Epinephrine and anaphylaxis outcomes

A central tenant of prehospital anaphylaxis management is timely epinephrine administration by patients, caregivers, or emergency medical services (EMS) personnel to minimize the risk of adverse outcomes, including biphasic reactions, hospitalizations, and fatalities.¹ Alarmingly, studies have consistently found epinephrine under-use in community settings for many reasons.² This glaring care gap has been hypothesized to increase the risk of adverse outcomes.³ However, conflicting data exist about whether delayed epinephrine administration, including not receiving prehospital epinephrine, increases the risk of adverse outcomes.

In this issue of Annals of Allergy, Asthma & Immunology, Hlady et al⁴ conducted an integrated single-center prospective and retrospective cohort study of children and adults with anaphylaxis (n = 1107) to evaluate whether there are differences in rates of biphasic reactions, emergency department (ED) length of stay, and hospitalizations among patients who do and do not receive prehospital epinephrine. The authors found that patients who received prehospital epinephrine (36.7%) were less likely to have biphasic reactions (5.4% vs 9.3%; odds ratio: 0.56, 95% CI: 0.34-0.92) and had shorter ED length of stay (median: 4.0 hours vs 4.7 hours). There was no statistical difference in hospitalization rates between the 2 groups in the multivariable model (adjusted odds ratio: 1.08, 95% CI: 0.71-1.64).

The authors reasonably conclude that “timely administration of prehospital epinephrine is associated with improved patient outcomes.” However, an alternative interpretation is that although 2 of the study’s outcomes achieved statistical significance, they may have negligible clinical significance for patients and the health care system. Although the rate of biphasic reactions was lower in the prehospital epinephrine group, there was only a slight difference in ED length of stay and no difference in hospitalization rates, a key measure of health care utilization. It could be argued that although we would not discourage prehospital epinephrine use, there is no pragmatic difference in outcomes such use promotes.

Anaphylaxis guidelines have been developed based on retrospective and prospective observational study data and the trend toward well-intended practices, which often lack quality, high-certainty evidence and may skew toward trying to limit uncommon outcomes (eg, fatalities).⁵ However, these studies are subject to potential confounders, including confounding by severity bias. Because patients perceived to be having severe reactions may be managed differently (eg, more aggressively) than patients perceived to have less severe reactions, an intervention (eg, how quickly a patient receives epinephrine) may be reported as associated/not associated with an outcome when the measured effect is instead secondary to baseline differences in the exposed and non-exposed groups. Although investigators can try controlling for confounders, this is especially difficult in observational and retrospective studies prone to missing (prehospital care) and inaccurate data (symptom severity and reaction courses).

Another limitation of observational studies is that investigators must account for the range of reaction severities,⁶ organ system combinations, and the limited number of near-fatal (eg, intubation and vasopressor support) and fatal reactions. As such, study results tend to be skewed to “negative findings” because they are not powered to detect statistically and clinically significant differences in rare presentations. Other confounders may relate to underlying social and health disparities, such as unmeasured effects secondary to race, income, or ethnicity, which affect access to medications (epinephrine), primary, subspecialty, and EMS care and education and support regarding anaphylaxis prevention and management.

This raises the question of how we should interpret and apply findings from the study by Hlady et al⁴ in clinical care, particularly with findings that trend on the border of significance (in either direction). First, these findings should not dissuade patients, caregivers, or health care professionals about the importance of timely epinephrine administration. On the contrary, epinephrine should be given immediately to patients with anaphylaxis and encouraged for patients who do not yet fulfill anaphylaxis criteria based on clinical judgment and experience. In this sense, using epinephrine, especially in non–health care settings, should be viewed as a therapy that may affect uncommon outcomes (preventing fatalities) while most certainly improving common outcomes such as symptom resolution. Prompt epinephrine use is the most effective treatment of reactions of any severity, including anaphylaxis. Using epinephrine to treat reactions that do not fulfill anaphylaxis criteria should not be misconstrued as recommending epinephrine for all findings (eg, a few isolated hives), which may contribute to “epinephrine creep” (and is not a harmful practice though one arguably of variable necessity) but instead acknowledges that the decision to use epinephrine lies along a treatment spectrum with “it’s probably fine” bookended between the clearcut recommendations of “give” and “don’t give” epinephrine.

Second, given that no randomized clinical trials of epinephrine have been conducted, we still do not know how to define “timely” epinephrine administration or whether “early” use before symptoms progress to anaphylaxis prevents adverse outcomes because these are hypotheses that are challenging to test rigorously. A definitive randomized clinical trial is needed to answer these questions. There would be equipoise in conducting such a study in the allergy clinic setting because epinephrine would not be withheld for patients with anaphylaxis; instead, one treatment group would receive early epinephrine for symptoms that do not fulfill anaphylaxis criteria, and the other would receive epinephrine for symptoms that do fulfill criteria.

Third, although epinephrine is postulated as lifesaving, evidence suggests that a small subset of fatal reactions occur despite appropriate epinephrine use. These recalcitrant phenotypes are poorly understood but highlight the highly synchronized actions that must occur to prevent patient demise, including immediate anaphylaxis recognition, epinephrine administration (and redosing), EMS activation, and advanced cardiopulmonary resuscitation, which may factor into how “lifesaving” epinephrine may be.

Fourth, as evident in this study, the low rate of prehospital epinephrine use (36.7%) reinforces the need to develop more effective and practical strategies to ensure patients and caregivers can recognize and manage life-threatening reactions. There is a pressing need to develop a readily accessible and easy-to-use clinical support tool for patients and caregivers in the community that provides patient-specific management guidance during reactions to ensure appropriate and timely epinephrine use, redosing, and EMS activation.

In conclusion, we applaud the authors for addressing a fundamental anaphylaxis knowledge gap.⁷ Although it is challenging to reveal that prehospital epinephrine administration affects clinical outcomes, we should continue to promote timely epinephrine administration even though the most likely outcome we can affect is reaction resolution and potentially patient and caregiver quality of life. However, these outcomes are not trivial, especially as they may become more salient based on the 2023 US anaphylaxis guidelines that support the at-home management of resolved anaphylaxis for select patients.⁸ In addition, the US Food and Drug Administration’s approval of the first non-injectable epinephrine delivery device heralds a new era in anaphylaxis treatment.⁹ This device and others in the pipeline will hopefully improve prehospital epinephrine use by overcoming needle phobia; however, research is needed to determine whether this hypothesis proves true and the impact of purported higher epinephrine rates on quality of life and other clinical outcomes.