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Reference: . Timing of repeat epinephrine to inform paediatric anaphylaxis observation periods: a retrospective cohort study. Lancet Child & Adolescent Health. July 2025
Dr. Kammeron Brissett
Guest Skeptic: Dr. Kammeron Brissett is a pediatric emergency medicine fellow at Children’s National Hospital in Washington, DC. She completed her pediatrics residency and a chief year at Rainbow Babies and Children’s Hospital in Cleveland, Ohio. Her interests include injury prevention, social determinants of health, and advocacy.
Case: A 7-year-old boy with a peanut allergy presents to the emergency department (ED) after eating a cookie at a birthday party. Shortly afterwards, he developed hives and wheezing. His parents gave him an epinephrine auto-injector to improve his symptoms. In the ED, he feels much better. His vital signs are normal, and his lungs are clear. He has no other gastrointestinal or cardiovascular symptoms. The parents tell you, “Unfortunately, we’ve been through this before. It’s not the first time he has accidentally eaten something that may have had some peanuts in it. Last time, we sat in the ED for a few hours before going home. It’s been a long day. Can we just go home now?”
Background: Anaphylaxis is a serious, potentially life-threatening systemic allergic reaction with a fast onset. It is a clinical diagnosis that should be considered when:
- Acute illness with skin/mucosal involvement and either respiratory compromise or reduced blood pressure/end-organ symptoms; or
- Two or more of the following occurring rapidly after exposure: skin/mucosal involvement, respiratory compromise, reduced blood pressure, or persistent gastrointestinal symptoms; or
- Reduced blood pressure after exposure to a known allergen for the patient.
Early recognition and treatment with intramuscular epinephrine is crucial.
Sometimes, even after initial symptom improvement with IM epinephrine, anaphylaxis symptoms can recur even without exposure to the known trigger. This is called a biphasic reaction and can happen up to 72 hours later.
The SGEM discussed anaphylaxis and biphasic reactions 13 years ago on SGEM#57. The bottom line was that prolonged observation is likely unnecessary in patients whose symptoms resolve with therapy in the ED. Biphasic reactions are rare and can occur anywhere from 10 minutes up to 6 days. We already have problems with boarding and overcrowding. We can’t keep all patients with anaphylaxis for 6 days. So, when can we send them home?
Traditionally, ED observation after anaphylaxis has been around 4 to 6 hours to monitor for biphasic reactions. The Resuscitation Council UK recommends a risk-stratified approach: A patient can be discharged after 2 hours when there’s a good response to a single dose of epinephrine, the symptoms have resolved, the child and family has another epinephrine autoinjector and knows how to use it, and has adequate supervision after discharge. They recommend at least 6 hours of observation if two IM doses of epinephrine were needed or there was a prior biphasic reaction. Finally, they recommend at least 12 hours observation if there was severe respiratory compromise, >2 doses of epinephrine, ongoing allergen absorption, late-night presentation/limited access to care, or difficult access to emergency services.
The National Institute for Care and Health Excellence (NICE) is even a bit more conservative, recommending any child under age of 16 with suspected anaphylaxis be admitted. What about in the US?
In the United States, the 2023 AAAAI/ACAAI Joint Task Force Practice Parameter (JTFPP) emphasizes individualized, risk-based observation and shared decision-making, noting that risk for biphasic reactions is higher with more severe initial reactions and when >1 dose of epinephrine is required. It also highlights that patients with a prompt, complete, and durable response to epinephrine may not always require activation of EMS or prolonged monitoring, underscoring tailored disposition planning.
Clinical Question: Among children treated with epinephrine for anaphylaxis, what is the timing and incidence of repeat epinephrine that could inform safe observation periods?
Reference: . Timing of repeat epinephrine to inform paediatric anaphylaxis observation periods: a retrospective cohort study. Lancet Child & Adolescent Health. July 2025
- Population: Children 6 months to 17 years presenting to 31 EDs (30 US, 1 Canada) with an acute allergic reaction treated with epinephrine from 2016 to 2019.
