Q&A: Epinephrine auto-injectors may not be adequate in preventing fatal anaphylaxis
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Key takeaways:
- Epinephrine autoinjectors may have little effect on surviving anaphylaxis events.
- Research is needed in discovering a method of delivery of steady levels of epinephrine to prevent fatal anaphylaxis.
Epinephrine autoinjectors may be associated with short-lived peak plasma levels, unpredictable cardiovascular responses as well as varying epinephrine absorption, according to a review published in Clinical and Experimental Allergy.
Through a review of different randomized controlled trials that included human as well as animal subjects, researchers concluded that while IV administered epinephrine infusions effectively prevented fatal anaphylaxis, epinephrine autoinjectors were not always successful.
Some critical studies have shown that prolonged and continuous IV epinephrine infusions are required to combat the fatal effects of anaphylaxis in some patients. Researchers also noted that even though the rates of epinephrine autoinjector availability have risen, the rates of fatal anaphylaxis have not dropped.
Healio spoke with Robert J. Boyle, MBChB, PhD, from the National Heart and Lung Institute, Imperial College London, about the review and what he and his research team found.
Healio: What prompted this review?
Boyle: Both in the accumulating evidence from our own department’s studies, and in work published elsewhere, we have been gradually losing confidence in the ability of epinephrine autoinjectors to save lives. But we wanted to systematically look at the evidence, to see whether this lack of confidence was justified; and, if so, to try to understand why epinephrine autoinjectors may not be very effective for preventing fatal anaphylaxis.
Healio: How effective are autoinjectors in saving lives?
Boyle: Although epinephrine autoinjectors are not explicitly marketed as lifesaving devices, it is clearly the intention of prescribers, patients and carers that using an epinephrine autoinjector should increase the probability of recovery from an episode of anaphylaxis.
Overall, however, there is no compelling evidence that they can do this. Indeed, all the available evidence suggests that epinephrine autoinjectors probably have little or no effect on survival.
Healio: What factors make them effective?
Boyle: Epinephrine autoinjectors contain epinephrine, and we do know from animal experiments that a continuous infusion of epinephrine into a vein is a very effective way of saving the life of someone suffering severe anaphylaxis.
Healio: What factors get in the way of their effectiveness?
Boyle: The dose of epinephrine in an autoinjector is a modest dose, and it is delivered in a single shot, which means its effects in the body don’t last very long. It is also injected into the muscle, where absorption is very variable. Autoinjectors which squirt the epinephrine out fast, such as EpiPen (Pfizer) and Jext (ALK-Abelló), may release the epinephrine too fast so that it can sometimes be harmful.
But even for autoinjectors which release epinephrine more slowly, absorption through muscle is very variable and effects are short-lived. If someone is going to die from anaphylaxis, which thankfully is a very, very rare event, they need quite a lot of epinephrine, delivered as a steady infusion, sometimes for several hours. A single low-dose shot, which is variably and unpredictably absorbed, is probably just not enough.
Healio: What do you think of alternative devices such as nasal spray or sublingual epinephrine?
Boyle: Absorption is also quite variable with these devices, and they have been compared against autoinjectors as the standard, when autoinjectors are likely ineffective for preventing fatal anaphylaxis. However, it is important to develop better devices, including exploration of alternative routes of epinephrine delivery, which might provide more sustained plasma epinephrine levels than autoinjectors.
Healio: Were there any particularly surprising or significant findings you would like to spotlight?
Boyle: We also looked at whether adrenaline autoinjectors have other benefits and were surprised to find that the small number of studies on quality of life tend to suggest that adrenaline autoinjectors have an adverse impact on quality of life.
Healio: How can doctors use these findings to improve the care they provide?
Boyle: When discussing epinephrine autoinjectors, doctors should be honest with their patients by acknowledging that these are unlikely to save lives, although a small beneficial effect cannot be excluded. During an episode of anaphylaxis, calling an ambulance may be as important as using an epinephrine autoinjector. Doctors should also acknowledge that epinephrine autoinjectors sometimes have an adverse effect on quality of life — presumably, due to heightened anxiety about the potential for fatal anaphylaxis, leading to increased social, dietary or other restrictions and/or emotional burden.
Healio: How can this research inform future public health policy/ future research?
Boyle: Future research is needed to understand mechanisms of fatal anaphylaxis, to identify people who are at risk for the very rare outcome of fatal anaphylaxis, and to develop better treatments for life-threatening anaphylaxis.
Reference:
- Can adrenaline auto-injectors prevent fatal anaphylaxis? https://www.eurekalert.org/news-releases/1060201#:~:text=Investigators%20noted%20that%20data%20from,impact%20in%20such%20deadly%20cases.. Published Oct. 9, 2024. Accessed Oct. 11, 2024.
