Don't Delay, Epi Right Away: Updates in Management of Anaphylaxis

Column Author: Maya Gibson, MD | Resident of Pediatrics

Column Editor: Kathleen Berg, MD, FAAP | Hospitalist - Pediatrics; Associate Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Clinical Assistant Professor of Pediatrics, University of Kansas School of Medicine

Anaphylaxis is a severe allergic reaction that is mediated by IgE binding and cross-linking of the IgE receptor on mast cells and basophils.¹ The leading causes of anaphylaxis in children are food allergens and stinging insects.² Although not as common, anaphylaxis due to drugs is one of the leading causes of fatal anaphylaxis. Commonly implicated drugs include penicillins, cephalosporins, sulfonamides, aspirin and other nonsteroidal anti-inflammatory drugs.³ 

In 2005, the National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network convened to create diagnostic criteria for anaphylaxis.⁴ One of the three criteria must be fulfilled:

1. Acute onset of illness with involvement of skin, mucosal tissue or both with either respiratory symptoms or reduced blood pressure and/or associated symptoms of end-organ dysfunction.
2. Two or more of the following occurring rapidly after exposure to a likely allergen: involvement of skin or mucosal tissue, respiratory symptoms, reduced blood pressure, or gastrointestinal symptoms.
3. Reduced blood pressure due to exposure to a known allergen.

Within the emergency department (ED) these criteria have a 95% sensitivity, 71% specificity, positive likelihood ratio of 3.26 and negative likelihood ratio of 0.07.⁵ In 2020, updated practice parameters supported the continued use of these diagnostic criteria and provided additional recommendations.¹  

A well-known phenomenon known as biphasic anaphylaxis may occur one to 78 hours following resolution of initial anaphylaxis.⁶ This phenomenon has been observed in 1%-20% of patients. Risk factors for biphasic anaphylaxis include more severe initial presentation (OR, 2.11; 95% CI, 1.23-3.61) or repeated epinephrine doses (OR, 4.82; 95% CI, 2.70-8.58).¹ Additional risk factors may include wide pulse pressure, unknown anaphylaxis trigger, cutaneous signs and symptoms, and drug trigger in children.  

The diagnosis of anaphylaxis is clinical. Neither imaging nor laboratory studies are generally needed. Quick diagnosis followed by appropriate treatment is imperative.

Epinephrine 

The treatment of anaphylaxis is epinephrine, epinephrine, and epinephrine! In a recent study in the ED, up to 80% patients with anaphylaxis did not receive epinephrine.⁷ Intramuscular (IM) epinephrine is the preferred route, and it should be given in the anterolateral thigh. Dosing is 0.01 mg/kg of a 1:1000 [1 mg/mL] solution to a max of 0.5 mg in adults and 0.3 mg in children <25-30 kg. Epinephrine is a nonselective adrenergic agonist that causes vasoconstriction thereby increasing cardiac output, bronchodilation, and stabilization of mast cells and basophils. The effect is observed within 10 minutes. If needed, dosing can be repeated every five to 15 minutes until resolution of anaphylaxis.  

Antihistamines and glucocorticoids 

Many practitioners will use antihistamines and glucocorticoids in the treatment of anaphylaxis, often delaying the time to providing epinephrine.⁷ Antihistamine’s onset of action is within 30 minutes and glucocorticoids is four to six hours. Although histamine plays a role in the pathogenesis of anaphylaxis, antihistamines will not effectively treat hypotension or bronchospasm. Evidence does not suggest that the risk of biphasic reaction is decreased by first-generation antihistamines (OR, 0.71; 95% CI, 0.47-1.06), second-generation antihistamines (OR, 1.21; 95% CI, 0.80-1.83), or glucocorticoids (OR, 0.87; 95%, CI, 0.74-1.02).¹ One study observed that glucocorticoids were associated with a decreased length of hospital stay but did not have an effect of return to the ED within three days.⁸ Interestingly, observational studies suggested there may be an increased risk of biphasic anaphylaxis in children who were treated with glucocorticoids (OR, 1.55; 9% CI, 1.01-2.38).¹ However, the quality of evidence is low and more research is needed in this area. 

Following treatment, patients should be observed for at least one hour following resolution of anaphylaxis. This observation is associated with a 95% negative predictive value of biphasic anaphylaxis.⁹ In cases of severe anaphylaxis, consider extended observation. Six hours of observation is associated with a 97.3% negative predictive value of biphasic anaphylaxis, but impractical for routine care. At the time of discharge, discussion about possible triggers is imperative. Each patient should receive an epinephrine auto-injector with appropriate education.  

Key points:

1. Administer intramuscular epinephrine immediately. 
2. Antihistamines or glucocorticoids should not be used in place of epinephrine. They may have a role as adjunctive therapy, but do not decrease the risk of biphasic reaction.
3. Following treatment, observe patients until signs and symptoms of anaphylaxis have resolved.  
4. Anticipatory guidance and education of epinephrine auto-injectors should be provided to all patients.  

References: 

1. Shaker MS, Wallace DV, Golden DBK, et al. Anaphylaxis—a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis. J Allergy Clin Immunol. 2020;145(4):1082-1123. doi:10.1016/j.jaci.2020.01.017 
2. Wood RA, Camargo CA Jr, Lieberman P, et al. Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States. J Allergy Clin Immunol. 2014;133(2):461-467. doi:10.1016/j.jaci.2013.08.016 
3. Sousa-Pinto B, Fonseca JA, Gomes ER. Frequency of self-reported drug allergy: a systematic review and meta-analysis with meta-regression. Ann Allergy Asthma Immunol. 2017;119(4):362-373.e2. doi:10.1016/j.anai.2017.07.009 
4. Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391-397. doi:10.1016/j.jaci.2005.12.1303 
5. Simons FE, Ardusso LR, Bilò MB, et al. International consensus on (ICON) anaphylaxis. World Allergy Organ J. 2014;7(1):9. doi:10.1186/1939-4551-7-9  
6. Pourmand A, Robinson C, Syed W, Mazer-Amirshahi M. Biphasic anaphylaxis: a review of the literature and implications for emergency management. Am J Emerg Med. 2018;36(8):1480-1485. doi:10.1016/j.ajem.2018.05.009 
7. Zeke A, Sudhir A. Management of allergic reactions and anaphylaxis in the emergency department. Emerg Med Pract. 2022;24(7):1-24.  
8. Michelson KA, Monuteaux MC, Neuman MI. Glucocorticoids and hospital length of stay for children with anaphylaxis: a retrospective study. J Pediatr. 2015;167(3):719-24.e243. doi:10.1016/j.jpeds.2015.05.033 
9. Kim TH, Yoon SH, Hong H, Kang HR, Cho SH, Lee SY. Duration of observation for detecting a biphasic reaction in anaphylaxis: a meta-analysis. Int Arch Allergy Immunol. 2019;179(1):31-36. doi:10.1159/000496092