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Chapter 6

Why Epi Might (and might not) Work in Cardiac Arrest

Rob Orman, MD and Amal Mattu, MD
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22:20

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The pendulum never seems to stop swinging when it comes to the efficacy of epi in cardiac arrest.

 

Pearls:

  • Epi appears to be most beneficial if given within the first 15-20 minutes after cardiac arrest

  • Continued dosing of epi beyond the 20 minute mark (post cardiac arrest) seems to produce more rapid deterioration and is not supported by the literature.

  • Two studies from Japan suggest that epi yields neurologic benefit if given within the first 20 minutes of cardiac arrest.

  • There are three time sensitive phases which guide the management of cardiac arrest:  the electrical phase (first 5 minutes post arrest), circulatory phase (5-20 minutes post arrest), and metabolic phase (>20 minutes post arrest).  Epi appears to be beneficial if given during the circulatory phase.

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  • While studies suggest that IV epinephrine can improve rates of return of spontaneous circulation after cardiac arrest, less clear is whether epi improves neurologic outcome.  Two retrospective studies from Japan suggest that epi does yield neurologic benefit.

    • Sagisaka R, et al. Effects of repeated epinephrine administration and administer timing on witnessed out-of-hospital cardiac arrest patients. Am J Emerg Med. 2017 Oct;35(10):1462-1468. PMID: 28473275.

      • The conclusion of this study is that epinephrine administration improved neurologic outcome when epinephrine was administered within 20 minutes after an emergency call for witnessed cardiogenic, out-of-hospital, cardiac arrest.

    • Ueta H, et al. Quick epinephrine administration induces favorable neurological outcomes in out-of-hospital cardiac arrest patients. Am J Emerg Med. 2017 May;35(5):676-680. PMID: 28087097.

      • This study found that epinephrine is associated with improved neurologic outcome as long as the victim was reached within 16 minutes and EMS administered epinephrine as quickly as possible.

  • The pendulum never seems to stop swinging when it comes to the efficacy of epinephrine in cardiac arrest.  

    • 20-25 years ago, the push was to use escalating doses of epinephrine starting at 1 mg and increasing to 3 mg, then 5 mg, and continuing at 5 mg as needed.  Some protocols started directly with 5 mg and continued with 5 mg thereafter. These protocols were based on early studies which suggested that higher doses of epi resulted in improved survival to hospital admission.

    • Subsequent analyses, 5-10 years later, showed that many of the people who got high doses of epi were dying at the same rate, or perhaps even higher rate.  Also, amongst the survivors, the neurologic outcome was worse.

    • Over the past few years, a few studies have reported that epi, even in 1 mg doses, could be potentially harmful and not helpful.

    • The most recent literature seems to be coming back to a middle zone whereby there probably is some benefit to epinephrine, but only if given in a certain time period.  These studies suggest that epi is most beneficial if given in the first 15-20 minutes after cardiac arrest. Continued dosing of epi beyond the 20 minute mark (post cardiac arrest) seems to produce more rapid deterioration and is not supported by the literature.

  • There has been a resurgence in thinking about three time sensitive phases which guide the management of cardiac arrest.

    • The electrical phase is the first 5 minutes of cardiac arrest.  This is the period of time where the heart is most amenable to defibrillation  (if the patient has a shockable rhythm).

    • The next 10-15 minutes (or 5-20 minutes after arrest) is the circulatory phase. This is the time when good chest compressions are critical and when epinephrine is most beneficial.

    • The third phase extends beyond 20 minutes and is referred to as the metabolic phase.  This is when metabolic processes are breaking down and patients develop acid-base problems and electrolyte disorders.  Continued epinephrine during this phase can produce further cardiac ischemia, a decrease in cerebral blood flow, and worse neurologic outcomes.

    • Weisfeldt ML, Becker LB. Resuscitation after cardiac arrest: a 3-phase
      time-sensitive model. JAMA. 2002 Dec 18;288(23):3035-8. PubMed PMID: 12479769

    • Ueta H, et al. Quick epinephrine administration induces favorable neurological outcomes in out-of-hospital cardiac arrest patients. Am J Emerg Med. 2017 May;35(5):676-680. PMID: 28087097

  • In cardiac arrest, epinephrine has two major effects, the alpha and the beta.  It is the alpha effect which is most beneficial.

    • The beta effect is the bad effect of epi, because it produces further cardiac ischemia and increased myocardial oxygen demand.  In people who survive cardiac arrest, the more epi they get, the more likely they are to have persistent cardiac ischemia and recurrent heart attacks  in the early phase post resuscitation. This is due to the beta effect.

    • It’s the alpha effect, which produces peripheral vasoconstriction and brings blood back to the central circulation, that yields the benefit of epi. The alpha effect also increases coronary perfusion.

    • During the first 20 minutes after cardiac arrest, the benefit of epinephrine is due to its alpha effect which improves central and coronary perfusion. Beyond 20 minutes,  the beta effect starts having dramatic adverse consequences.

  • Is there a role for vasopressin in cardiac arrest management? Probably not.

    • Once the darling of emergency medicine literature, vasopressin has recently fallen out of favor.  Initial excitement about vasopressin was due to the notion that it seemed to produce all of the beneficial alpha effects of epinephrine without the detrimental beta effects.  

    • Early studies showed that vasopressin increased ROSC and survival to hospital admission, but when researchers looked at survival to discharge and survival with neurologic outcome, it appeared that patients who received vasopressin had a trend toward worse neurologic outcome. In other words, vasopressin started looking like it had the same results as high-dose epinephrine.

GoodCPR -

OK OK... Stop the train... My 2 neurons just made a connection.
If the ß effect of epi is the undesirable effect and all we want is the α effect. Then why don't we use Phenylephrine?! It is pure α agonist, it is like perfusion in a vial. What does Amal Jedi say?

Rob O. -

I was thinking the same thing as well! Here is the response from Amal.....

good question

phenylephrine sounds ideal, but it's been studied many years ago and didn't pan out, so they went back to EPI

Mark H. -

I have had this same thought. What's the scoop?

Stephen P., EM Pharmacist -

Great episode. I was hoping to hear thoughts about the role of epinephrine during the electrical phase.

Delivering epinephrine quickly in out of hospital arrest, where several minutes have elapsed, makes sense. Extrapolating this to patients with in-hospital arrest when intervention often occurs within seconds is not straightforward. For patients with VF/FT using epinephrine during the electrical phase seems counterproductive. Why give a tachyarrhythmia a ß agonist? Andersen BMJ 2016 studied this and found Epi in the first 2 minutes was associated with worse outcomes. Does it make sense to deliver electricity first and reserve Epi for the circulatory phase? Interestingly, this is exactly what ACLS currently recommends - two shocks before the first epinephrine. In my institution I still see Epi delivered immediately to VF/VT and in a previous episode How To Master CPR, Bill Reed's approach was described as 3 doses epinephrine in the first 10 minutes.

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