(February 2023)

Epinephrine is an endogenous catecholamine non-selective agonist of all adrenergic receptors with a major role in emergency medicine on a variety of different diagnoses. 

• Anaphylaxis
  Epinephrine acts on several pathophysiological pathways that cause anaphylaxis. To this date, it is the only established therapy to treat this condition with a proven efficacy (1, 3, 4). 

• Cardiac arrest
  Current guidelines include epinephrine as part of standard treatment during cardiac arrest in children and adults, being the only recommended drug regardless of initial rhythm (10, 11) mainly because it is associated with an increased rate of ROSC* and short-term survival (6, 7, 8, 13). Benefits of epinephrine predominate in an early administration (<10 minutes) of non-shockable cardiac arrest (12, 13). 

• Severe asthma crisis
  Consider IV or IM epinephrine in the crashing asthmatic patient to deliver a systemic Beta-2 agonist agent (when inhaled bronchodilators have trouble getting into the lower airway). Give as a push-dose if administered IV, and an equivalent anaphylaxis dose for IM administration.

*ROSC: Return of Spontaneous Circulation

Adult dose for anaphylaxis
0.01mg/kg (max 0.5mg per dose) IM into the anterolateral aspect of the thigh.

• Can be repeated every 5-15 min if necessary.

• If no response, consider a continuous IV infusion of epinephrine.

Adult dose for cardiac arrest
1mg every 3 to 5 minutes IV or IO.

• In shockable rhythms early defibrillation should be perform as soon as possible, before any other resuscitation interventions.

FDA-Labeled (5)

• Anaphylaxis

• Hypotension associated with septic shock (norepinephrine is preferred as first-line medication)

Off-label

• Cardiac arrest

• Symptomatic AV heart block unresponsive to atropine

• Croup (alternative to nebulized racepinephrine)

• Severe asthma

• Epistaxis (topical, diluted)

Anaphylaxis (3)

• Adult dose for anaphylaxis
  0.01mg/kg (max 0.5mg per dose) IM into the anterolateral aspect of the thigh.

  • Can be repeated every 5-15 min if necessary.

  • If there is no response, consider a continuous IV infusion of epinephrine.
    
    

Cardiac Arrest (10)

• Adult dose for cardiac arrest
  1mg every 3 to 5 minutes IV or IO.

  • In shockable rhythms early defibrillation should be performed as soon as possible, before any other resuscitation interventions.

Crashing asthmatic

• Adult dose for the crashing asthmatic

  • IV: consider use as push-dose epinephrine (50-100ug every 5-10 min).

  • IM: 0.01mg/kg (max 0.5mg per dose) into the anterolateral aspect of the thigh.

Anaphylaxis (3)

• Pediatric dose for anaphylaxis
  0.01mg/kg (max 0.3mg per dose) IM into the anterolateral aspect of the thigh.

  • Can be repeated every 5-15 min if necessary.

  • If there is no response, consider a continuous IV infusion of epinephrine.

Cardiac Arrest (11)

• Pediatric dose for cardiac arrest
  0.01mg/kg every 3 to 5 minutes, IV or IO
  0.1mg/ml concentration, max 1mg per dose

  • In shockable rhythms early defibrillation should be performed as soon as possible, before any other resuscitation interventions

Crashing asthmatic

• Pediatric dose for the crashing asthmatic

  • IV: 0.5-1ug/kg, repeat every 5-10 min if necessary

  • IM: 0.01mg/kg (max 0.3mg per dose) into the anterolateral aspect of the thigh, repeat every 5-15 min if necessary

• As a non-selective adrenergic agonist, epinephrine increases peripheral vascular resistance through vasoconstriction and has chrono-inotropic effects in order to increase cardiac output (3). Epinephrine antagonizes the consequences of anaphylaxis-mediated cardiovascular collapse, soft tissue edema (that leads to gastrointestinal symptoms and airflow obstruction secondary to upper and lower respiratory tract compromise), as well as the release of other inflammatory mediators. 
  
  

• Antihistamines (ATH) and glucocorticoids (GCs) are almost universally prescribed for anaphylaxis and other allergic reactions, but have a longer onset of action, and their pharmacological target does not antagonize anaphylaxis pathophysiology. 

  • ATH may treat urticaria and itching, improving symptoms during anaphylaxis (3).

  • ATH and GCs are not recommended as first-line therapy that could delay epinephrine administration (3). 

  • ATH and GCs utility as adjuncts is questionable on whether to treat the main episode and to prevent biphasic anaphylaxis (3).
    
    

• The effects of epinephrine can divided by receptor functions (2):

• 𝛼-1 (alpha-1) peripheral receptors

  •  Increases vasoconstriction,  increasing systemic vascular resistance.

  •  Reduces upper airway edema, mucosal and peripheral edema.

• β1/ β2 (beta-1 and beta-2) cardiac receptors

  • Increases cardiac output by increasing inotropism and chronotropism. The α-1 vasoconstrictor effect has a major impact on systemic vascular resistance than b2-peripheral receptor activation.

• β2 (beta-2) bronchial receptors

  • Produces bronchodilation by smooth muscle relaxation.

•  β2 (beta-2) Lymphocyte receptor (present in mast cells and basophils)

  • Reduces degranulation of inflammatory cells and histamine release. 

  • In anaphylaxis, stimulation of mast cells and basophils release inflammatory mediators such as histamine, producing vasodilation, cardiac depression (as mast cells are present through the myocardium and the intima of coronary arteries) and finally cardiovascular collapse.

