Introduction

1. There are greater than 350,000 out-of-hospital cardiac arrests annually, and nearly 90% of them are fatal.
2. The effects of epinephrine on animal hemodynamics have been studied since the late 1800s.
3. While the first advanced cardiac life support (ACLS) guidelines were first published in 1974, the role of epinephrine remains controversial.

	Epinephrine [Adrenalin®]
Dose	Cardiac arrest: 1 mg IV/IO every 3 to 5 minutes
Mechanism of Action	Receptor Activity	Pharmacological Action	Effect
α agonist	Peripheral vasoconstriction	↑ myocardial and cerebral blood flow
β agonist	↑ heart rate and contractility	↑ myocardial oxygen demand
Indications	Asystole/pulseless electrical activity (PEA) Pulseless ventricular tachycardia/fibrillation
Pharmacokinetics	Onset: immediate  Distribution: 1-2 minutes to reach central circulation during CPR Metabolism: rapid hepatic degradation Elimination: urine (inactive metabolites) Half-life: <5 minutes
Adverse Effects	Tachyarrhythmias, myocardial ischemia, may decrease cerebral perfusion, mesenteric ischemia, extravasation leading to necrosis, lactic acidosis
Dosage Forms	Vial: 1 mg/mL (1 mL & 30 mL) Pre-filled syringe: 1 mg/10 mL (10 mL)
Compatibility	Compatible with: NS, D5W, and LR        Incompatible with sodium bicarbonate

Overview of Evidence
Author (Year)	Study Design/Patient Population	Intervention	Results
Pearson, 1963	Animal study (n=80)   Asphyxiated dogs with asystole and ventricular fibrillation	Epinephrine 1 mg  Positive-pressure breathing Chest compressions Defibrillation	↑ ROSC in dogs that received epinephrine 5 min and 10 min after asystole    ↑ ROSC in dogs that received epinephrine 1 min after ventricular fibrillation   Ventricular fibrillation occurred only in the epinephrine group
Stiell, 1992	RCT (650)   Out-of-hospital cardiac arrest	Epinephrine 7 mg every 5 min   Epinephrine 1 mg every 5 min	No difference in survival to hospital admission or discharge and neurologic outcomes between low- and high-dose epinephrine
Brown, 1992	RCT (n=1280)   Out-of-hospital cardiac arrest	Epinephrine 0.2 mg/kg   Epinephrine 0.02 mg/kg	No difference in ROSC, survival to hospital admission and discharge, or neurological outcomes between low- and high-dose epinephrine
Choux, 1995	RCT (n=536)   Out-of-hospital cardiac arrest	Epinephrine 5 mg every 5 min   Epinephrine 1 mg every 5 min	No difference in ROSC at any time, admission to hospital, or neurological outcomes between low- and high-dose epinephrine
Sherman, 1997	RCT (n =140)   Out-of-hospital cardiac arrest	Epinephrine 0.1 mg/kg   Epinephrine 0.01 mg/kg	No difference in rhythm improvement, ROSC, neurologic outcomes, or discharge from hospital between low- and high-dose epinephrine
Gueugniaud, 1998	RCT (n= 3327)   Out-of-hospital cardiac arrest	Epinephrine 5 mg every 3 min   Epinephrine 1 mg Every 3 min	↑ ROSC in high-dose epinephrine group   No difference in admission to hospital, 24hour survival, discharge from hospital, or neurological outcomes between low- and high-dose epinephrine
Fisk, 2018	Pre-post study (n= 2255)   Out-of-hospital cardiac arrest	Epinephrine 1 mg at 4 min, then 1 mg every 8 min (2 min for non-shockable rhythms)   Epinephrine 0.5 mg at 4 min and 8 min, then 0.5 mg every 8 min (2 min for nonshockable rhythms)	No difference in any ROSC, sustained ROSC, survival to discharge, or favorable neurological outcomes between low- and high-dose epinephrine
Stiell, 2004   (OPALS)	Pre-Post study (n=5638)   Out-of-hospital cardiac arrest	• Rapid defibrillation ACLS (endotracheal intubation & IV medications)	98.5% of ACLS group received epinephrine   ↑ ROSC and survival to hospital admission in group receiving epinephrine   No difference in survival to hospital discharge and neurological outcomes
Olasveengen, 2009	RCT (n=851)   Out-of-hospital cardiac arrest	ACLS with IV medications   ACLS without IV medications	79% of IV medication group received epinephrine   ↑ ROSC at any time and survival to hospital admission in group receiving epinephrine   No difference in survival to hospital discharge and neurological outcomes
Author (Year)	Study Design/Patient Population	Intervention	Results
Jacobs, 2011	RCT (n=534)   Out-of-hospital cardiac arrest	Epinephrine   Placebo	↑ ROSC and survival to hospital admission in group receiving epinephrine   No difference in survival to hospital discharge or neurological outcomes
Hagihara, 2012	Observational study (n=417,188)   Out-of-hospital cardiac arrest	Epinephrine   No epinephrine	↑ ROSC in group receiving epinephrine   ↓ 1-month survival and neurological outcomes in epinephrine group
Perkins, 2018   (PARAMEDIC- 2)	RCT (n=8007)   Out-of-hospital cardiac arrest	Epinephrine 1 mg every 3-5 min   Placebo	↑ ROSC, survival to hospital admission, and 30-day survival in epinephrine group   No difference in favorable neurologic outcome at hospital discharge   ↑ severe neurologic impairment in group receiving epinephrine

Conclusions

1. The dose of epinephrine is based on animal studies from the 1960s, in which epinephrine was administered immediately after the induction of cardiac arrest.
2. There have been no differences found between standard and high-dose epinephrine.
3. Epinephrine may lead to increased ROSC and survival to hospital admission but has not been found to consistently improve long-term outcomes.
4. Bottom Line: Quality chest compressions and early defibrillation continue to be the standard of care in ACLS and should not be delayed for administration of epinephrine.

References

• Attaran RR, Ewy GA. Epinephrine in resuscitation: curse or cure? Future Cardiology. 2010;6(4).
• Callaway C. Epinephrine for cardiac arrest. Current Opinion in Cardiology. 2013;28(1):36-42.
• Epinephrine [package insert] Lake Forest, IL: Hospira, Inc.; 2019.
• Pearson JW, Redding JS. Epinephrine in cardiac resuscitation. Am Heart J. 1963;66:210-214. 
• Stiell IG, Hebert PC, Weitzman BN, et al. High-dose epinephrine in adult cardiac arrest. N Engl J Med.

1992;327(15):1045-1050. Choux C, Gueugniaud PY, Barbieux A, et al. Standard doses versus repeated high doses of epinephrine in cardiac arrest outside the hospital. Resuscitation. 1995;29(1):3-9.

• Sherman BW, Munger MA, Foulke GE, Rutherford WF, Panacek EA. High-dose versus standard-dose epinephrine treatment of cardiac arrest after failure of standard therapy. Pharmacotherapy. 1997;17(2):242-247. 
• 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. European Epinephrine Study Group. N Engl J Med. 1998;339(22):1595-1601.
• Fisk CA, Olsufka M, Yin L, et al. Lower-dose epinephrine administration and out-of-hospital cardiac arrest outcomes. Resuscitation. 2018;124:43-48.
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• Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L. Intravenous drug administration during out-ofhospital cardiac arrest: a randomized trial. JAMA. 2009;302(20):2222-2229.
• 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.
• 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.
• 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.