Introduction

  • Out-of-hospital cardiac arrest strikes more than 350,000 people in the United States each year, and roughly 9 in 10 do not survive.
  • Epinephrine has been the cornerstone vasopressor in ACLS since the first guidelines in 1974. Its alpha-1 effect raises aortic diastolic pressure and coronary perfusion pressure, which drives return of spontaneous circulation (ROSC).
  • Yet after decades of use, epinephrine has never been proven to improve neurologically intact survival, and a growing body of evidence suggests it may worsen brain outcomes in those who do survive.
  • The paradox in one line: epinephrine gives more patients a pulse, but those patients are more likely to survive with severe neurological impairment than if they had received placebo.

Clinical Detail

Dose. 1 mg IV/IO every 3 to 5 minutes, with no weight-based adjustment (2025 AHA). Onset is immediate; the half-life is under 5 minutes, which is why repeat dosing is required.

Why it works. Epinephrine is a potent alpha-1, alpha-2, beta-1, and beta-2 agonist. Its resuscitative benefit is alpha-1 mediated systemic vasoconstriction, which raises aortic diastolic pressure and coronary perfusion pressure (CPP). Paradis established a CPP above 15 mmHg as the threshold that predicts ROSC. Beta effects raise heart rate and contractility but also myocardial oxygen demand.

Why it may harm the brain. Alpha-1 receptors also line the cerebral vasculature. The same vasoconstriction that helps the coronary circulation may constrict cerebral microvessels and reduce brain perfusion during and after CPR. Three mechanisms have been proposed:

  • Cerebral vasoconstriction during CPR reduces brain blood flow even as coronary flow improves.
  • Post-ROSC capillary no-reflow. Oghifobibi directly imaged epinephrine-induced penetrating arteriole constriction and capillary stalling 30 to 60 minutes after ROSC; placebo animals showed compensatory dilation.11
  • Blood-brain barrier disruption and impaired autoregulation. Semenas showed epinephrine raised BBB permeability and intracranial pressure and impaired autoregulation versus vasopressin.12

Adverse effects. Tachyarrhythmias, myocardial ischemia, reduced cerebral perfusion, mesenteric ischemia, extravasation necrosis, and lactic acidosis. Epinephrine is incompatible with sodium bicarbonate in the same line.

Evidence

The signal is remarkably consistent across three decades: epinephrine improves ROSC and short-term survival, but not the neurological quality of who survives.

Study (Year)Design / NInterventionKey outcome
Brown 19926RCT, N=1280High-dose (0.2 mg/kg) vs standard 1 mgNo difference in ROSC, survival, or neurologic outcome
Gueugniaud 19987RCT, N=3327Repeated high vs standard doseMore ROSC; no gain in survival to discharge or neurologic outcome
Olasveengen 20095RCT, N=851IV drugs vs no IV accessHigher short-term ROSC; survival and neurologic outcome not significant
Jacobs 20113Double-blind RCT, N=534Epinephrine 1 mg vs placeboROSC 23.5% vs 8.4%; survival not significant; both poor-neurologic survivors were in the epinephrine arm
Hagihara 20124Observational, N=417,188Prehospital epinephrine vs noneROSC up (aOR 2.51); 1-month survival down (aOR 0.54); good neurologic survival down (aOR 0.21)
PARAMEDIC2, Perkins 20181RCT, N=8014Epinephrine 1 mg q3-5 min vs placebo30-day survival 3.2% vs 2.4% (OR 1.39); favorable neurologic outcome not significant; severe impairment (mRS 4-5) in 31% vs 18% of survivors
Haywood 20212PARAMEDIC2 long-term3, 6, and 12-month outcomesSurvival benefit persisted; neurologic outcomes remained not significant
Aves 20208Meta-analysis, 17 RCTs, N=21,510Standard epinephrine vs placebo and othersROSC RR 3.09; survival to discharge RR 1.44; no improvement in neurologic outcome
Fukuda 20219Cohort, N=119,946Time to epinephrineEach 1-minute delay aOR 0.91 for good neurologic survival; early (≤20 min) 2.2% vs delayed 0.8%
Jaeger 202210Registry, propensityRecommended vs higher vs lower cumulative doseHigher cumulative adrenaline dose tracked with worse 30-day neurologic outcome
Oghifobibi 202211Preclinical, imagingEpinephrine vs placeboDirect visualization of cerebral capillary no-reflow after ROSC
Semenas 201412Preclinical, pigletEpinephrine vs vasopressinIncreased BBB permeability and intracranial pressure; impaired autoregulation