For more information:
Robert J. Boyle can be reached at r.boyle@imperial.ac.uk.
Perspective
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First, let me acknowledge that this is an important and comprehensive review of the use of epinephrine in the treatment of anaphylaxis. The authors are truly experts. In fact, Richard Pumphrey, FRCPath, and Paul J. Turner, FRCPCH, PhD, are among the world’s top experts in the field.
My only problem with this article is the title, “Adrenaline Auto-Injectors for Preventing Fatal Anaphylaxis.” The purpose of epinephrine autoinjection is not to prevent death. It is to “treat acute allergic reactions including anaphylaxis,” in the words of the FDA.
Also, the focus of this review is on the most severe cases of anaphylaxis, but severe anaphylactic shock is not the most common presentation. Most cases in the community are mild or moderate and should respond very well to immediate use of epinephrine. This article deals mostly with the fatal and near-fatal cases in which epinephrine injection may not be effective enough.
Previous reports have shown that preventing death is not, and should not be, the main purpose of prescribing epinephrine. Contrary to popular belief, anaphylaxis is rarely fatal. Epinephrine is used infrequently even when prescribed, so it often seems like this is the reason for a fatal outcome, but is it really? About 1% to 2% of all cases of anaphylaxis are refractory to treatment with epinephrine, and these may be the ones most likely to die, despite prompt use of epinephrine.
This does not change the strength of the recommendation to use epinephrine promptly for anaphylaxis. It is the only thing that works (although IV fluids are also important in many cases), and it clearly prevents worsening or biphasic reactions, need for repeat doses of epinephrine, hospitalization and ICU admission. So, this paper does not imply that using epinephrine is futile. It just says that the rationale that it will prevent fatal anaphylaxis is probably flawed.
I have only had one patient ever die from anaphylaxis, and it was despite prompt use of an epinephrine autoinjector. But I have often seen epinephrine stop a reaction completely and quickly, and I would strongly recommend it to anyone having anaphylaxis — not to prevent death but to clear up a potentially nasty and scary reaction as quickly as possible.
This review leads us to challenge the fear of death that has been promoted for decades as the reason to use epinephrine. To experts and researchers in the field, it also suggests that IV epinephrine infusion is the best treatment, so ideally this would be the first thing done by EMS or ED personnel (rather than additional injections). But this is not relevant to what the patient can do in the field.
I worry that articles such as this erode confidence in epinephrine treatment. The authors contend that the failure of the number of deaths to decrease is because epinephrine autoinjectors cannot prevent them, but they do not give enough attention to the biggest problems with epinephrine autoinjectors: people are afraid to use them; people believe other medications, such as Benadryl (Johnson & Johnson) will help; people think it’s OK to “wait and see” if they get worse before using it; or they simply don’t use them at all.
So, the most important message for clinicians for now is not that epinephrine doesn’t prevent death, which may have some validity, but that people should use epinephrine as soon as possible when anaphylaxis begins. If people actually did that all that time, maybe we would see some decline in the number of deaths, but we would most certainly see a marked decline in the number of ED visits and hospitalizations, based on recommendations in the 2023 anaphylaxis practice parameter update.
The discussion of the research findings that are reviewed is of limited utility to the clinician, other than emergency/intensive care specialists. The suggestion that IV infusion of epinephrine is what is needed to treat severe anaphylactic shock (and hopefully prevent death) does not help doctors to counsel patients who are concerned about what to do if they have another episode of anaphylaxis.
However, it should be noted by emergency care specialists and intensive care doctors who have to treat these patients in the hospital. The take-home message for doctors would be to counsel patients that fear of dying is unwarranted, and that the best thing they can do is to use their epinephrine autoinjector without hesitation immediately upon the beginning of symptoms of anaphylaxis.
The next step is education. What is needed is professional and public education to underscore the rarity of fatal anaphylaxis, the benefits of immediate use of epinephrine autoinjectors at the onset of anaphylaxis, and the need for ED doctors to not only give epinephrine as immediate treatment (which most ED doctors still don’t do!) but to consider IV epinephrine infusion for patients in shock. Both patients and doctors still think that antihistamines and steroids are appropriate treatment for anaphylaxis. According to the anaphylaxis practice parameters for 2023, they are not!
References:
Dribin TE, et al. J Allergy Clin Immunol Pract. 2023;doi:10.1016/j.jaip.2023.02.002.
Golden DBK, et al. Ann Allergy Asthma Immunol. 2023;doi:10.1016/j.anai.2023.09.015.
Greenhawt M. Ann Allergy Asthma Immunol. 2023;doi:10.1016/j.anai.2023.04.003.
Turner PJ, et al. J Allergy Clin Immunol Pract. 2017;doi:10.1016/j.jaip.2017.06.031.
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