiving doses at shorter or longer intervals. In that cohort, 99% of patients treated at standard 3- to 5-minute intervals had poor neurologic outcomes, defined as Cerebral Performance Category 3-5. Whether alternative timing strategies improve outcomes compared with placebo remains uncertain.

Current Guidelines

The 2025 guidelines from the European Resuscitation Council continue to recommend 1 mg epinephrine every 3-5 minutes during advanced life support. This also has legal implications because any deviation from the guideline (specialist standard) must be comprehensibly justified.

Recent updates have focused on technical refinements such as defibrillator precharging and vector change for refractory ventricular fibrillation rather than reexamining neurologic trade-offs associated with epinephrine.

Epinephrine has not been reassessed with neurologic outcomes as a central consideration. This leaves emergency physicians facing a practical dilemma during resuscitation. Treatment algorithms call for rapid administration, yet it remains unclear whether the resulting neurologic risk aligns with patient preferences. Rates of neurologically intact survival showed no significant difference between with and without epinephrine, with favorable neurologic outcome at 30 days reported in 2.2% of the epinephrine group and 1.9% of the placebo group.

Ethical Considerations

Current practice highlights shortcomings in the way advance care planning is applied. Advance directives often reduce decision-making to a simple choice for or against resuscitation, without addressing acceptable quality of life after successful resuscitation. As a result, preferences related to interventions such as epinephrine administration are rarely considered. Because patients are rarely asked whether they would accept survival with severe neurologic impairment, standardized protocol often takes precedence over individual life goals.

Patient-centered resuscitation care, however, must recognize that survival is not simply a technical procedure. The use of epinephrine introduces a risk that many individuals, according to survey data, clearly reject: survival with severe disability.

The fundamental decision is therefore not only whether to attempt resuscitation but also whether resuscitation should proceed with or without epinephrine, with presumed patient preferences carrying greater weight than automatic adherence to protocol.

Horst Gross, MD, specialist in anesthesiology and intensive care medicine. He studied journalism and medicine and works as a practicing physician and medical writer.

This story was translated from Coliquio, part of the Medscape Professional Network.