Epinephrine Auto-Injectors May Not Be Reliably Effective in Preventing Fatal Anaphylaxis

Utilizing epinephrine (adrenaline) auto-injectors (AAIs) such as EpiPens (Viatris) for the treatment of anaphylaxis can lead to variable and short-lived effects that may not be sufficient in the case of fatal anaphylaxis, according to a recent review published in Clinical & Experimental Allergy.^1,4

Epinephrine auto-injectors are a first-line treatment for anaphylaxis. | Image Credit: © Andrey Popov | stock.adobe.com

Anaphylaxis is considered a medical emergency because the severity of it cannot be easily predicted in patients at-risk. These patients are often prescribed AAIs for self-administration to help facilitate the early administration of intramuscular (IM) epinephrine.¹

Data is lacking regarding the effectiveness of current adrenaline treatments in preventing fatal anaphylaxis, including AAIs, partly because of the difficulty of studying the condition. Fatal anaphylaxis is particularly rare, unpredictable, and fast-moving; determining the effectiveness of AAIs in treating the condition remains a major unmet need.¹

Specifically, there is a lack of evidence from randomized control trials (RCTs) regarding the efficacy of epinephrine in anaphylaxis. Systematic reviews of available evidence from Sheikh et al and Dhami et al could not come to any definitive conclusions, with each group having difficulty finding any studies that have covered the topic at all.^1-3

There are major challenges to designing such trials, including difficulty identifying a proper outcome measure and providing a proper definition for anaphylaxis. Furthermore, the pathophysiology of fatal anaphylaxis is not well-characterized, making surrogate outcome measures for potentially fatal anaphylaxis lacking.^1-3

The current investigators sorted through the currently available evidence for epinephrine preventing fatal anaphylaxis, which included epidemiology, animal studies, and human observational studies with limited populations. They sought to review the role of epinephrine in anaphylaxis management and evaluate the effectiveness of AAIs in preventing fatal outcomes.¹

Epidemiological data indicates that anaphylaxis incidence has increased in recent years, while at the same time, population rates of fatal anaphylaxis have remained stable. From 1992 to 2012, anaphylaxis hospital admissions increased with stable fatality rates. During the same period, AAI prescriptions also increased. The investigators expected an increase in AAI-prescribing may lead to a fall in rates of fatal anaphylaxis—importantly, this was not the case, suggesting that AAIs may be ineffective in preventing fatal anaphylaxis.¹

RCTs of anaphylaxis management in ovalbumin-sensitized rates have been conducted. In one trial by Zheng, every rat that was randomized to “no treatment” died within 15 minutes, while rats randomized to adrenaline survived. Notably, these rats received epinephrine through continuous intravenous (IV) infusion. Trials in canines have indicated similar results, showing that continuous IV infusion leads to faster and more sustained recovery compared with IM administration.¹

The few published studies in humans regarding epinephrine for managing anaphylaxis have indicated that epinephrine is, indeed, effective—however, this was seen particularly regarding IV administration, rather than IM administration through an AAI. Resolution of anaphylaxis symptoms was seen more rapidly with IV infusions of epinephrine, and patients treated required a lower total dose of epinephrine.¹

Overall, minimal use of timely epinephrine in most cases of fatal and non-fatal anaphylaxis was observed across epidemiological data and retrospective case analyses. However, “the clinical studies suggest that prolonged, continuous IV infusions are required for treating severe anaphylaxis,” the investigators said.¹

“For effective management of the most severe allergic reactions, adrenaline given by continuous IV infusion, with appropriate fluid resuscitation, is likely to be required—how this is safely achieved in the pre-hospital setting remains to be determined,” the study authors concluded.⁴

REFERENCES

1. Sim M, Sharma V, Li K, et al. Adrenaline auto-injectors for preventing fatal anaphylaxis. Clinical & Experimental Allergy. Early view. 2024. doi:10.1111/cea.14565

2. Sheikh A, Shehata YA, Brown SGA, et al. Adrenaline for the treatment of anaphylaxis: Cochrane systematic review. Allergy. 2009;64(2):204-212. doi:10.1111/j.1398-9995.2008.01926.x

3. Dhami S, Panesar SS, Roberts G, et al. Management of anaphylaxis: a systematic review. Allergy. 2014;69(2):168-175. doi:10.1111/all.12318

4. Wiley. Can adrenaline auto-injectors prevent fatal anaphylaxis? EurekAlert! News Release. Released October 9, 2024. Accessed October 28, 2024. https://www.eurekalert.org/news-releases/1060201