In recent years, epinephrine utility has been questioned because of conflicting data on long term survival and its association with detrimental neurological outcomes (7, 9). 

2020 Adult Advanced Life Support Guidelines state the following (10): 

• “Concerns have been expressed about epinephrine increasing the number of survivors with unfavorable neurological outcome in the PARAMEDIC2 trial (Pre-Hospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest). 

• The opinion of the ALS Task Force, however, is that any drug that increases the rate of ROSC and survival, but is given after several minutes of cardiac arrest when some degree of neurological damage may already have occurred, will likely increase the number of survivors with both favorable and unfavorable neurological outcome. Determining the likelihood of favorable or unfavorable neurological outcome at the time of starting resuscitation is currently not feasible. Therefore, the task force consensus is that continuing to use a drug that increases survival and focusing efforts on providing earlier CPR, earlier drug administration, and improved post-resuscitation care for all patients is likely to increase survival with a favorable neurological outcome.”

PARAMEDIC-2 compendium available at The Bottom Line - PARAMEDIC2

Anaphylaxis

• Shaker MS, Wallace DV, Golden DBK, et al. Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis. J Allergy Clin Immunol. 2020;145(4):1082-1123. doi:10.1016/j.jaci.2020.01.017
  Pubmed

Cardiac Arrest Advanced Cardiovascular Life Support 

• Adults

  • Berg KM, Soar J, Andersen LW, et al. Adult Advanced Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2020;142(16_suppl_1):S92-S139. doi:10.1161/CIR.0000000000000893
    AHA-Circulation (Open Access)

    • Text extract:

"Treatment Recommendations

• • • • We recommend administration of epinephrine during CPR (strong recommendation, low to moderate certainty of evidence).

      • For nonshockable rhythms (pulseless electric activity/asystole), we recommend administration of epinephrine as soon as feasible during CPR (strong recommendation, very low-certainty evidence).

      • For shockable rhythms (VF/pVT), we suggest administration of epinephrine after initial defibrillation attempts are unsuccessful during CPR (weak recommendation, very low-certainty evidence)."

• Pediatrics

  • Topjian AA, Raymond TT, Atkins D, et al. Part 4: Pediatric Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020;142(16_suppl_2):S469-S523. doi:10.1161/CIR.0000000000000901
    AHA-Circulation (Open Access)

Anaphylaxis

1. Campbell RL, Li JT, Nicklas RA, Sadosty AT; Members of the Joint Task Force; Practice Parameter Workgroup. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol. 2014;113(6):599-608. doi:10.1016/j.anai.2014.10.007
   Pubmed

2. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13th edition. McGraw Hill; 2017.
   McGraw-Hill

3. Shaker MS, Wallace DV, Golden DBK, et al. Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis. J Allergy Clin Immunol. 2020;145(4):1082-1123. doi:10.1016/j.jaci.2020.01.017
   Pubmed

4. McHugh K, Repanshek Z. Anaphylaxis: Emergency Department Treatment. Emerg Med Clin North Am. 2022 Feb;40(1):19-32. doi: 10.1016/j.emc.2021.08.004. Epub 2021 Oct 29. PMID: 34782088.
   Pubmed

5. NIH-NLM (National Institutes of Health National Library of Medicine). DailyMed. Label: Adrenalin - epinephrine injection. Updated in December 2022. Accessed in February 2023.
   DailyMed

Cardiac arrest

6. Olasveengen TM, Wik L, Sunde K, Steen PA. Outcome when adrenaline (epinephrine) was actually given vs. not given - post hoc analysis of a randomized clinical trial. Resuscitation. 2012;83(3):327-332. doi:10.1016/j.resuscitation.2011.11.011
   Pubmed

7. Loomba RS, Nijhawan K, Aggarwal S, Arora RR. 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. doi:10.1016/j.jcrc.2015.08.016
   Pubmed

8. Shao H, Li CS. Epinephrine in Out-of-hospital Cardiac Arrest: Helpful or Harmful?. Chin Med J (Engl). 2017;130(17):2112-2116. doi:10.4103/0366-6999.213429
   Pubmed

9. PARAMEDIC-2: 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. doi:10.1056/NEJMoa1806842
   NEJM (Open Access)

10. Berg KM, Soar J, Andersen LW, et al. Adult Advanced Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2020;142(16_suppl_1):S92-S139. doi:10.1161/CIR.0000000000000893
    AHA-Circulation (Open Access)

11. Topjian AA, Raymond TT, Atkins D, et al. Part 4: Pediatric Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020;142(16_suppl_2):S469-S523. doi:10.1161/CIR.0000000000000901
    AHA-Circulation (Open Access)

12. Okubo M, Komukai S, Callaway CW, Izawa J. Association of Timing of Epinephrine Administration With Outcomes in Adults With Out-of-Hospital Cardiac Arrest. JAMA Netw Open. 2021;4(8):e2120176. Published 2021 Aug 2. doi:10.1001/jamanetworkopen.2021.20176
    Pubmed Central (Open Access)

13. Fernando SM, Mathew R, Sadeghirad B, et al. Epinephrine in Out-of-Hospital Cardiac Arrest - A Network Meta-Analysis and Subgroup Analyses of Shockable and Non-Shockable Rhythms [published online ahead of print, 2023 Jan 31]. Chest. 2023;S0012-3692(23)00165-4. doi:10.1016/j.chest.2023.01.033
    Pubmed