Epinephrine Auto-Injectors for In Hospital Use

Expanding on a previous post where we discussed the importance of IM administration of epinephrine for anaphylaxis (vs subcutaneous), I wanted to discuss epinephrine auto-injectors for in hospital use.

The mechanism and effects of epinephrine for anaphylaxis is several fold.[1]  Through alpha-1 agonism, vasoconstriction followed by increased peripheral vascular resistance leads to increased blood pressure as well as limiting the degree of mucosal edema. Beta-1 agonism increases the inotropy and chronotropy, and beta-2 agonism leads to bronchodilation, decreased mast cell activation, thereby decreasing histamine, leukotriene, platelet activating factor release but also skeletal muscle vasodilation (hence adequate absorption from IM administration).
IM administration in a hospital setting can be accomplished using 0.01mg/kg (max 0.5 mg in adults) of an epinephrine 1:1000 concentration and an IM needle. Confusion regarding which concentration of epinephrine to use (1:1000 or 1:10000), what mg/mL concentration the ratios represent, accidental SQ administration by someone not aware that IM is preferred, or accidental IV administration, can lead to significant drug errors and iatrogenic epinephrine overdose.[2]  Thus, epinephrine auto-injectors offer an advantage in that there is no confusion as to the concentration or dose since it is standardized (0.3 mg of 1:1000 for adults, 0.15 mg of 1:1000 for children), and IM administration is ensured since it is difficult (but not impossible) to administer any other route.
However, limitations exist. Administration delays can occur as a result of individuals who are not familiar with the device and how to use it (although the instructions are written and illustrated on the side of the auto-injector). Similarly from lack of familiarity, the person administering the auto-injector may accidentally inject their thumb.  For obese patients, the length of the needle is fixed and cannot be altered, placing a higher risk of accidental subcutaneous administration. EpiPen for example has a 22g needle with an exposed needle length of 0.58 inches.[3,4] In these situations however, the same risk could exist with a conventional needle and other routes should be sought (ie, IV dose of 0.01 to 0.1 mg). The pharmacologic shelf-life of epinephrine itself is short since it is easily oxidized to a substance called adrenochrome.[5] Interestingly, adrenochrome tints the solution red/brown- something to always be aware of with epinephrine. But as a result of its oxidation, the shelf-life of epinephrine auto injectors is no more than 24 months (usually 18).  Within a hospital setting, the product may expire since it is not as routinely used or as versatile as other epinephrine dosage forms.
There is, however, a significant pharmacokinetic advantage. Ensuring IM administration in the thigh, auto-injector achieves similar concentrations compared to conventional IM administration. Interestingly, the auto-injector then leads to a bi-phasic peak, something conventional IM administration does not do. This biphasic peak (40 min after administration) is thought to be as a result of further absorption after a period of vasoconstriction. Clinically, this may lessen rebound hypotension or recurrent shock since the usual duration of action of conventionally administered epinephrine is approximately 40 minutes.[6]
Epinephrine auto-injectors for in hospital use have their advantages and disadvantages. At the end of the day, if the same effort of education and training went into the existing epinephrine uses and dosage forms as the education and training essential for safe and effective use of in hospital auto-injectors, conventional epinephrine could still be ideal.
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references for Epinephrine Auto-Injectors for In Hospital Use

1. Westfall TC. Adrenergic agonists and antagonists. In: Goodman & Gillman’s: The pharmacological basis of therapeutics, 11th ed. NY, NY: McGraw-Hill.
2. Kanwar M, Irvin CB, Frank JJ, et al. Confusion about epinephrine dosing leading to iatrogenic overdose. Ann Emerg Med 2010; 55:341-44
3. Stecher D, et al. Epinephrine auto-injectors: is needle length adequate for delivery of epinephrine intramuscularly. Pediatrics 2009; 124:65-70
4. Song TT, Nelson MR, Chang JH, et al. Adequacy of the epinephrine autoinjector needle length in delivering epinephrine to the intramuscular tissues. Ann Allergy Asthma Immunol 2005; 94:539–542.
5. Simons KJ, et al. Epinephrine and its use in anaphylaxis. Current Opinion in Allergy and Clinical Immunology 2010, 10:354–361
6. Simons FE, et al. Epinephrine absorption in adults: Intramuscular versus subcutaneous injection. J Allergy Clin Immunol 2001; 108:871-3