Epinephrine in Anaphylaxis: Too Little, Too Late

Jay Adam Lieberman; Julie Wang


Curr Opin Allergy Clin Immunol. 2020;20(5):452-458. 

In This Article

Data Supporting the use of Epinephrine in Anaphylaxis

Given that all guidelines suggest epinephrine as the only first-line therapy for anaphylaxis, one might assume that there are overwhelming data to support this. Unfortunately, however, this is not the case. In fact, it has been well documented that there are no randomized or placebo-controlled studies examining epinephrine in the management of anaphylaxis.[8] Due to the lack of evidence, the most recent 2020 United States Practice Parameter guideline on anaphylaxis recommended the use of epinephrine as a 'good practice statement' recommending to 'administer epinephrine as the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis'.[5] In an accompanying article, the authors acknowledged that good practice statements were made when there is high certainty that the recommendation will do more good than harm, but little or no direct evidence.[6]

Overwhelming support for the use of epinephrine then is mainly based upon the known pharmacologic actions of epinephrine, some animal data, and few observational and retrospective human studies. Via its actions on α-1 receptors, epinephrine can increase vascular resistance reversing mucosal edema, hypotension, and shock; via action on β-1 receptors, it can increase cardiac output; and via action on β-2 receptors, it can lead to bronchodilation. These are all ideal effects in the treatment of anaphylaxis.[9]

Unfortunately, though the actual animal and human data to support these actions are not as concrete.

Animal Studies

There are a few well designed animal studies examining the role of epinephrine in the treatment of anaphylaxis. In a ragweed-induced canine anaphylaxis model, epinephrine when given intravenous after maximal hypotension was able to transiently increase mean arterial resistance and stroke volume as compared with placebo.[10] However, intramuscular and subcutaneous epinephrine did not alter hemodynamics at all when compared with placebo. This early study suggested that epinephrine had minimal effect once hemodynamic collapse occurred.

In a follow-up study in the same ragweed-induced canine model, administration of epinephrine via different routes was studied when given at the initiation of allergen challenge rather than once hypotension peaked.[11] Results from this study showed that only constant infusion of epinephrine (not intravenous bolus, intramuscular, or subcutaneous routes) led to significant changes in mean arterial pressure or cardiac output compared with no treatment.

Similar findings have been observed in an ovalbumin-induced rat model, in which epinephrine given by intravenous bolus ×2 after the onset of shock, followed by continuous infusion, improved hemodynamics and survival, with no effects seen with saline bolus followed by infusion.[12,13] Data from these studies indeed suggest that epinephrine can restore cardiovascular function in animal models of anaphylactic shock; however, to achieve meaningful clinical effects, it must be given by continuous intravenous infusion, a route rarely used in the management of anaphylaxis in humans.

Human Studies

As mentioned earlier, there are no randomized clinical trials of epinephrine for anaphylaxis in humans, thus information on the utility of epinephrine in outcomes of anaphylaxis can only be gleaned from examining outcomes from other means.

Perhaps the best reports are from older, small, prospective studies examining sting challenges in placebo-controlled venom immunotherapy studies.[14,15] In these studies, many patients who received placebo immunotherapy developed anaphylaxis upon sting challenge. In the older study, Smith et al. showed that 11/14 patients who reacted had initial cutaneous symptoms that responded to epinephrine. However, 3/14 patients developed immediate hypotension, and only 1 of these responded epinephrine.[14] Brown et al. showed that all 21 patients with systemic reactions to sting challenge responded to epinephrine. However, it is important to note that all patients were treated with intravenous epinephrine at doses higher than typically provided to patients and for prolonged time (mean dose 590 μg and 115 min). In addition, those patients with hypotension required even higher doses for longer infusions (mean dose 762 μg and 169 min).[15] Thus, from these studies, it appears epinephrine can treat anaphylaxis, but may require higher doses and intravenous form in severe reactions.