Conclusions

  • Epinephrine consistently improves ROSC and short-term survival. PARAMEDIC2, the largest placebo-controlled trial (N=8014), showed 30-day survival 3.2% vs 2.4% (OR 1.39).1
  • Despite this, no RCT has shown a significant gain in neurologically intact survival. PARAMEDIC2 found severe neurologic impairment (mRS 4-5) in 31% of epinephrine survivors versus 18% of placebo survivors.1
  • Proposed mechanisms: cerebral vasoconstriction during CPR, post-ROSC capillary no-reflow, and blood-brain barrier disruption with impaired autoregulation.1112
  • Cumulative dose is a signal, not a ceiling. Higher total epinephrine is associated with worse neurologic outcome, but this evidence is observational and largely reflects longer arrests. No guideline sets a maximum cumulative dose, and it is not a reason to cap or stop epinephrine.10
  • 2025 AHA guidance (Part 9). Give epinephrine 1 mg every 3 to 5 minutes (Class IIa, LOE B-R); IV access is preferred, with IO if IV is delayed or unavailable. For non-shockable rhythms, give it as soon as feasible; for shockable rhythms, give it after initial defibrillation attempts have failed (both Class IIa).13
  • Bottom line: the message is not to withhold epinephrine, which remains standard of care. Give it, and give it early per rhythm. Quality chest compressions and early defibrillation remain the foundation and should not be delayed for a drug.

References

  1. 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(8):711-721. PMID 30021076.
  2. Haywood KL, Ji C, Quinn T, et al. Long term outcomes of participants in the PARAMEDIC2 randomised trial of adrenaline in out-of-hospital cardiac arrest. Resuscitation. 2021;160:84-93. PMID 33524488.
  3. Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial. Resuscitation. 2011;82(9):1138-1143. PMID 21745533.
  4. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA. 2012;307(11):1161-1168. PMID 22436956.
  5. Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA. 2009;302(20):2222-2229. PMID 19934423.
  6. Brown CG, Martin DR, Pepe PE, et al. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. N Engl J Med. 1992;327(15):1051-1055. PMID 1522840.
  7. Gueugniaud PY, Mols P, Goldstein P, et al. A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. N Engl J Med. 1998;339(22):1595-1601. PMID 9828247.
  8. Aves T, Chopra A, Patel M, Lin S. Epinephrine for out-of-hospital cardiac arrest: an updated systematic review and meta-analysis. Crit Care Med. 2020;48(2):225-229. PMID 31939791.
  9. Fukuda T, Ohashi-Fukuda N, Inokuchi R, Kondo Y, Taira T, Kukita I. Timing of intravenous epinephrine administration during out-of-hospital cardiac arrest. Shock. 2021;56(5):709-717. PMID 33481550.
  10. Jaeger D, Baert V, Javaudin F, et al. Effect of adrenaline dose on neurological outcome in out-of-hospital cardiac arrest: a nationwide propensity score analysis. Eur J Emerg Med. 2022;29(1):63-69. PMID 34908000.
  11. Oghifobibi OA, Bruder ED, Nwokoye JO, et al. Resuscitation with epinephrine worsens cerebral capillary no-reflow after experimental pediatric cardiac arrest. J Cereb Blood Flow Metab. 2022;42(12):2255-2269. PMID 35854408.
  12. Semenas E, Sharma HS, Wiklund L. Adrenaline increases blood-brain-barrier permeability after haemorrhagic cardiac arrest in immature pigs. Acta Anaesthesiol Scand. 2014;58(5):620-629. PMID 24580085.
  13. Part 9: Adult Advanced Life Support: 2025 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2025. doi:10.1161/CIR.0000000000001376.
Tags:epinephrine cardiac arrest ROSC ACLS neurological outcome PARAMEDIC2

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Educational summary for pharmacists. Not a substitute for clinical judgment or the full AHA guidelines.