- Excluded: Transfers from outside facilities, ED medication-induced reactions, missing pre-ED symptom documentation; comorbidities requiring tailored management
- Intervention: ED observation following the first epinephrine dose and need for additional epinephrine
- Comparison: Comparisons were made across severity strata (no respiratory/cardiovascular involvement vs respiratory involvement only vs cardiovascular involvement).
- Outcome:
- Primary Outcome: Time from first to last epinephrine dose (repeat epinephrine as a proxy for clinically significant ongoing/recurrent reaction).
- Secondary Outcomes: Biphasic anaphylaxis and non-anaphylaxis, persistent anaphylaxis and non-anaphylaxis, refractory anaphylaxis, other return-care outcomes
- Trial: Multicenter retrospective cohort
Authors’ Conclusions: “A 2-h observation period is probably safe for most children who present to an emergency department with an acute allergic reaction requiring epinephrine. A 4-h observation period might be enough for patients with cardiovascular involvement who appear well.”
Quality Checklist for Observational Study:
- Did the study address a clearly focused issue? Yes
- Did the authors use an appropriate method to answer their question? Yes
- Was the cohort recruited in an acceptable way? Yes
- Was the exposure accurately measured to minimize bias? Unsure
- Was the outcome accurately measured to minimize bias? Unsure
- Have the authors identified all-important confounding factors? Unsure
- Was the follow-up of subjects complete enough? Unsure
- How precise are the results? Unsure
- Do you believe the results? Yes
- Can the results be applied to the local population? Yes
- Do the results of this study fit with other available evidence? Yes
- Funding of the Study: National Center for Advancing Translational Sciences and The National Institute of Allergy and Infectious Diseases of the National Institutes of Health. The funders had no role in study design, data collection, data analysis, interpretation, or writing of paper. Two of the authors report receiving consultant fees. One is on the advisory board and gets stock options from biotech companies and royalty fees from the publisher.
Results: They included 5,641 eligible children with a median age of 7.9 years, with slightly more males (56%). 4956 (88%) fulfilled the National Institute of Allergy and Infectious Diseases and Food Allergy and Anaphylaxis Network criteria for anaphylaxis.
In that group, 1.5% met criteria for biphasic anaphylaxis and 10.7% had persistent anaphylaxis.
4.7% received repeat epi after 2 hours from initial dose. 1.9% received repeat epi dose after 4 hours.
Patients with cardiovascular involvement had higher rates of biphasic anaphylaxis.
Key Results: Around 95% of children can be safely discharged after 2 hours of observation without the need for additional epinephrine.
Among all patients, 5% received a repeat dose of epinephrine after 115 minutes. There were differences in patients with or without respiratory or cardiovascular involvement.
Primary Outcome: In the entire cohort, 4.7% received epi 2 hours after the initial dose, 1.9% received epi after 4 hours, 1.1% received epi after 6 hours, and 0.8% received epi after 8 hours.
Secondary Outcomes:
- 86 (1.5%) had biphasic anaphylaxis
- 236 (4.2%) had biphasic non-anaphylactic allergic reactions
- 605 (10.7%) had persistent anaphylaxis
- 1400 (24.8%) had persistent non-anaphylactic allergic reactions
- 118 (2.1%) had refractory anaphylaxis
Diagnosis of Anaphylaxis
We mentioned that anaphylaxis is a clinical diagnosis, but it’s not always clear-cut. In this retrospective review, the authors used ICD-10 codes and chart reviews to determine whether patients experienced anaphylaxis. They included patients who were treated with intramuscular, subcutaneous, or intravenous epinephrine. Potential biases include selection bias, information bias, and misclassification bias.
Not all the patients included in this study actually met criteria for anaphylaxis, which is acknowledged by the authors. Anaphylaxis Practice Guideline update in 2023 states, “treatment with epinephrine or clinical response to epinephrine should also not be used as a surrogate marker to establish a diagnosis of anaphylaxis because there are many cases in which patients receive epinephrine for milder reactions.” Some of these patients were included because authors reported that “the administration of epinephrine might have mitigated reaction progression.”
Appendix Table 3, which examines interrater reliability for agreement on anaphylaxis identification, reports kappa values ranging from 0.68 to 0.76, indicating substantial agreement but not perfect agreement.
