Epinephrine in Cardiac Arrest: Outdated?
Introduction
Epinephrine, as of 2022, is the primary medication provided during cardiac arrests under the 2020 ACLS guidelines. Epinephrine is administered via intravenous push in 1mg increments in alternating compression cycles - that is, every other 2 minute cycle of CPR. In the case of rhythms such as pulseless electrical activity or asystole, it is the only medication provided besides oxygen and fluid resuscitation. It makes up part of the core interventions provided to OHCA patients under ACLS guidelines in addition to high flow oxygen and ventilation, defibrillation, high quality compressions, and fluid resuscitation as required.
What is epinephrine?
Epinephrine is a beta-1, beta-2, and alpha adrenergic receptor agonist. It is a catecholamine that is naturally produced by the suprarenal/adrenal glands during times of crisis. It is one of the core hormones of the “fight or flight” response to stressors. It is used in a variety of medical applications ranging from cardiac arrest resuscitations and anaphylaxis treatment to anesthesia and vasoconstriction applications during surgeries.
Epinephrine is the primary medication for anaphylaxis, cardiac arrests, and has major applications in the management of most respiratory conditions. Epinephrine is also used in the context of croup management for pediatrics in its nebulized racemic form.
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Review of the receptors
Beta 1 - Activation of the beta 1 receptors prompts an increase in both cardiac contractility and heart rate. In the context of sympathetic tone and the “fight or flight” response, this allows the body to increase cardiac output in order to maintain perfusion to tissues under times of stress and continue delivering sympathomimetic hormones. Stroke volume is significantly increased in an otherwise healthy heart with beta-1 activation.
Beta 2 - Activation of the beta 2 receptors primarily bronchodilates and increases respiratory rate in order to compensate for increased oxygen demand. In the context of conditions such as anaphylaxis, this reverses the parasympathetic-mediated bronchoconstriction and helps the body meet its needs. Activation of this receptor is why patients that receive epinephrine often become tachypneic.
Beta 2 receptor agonists also work on sections of the smooth muscle of the body. It specifically works on vasodilation in the skeletal muscles and in the liver. Vasodilation of the liver allows for increased perfusion and thus drives quicker processing of glycogen to provide increased energy during the sympathetic episode. Vasodilation of the skeletal muscle primes the body to “fight” and allows for increased muscular strength.
Beta 3 - Beta 3 receptors are primarily responsible for lipolysis - that is, the breakdown of lipids and adipose tissue in order to generate ATP. This process also feeds into the action of the liver in driving glycolysis and releasing glycogen stores. This allows the body to meet its increased glucose/ATP and caloric demands during times of acute stress.
Alpha 1 - Alpha 1 receptors are primarily responsible for driving an increase in peripheral vascular tone and peripheral vascular resistance. In the context of anaphylaxis, activation of this adrenergic receptor allows for reversal of the histamine-mediated peripheral vasodilation and increased capillary permeability. An increase in peripheral vascular tone/resistance in combination with beta-1 mediated increased cardiac contractility and heart rate allows for the body to increase cardiac output and sustain better perfusion. Remember - cardiac output is simply heart rate combined with stroke volume.
There are other receptors that epinephrine works on, but these are the primary receptors that EMS is concerned with when using epinephrine as a rescue medication.
Epinephrine in the Context of Cardiac Arrest
Epinephrine in the context of cardiac arrest is intended to “kickstart” the heart into resuming normal, perfusing mechanical activity. It does so by activation of the aforementioned alpha and beta adrenergic receptors. For instance, alpha 1 receptor activation is thought to be important in the context of hypovolemic-mediated arrest because it allows for vasoconstriction - and thus drives an attempt to return to normal blood pressure (American Heart Association, 2000). After all, cardiac arrest is not always the absence of mechanical activity - it is merely an umbrella term for a state of severely compromised perfusion resulting in the absence of a palpable pulse and ultimately death. This is why both asystole (with total absence of electrical activity) and ventricular fibrillation (with quivering, inadequate mechanical activity) are both deemed cardiac arrest rhythms.
The standard dose for cardiac arrests in adults is 1mg 1:10,000 ratio intravenous push. Other applications include continuous epinephrine drips throughout the course of the arrest/resuscitation process.
Epinephrine has been used in resuscitation and cardiac arrest events since the beginning of ACLS in 1975 (American Heart Association, n.d.). However, its history is not without controversy. Recent studies have called into the question the efficacy of using epinephrine in cardiac arrest, and what role it should play in resuscitation algorithms.
The Controversy Behind Epinephrine
Controversy surrounding the use of epinephrine arose following a 2018 UK-based study titled: A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. The study, shortened to PARAMEDIC2 in popular literature, researched the difference in ROSC, 30 day survival rates, and neurological function at discharge in patients who did not receive epinephrine versus those that did. The study specifically focused on out of hospital cardiac arrests and did not include data from in-hospital cardiac arrests, which may follow slightly modified algorithms.
In the study, a control group of 4015 patients received epinephrine, versus an intervention group of 3999 patients - whom received normal saline in place of epinephrine (Perkins et al., 2018). Although cardiac arrests are often chaotic and difficult to manage in the field, current UK resuscitative guidelines were used in full for the rest of arrest management. The study primarily focused on survival at 30 days as a metric for resuscitation efficacy (Perkins et al., 2018).
The study found that those that received epinephrine produced a statistically significant difference in ROSC and 30 day survival rates in the interventional group (Perkins et al., 2018). 3.2 percent of those that received epinephrine were alive at the 30 day mark, versus 2.4 percent of the interventional group that did not receive epinephrine during resuscitation (Perkins et al., 2018). However, patients that received epinephrine had no improvement in neurological outcome - that is, more ROSCs were achieved, but a large group of those that were revived went on to not regain normal neurological function (Perkins et al., 2018). This study sparked questions about both a scientific and ethical question about the use of epinephrine.
The Ethical Problem
This revelation left providers struggling with the question of what post-cardiac arrest resuscitation is for in the first place. Is the goal of a resuscitation to merely return vital signs and spontaneous circulation, or is the goal of resuscitation to revive a patient with a normal or close to normal neurological function? Furthermore, is it morally correct for providers to withhold or provide resuscitative efforts based on a presumption of a poor neurological outcome? Is it worth producing more ROSC patients in vegetative states, potentially against the patient’s wishes, in order to produce a higher ROSC/”save” rate overall?
As of the 2020 ACLS guidelines, epinephrine remains in use as the primary medication provided for cardiac arrest resuscitation. Discussion continues at the time of writing about the role, if any, that epinephrine will play in cardiac arrest care.
Works Cited
American Heart Association. (n.d.). History of CPR. Cpr.Heart.Org. https://cpr.heart.org/en/resources/history-of-cpr#:%7E:text=1975,Life%20Support%20(ACLS)%20Textbook.
American Heart Association. (2000). Section 6: Pharmacology II: Agents to Optimize Cardiac Output and Blood Pressure. AHA Journals: Advanced Cardiac Life Support. https://www.ahajournals.org/doi/10.1161/circ.102.suppl_1.i-129
Perkins, G. D., Ji, C., Deakin, C. D., Quinn, T., Nolan, J. P., Scomparin, C., Regan, S., Long, J., Slowther, A., Pocock, H., Black, J. J., Moore, F., Fothergill, R. T., Rees, N., O’Shea, L., Docherty, M., Gunson, I., Han, K., Charlton, K., . . . Lall, R. (2018). A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. New England Journal of Medicine, 379(8), 711–721. https://doi.org/10.1056/nejmoa1806842
