Epinephrine has been a key component of ALS since the first CPR guidelines were published in the early 1960s, and its use has continued with little change in dose or timings over the past 60 years.

As well as its positive inotropic and chronotropic properties mediated through beta-agonist properties, the demonstration that epinephrine’s alpha-agonist effects increased aortic diastolic pressure to increase both coronary blood flow (associated with an increased chance of return of spontaneous circulation [ROSC]) and cerebral blood flow was also thought to be of benefit.1,2

However, there have been concerns about potentially harmful effects of epinephrine, mediated through reduced cerebral microvascular blood flow, cardiovascular instability after ROSC and adverse metabolic and immunomodulatory effects.

Recent prospective randomized trials concluded that although epinephrine generally increased the rate of ROSC, its use wasn’t associated with neurologically intact survival;3,4 findings supported by large observational studies.5–7

Of additional concern were several large database and registry studies finding that prehospital epinephrine was associated with a decreased chance of neurologically intact survival,8,9 particularly when given > 15–20 minutes after the cardiac arrest occurred, as tends to be the case in out-of-hospital cardiac arrests.10–12

Systematic reviews and meta-analyses of epinephrine in cardiac arrest reinforced concerns about the survival benefits of epinephrine therapy.13–15 This then led to a large prospective randomized trial of epinephrine in out-of-hospital cardiac arrest—the Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug administration In Cardiac arrest (PARAMEDIC-2) trial, which sought to establish whether the use of IV epinephrine, administered in accordance with current ALS guidelines is helpful or harmful.

This recently published study has demonstrated that, although epinephrine increased overall survival to hospital discharge (3.2% vs. 2.4%; unadjusted OR 1.39; p=0.017), there was no difference in neurologically intact survival to hospital discharge between groups (2.2% vs. 1.9%; unadjusted OR 1.18; p=NS). Significantly, survivors given epinephrine were more likely to be neurologically impaired, compared with those given placebo.16

However, much remains unanswered with regards to the optimal dose, dose interval and timing of epinephrine administration, although there are clues from registry and database studies suggesting that smaller doses given earlier and less frequently may be a better strategy.

In its current dosing strategy, epinephrine in cardiac arrest increases the chances of ROSC and survival to hospital discharge, but doesn’t increase neurologically intact survival. Whether epinephrine administration during cardiac arrest should continue in its current format, or whether alternative strategies may be more optimal, needs to be considered in detail. At a minimum, significant caution should be taken when administering epinephrine as currently recommended by ILCOR and AHA Guidelines.

References

1. Michael JR, Guerci AD, Koehler RC. Mechanisms by which epinephrine augments cerebral and myocardial perfusion during cardiopulmonary resuscitation in dogs. Circulation. 1984;69(4):822–835.

2. Brown CG, Werman, HA, Davis EA, et al. The effects of graded doses of epinephrine on regional myocardial blood flow during cardiopulmonary resuscitation in swine. Circulation. 1987;75(2):491–497.

3. Olasveengen TM, Sunde K, Brunborg C, et al. Intravenous drug administration during out-of-hospital cardiac arrest: A randomized trial. JAMA. 2009;302(20):2222–2229.

4. Jacobs IG, Finn JC, Jelinek GA, et al. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation. 2011;82(9):1138–1143.

5. Hagihara A, Hasegawa M, Abe T, et al. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA. 2012;307(11):1161–1168.

6. Nakahara S, Tomio J, Takahashi H, et al. Evaluation of pre-hospital administration of adrenaline (epinephrine) by emergency medical services for patients with out of hospital cardiac arrest in Japan: controlled propensity matched retrospective cohort study. BMJ. 2013;347:f6829.

7. Goto Y, Maeda T, Goto YN. Effects of prehospital epinephrine during out-of-hospital cardiac arrest with initial non-shockable rhythm: an observational cohort study. Crit Care. 2013;17(5):R188.

8. Dumas F, Bougouin W, Geri G, et al. Is epinephrine during cardiac arrest associated with worse outcomes in resuscitated patients? J Am Coll Cardiol. 2014;64(22):2360–2367.

9. Fukuda T, Ohashi-Fukuda N, Matsubara T, et al. Effect of prehospital epinephrine on out-of-hospital cardiac arrest: A report from the national out-of-hospital cardiac arrest data registry in Japan, 2011–2012. Eur J Clin Pharmacol. 2016;72(10):1255–1264.

10. Hayashi Y, Iwami T, Kitamura T, et al. Impact of early intravenous epinephrine administration on outcomes following out-of-hospital cardiac arrest. Circ J. 2012;76(7):1639–1645.

11. Ewy GA, Bobrow BJ, Chikani V, et al. The time dependent association of adrenaline administration and survival from out-of-hospital cardiac arrest. Resuscitation. 2015;96:180–185.

12. Tanaka H, Takyu H, Sagisaka R, et al. Favorable neurological outcomes by early epinephrine administration within 19 minutes after EMS call for out-of-hospital cardiac arrest patients. Am J Emerg Med. 2016;34(12):2284–2290.

13. Patanwala AE, Slack MK, Martin JR, et al. Effect of epinephrine on survival after cardiac arrest: A systematic review and meta-analysis. Minerva Anestesiol. 2014;80(7):831–843.

14. Lin S, Callaway CW, Shah PS, et al. Adrenaline for out-of-hospital cardiac arrest resuscitation: A systematic review and meta-analysis of randomized controlled trials. Resuscitation. 2014;85(6):732–740.

15. Loomba RS, Nijhawan K, Aggarwal S, et al. Increased return of spontaneous circulation at the expense of neurologic outcomes: Is prehospital epinephrine for out-of-hospital cardiac arrest really worth it? J Crit Care. 2015;30(6):1376–1381.

16. 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.