Repeat Epinephrine
The primary outcome for this study was the time from first to last administration of epinephrine. We must be careful and state that this is not the equivalent of a biphasic reaction.
The decision to administer a repeat dose of epinephrine is also not always clear-cut. It is pragmatic. The clinician may have decided to administer another dose of epinephrine despite the patient not meeting the exact definition of anaphylaxis or a biphasic reaction. Epinephrine may have been administered because the child exhibited concerning signs or symptoms.
For example, if a child was being observed in the ED after experiencing anaphylaxis and receiving that first dose of epi started saying that his throat was feeling weird again, we wouldn’t fault the clinician for choosing to give a second dose of epinephrine, but we just wouldn’t know if the child really needed it.
Confounding
Any observational study is at risk of confounding. One example we can see is if we look at Figure 3, it appears that the pre-emergency administration of epinephrine is a factor that increases the odds of repeat administration of epinephrine.
This is somewhat counterintuitive, as early recognition of anaphylaxis and administration of epinephrine should be beneficial. Instead, this may indicate disease severity. Sicker children received epinephrine in the pre-emergency setting.
We can also see something similar with steroid use in the emergency department associated with an increased odds of repeat epinephrine. I do not routinely give corticosteroids for anaphylaxis, given that the likelihood of benefit is low or uncertain. In this study, it may be more indicative of a patient who had a more severe reaction.
Risk of Repeat Epinephrine
The study team a priori defined the observation threshold at which the cumulative incidence of repeat epinephrine dosing increased by < 2% with each 1-hour increase in observation time. It’s not clear where this 2% came from.
The paper reports that this “was deemed clinically acceptable because it represented the optimal balance between prolonged observation with limited benefit and the likelihood of biphasic reaction occurring after discharge.”
Who decided this? Was it the authors? Was there any input from patients and families? Ultimately, individual clinicians and patients/families may have differing risk thresholds.
Bounce Backs for Biphasic Anaphylaxis
Assuming a patient who is discharged from the ED for anaphylaxis with an epinephrine autoinjector returns after a biphasic reaction. Is that necessarily a failure, or should it reflect negatively on the discharging clinician?
A significant part of our work in the ED is to provide anticipatory guidance and discuss signs and symptoms that would prompt the patient to return to the ED for care. It can be argued that a patient returning to the ED after discharge for a biphasic anaphylactic reaction who self-administered an epinephrine autoinjector is a good thing. This indicates that our anticipatory guidance was effective and well delivered.
Comment on the Authors’ Conclusion Compared to the SGEM’s Conclusion: In general, we agree that most pediatric patients likely do not require prolonged observation in the ED after being treated for anaphylaxis. However, the risk tolerance for a biphasic reaction may vary among patients, families, and clinicians.
SGEM Bottom Line: There is no high-quality evidence to support specific observation times in the ED after pediatric anaphylaxis. Engage in shared decision-making and consider your clinical judgement and the patient/family’s values.
Case Resolution: The 7-year-old boy improved rapidly after a single dose of IM epinephrine. During his time in the ED, he has no difficulty breathing or changes in hemodynamics. After discussion with the family, you recognize that they are familiar with signs and symptoms of anaphylaxis and know how to administer IM epinephrine auto-injector. You also confirm that the family has another epinephrine auto-injector at home and send them with a prescription for two new auto-injectors. Afterwards, you send them home.
Clinical Application: There is limited high-quality evidence on observation times for anaphylaxis. Specifically, there is no evidence that any particular observation period is superior, as biphasic reactions may occur up to 72 hours after the initial event. Institutional guidelines may vary. Remember the pillars of evidence-based medicine. Consider your clinical judgement and the patient or family’s values and preferences. Prior to discharge, ensure the patient feels better, that families and patients are aware of the signs and symptoms of anaphylaxis and biphasic reactions, and that they have another epinephrine autoinjector at home.
What Do I Tell the Patient/Family?
Sorry that this happened to your son. It’s great that he seems to be feeling better. It sounds like you have found yourself in this situation before. There’s no set amount of time we must observe him in the emergency department. Let’s briefly go over what symptoms to look out for at home and make sure that you can get another epinephrine autoinjector before you leave the ED.
Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.
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