Anaphylaxis is a severe, potentially life-threatening allergic reaction that can occur within seconds or minutes of exposure to an allergen.[1] It requires prompt recognition and immediate treatment with epinephrine to halt progression and resolve symptoms.[2] Epinephrine is the first-line treatment for anaphylaxis and the only medication that can reverse the dangerous effects of an anaphylactic reaction.[3] However, some people may question whether anaphylaxis can resolve without the administration of epinephrine in certain situations.
What is anaphylaxis?
Anaphylaxis is characterized by rapidly developing, life-threatening symptoms involving multiple body systems simultaneously, including:[1]
- Skin: flushing, hives, swelling
- Respiratory: breathing difficulty, throat tightness, cough, wheeze, stridor
- Gastrointestinal: vomiting, diarrhea, cramping pain
- Cardiovascular: lowered blood pressure, dizziness, fainting, tachycardia
Anaphylactic reactions are triggered through immunologic or non-immunologic mechanisms, with the most common triggers being foods, medications, insect stings, and latex.[4] Anaphylaxis can vary in severity from mild to life-threatening, but the rapid progression is unpredictable and patients must be monitored closely and treated promptly.[2]
Why is epinephrine crucial for anaphylaxis treatment?
Epinephrine is a natural catecholamine hormone released by the adrenal glands that functions as a neurotransmitter and hormone.[5] When administered during an anaphylactic reaction, epinephrine’s alpha-adrenergic vasoconstrictor effects reverse peripheral vasodilation and decrease mucosal edema in the airways, while its beta-adrenergic effects increase inotropy and chronotropy to improve cardiovascular function.[6]
Specifically, epinephrine:
- Constricts blood vessels to reverse vasodilation and fluid leakage
- Relaxes smooth muscles in the airways to improve breathing
- Stimulates the heart and increases blood pressure
- Alleviates hives, itching, and angioedema
- Suppresses further mediator release
These effects make epinephrine unique in its ability to mitigate the life-threatening respiratory and cardiovascular symptoms of anaphylaxis. No other medication has the same rapid, multifaceted mechanisms to control anaphylactic reactions. As such, epinephrine in intramuscular injection form is universally recommended as first-line therapy for anaphylaxis.[2], [3]
Barriers to epinephrine use
Despite clear guidelines designating epinephrine as the only first-line anaphylaxis treatment, it remains underutilized.[7], [8] Barriers contributing to the lack of prompt epinephrine administration include:
- Failure to recognize anaphylaxis symptoms
- Belief that the reaction is mild and does not require epinephrine
- Preference for antihistamines or corticosteroids instead of epinephrine
- Fear, anxiety, or misconceptions about epinephrine side effects
- Lack of available epinephrine auto-injectors
These barriers delay life-saving epinephrine treatment and can contribute to complications and fatalities from anaphylaxis. Increased education is needed to overcome barriers and emphasize the importance of prompt epinephrine in anaphylaxis management.
Can anaphylaxis resolve without epinephrine?
Anaphylaxis cannot be reliably expected to resolve without epinephrine treatment. While mild reactions may potentially recover with supportive care alone, there is no way to predict whether a reaction will rapidly progress to a life-threatening degree.
Key points regarding anaphylaxis resolution without epinephrine:
- Milder reactions may gradually resolve over several hours with antihistamines, supplemental oxygen, IV fluids, close monitoring, and avoidance of the allergen. However, at any point mild symptoms can quickly worsen.
- Up to 20% of anaphylactic reactions are initially misdiagnosed as mild and managed without epinephrine. However, fatalities occur in this situation when mild symptoms rapidly progress to respiratory or cardiac arrest.
- The onset of respiratory or cardiovascular symptoms during an allergic reaction requires immediate epinephrine to prevent death.
- There are no reliable clinical criteria to predict which reactions will remain mild versus rapidly progress to fatal anaphylaxis.
- Withholding epinephrine based on initial mild symptoms goes against all anaphylaxis guidelines and carries significant risk.
For these reasons, experts strongly advise prompt injection of epinephrine for any suspected anaphylactic reaction to halt rapid progression and avoid negative outcomes.
Are there exceptions where epinephrine may not be needed?
There are a few exceptional situations where anaphylaxis may potentially resolve without epinephrine:
- Mild cutaneous symptoms ONLY: Isolated hives, flush, pruritus may resolve with antihistamines and close monitoring. However, epinephrine should be immediately administered if any respiratory, cardiovascular, or gastrointestinal symptoms develop.
- Accidental allergen exposure: If the offending allergen is promptly removed and no symptoms develop, epinephrine may not be required. For example, if a peanut-allergic child tastes peanut butter but immediately spits it out and rinses their mouth, observation without epinephrine may be reasonable.
- Allergen immunotherapy: During gradual updosing to a maintenance allergen immunotherapy dose, certain mild symptoms may be tolerated without epinephrine. However, immunotherapy protocols specify that epinephrine must be given if any respiratory or cardiovascular symptoms occur.
In all other situations of known or suspected anaphylaxis, experts emphasize that epinephrine should be administered promptly without delay or observation for progression.
What are the risks of withholding epinephrine?
Withholding epinephrine for anaphylaxis carries substantial risks, including:[9], [10]
- Progression to life-threatening respiratory and/or cardiovascular collapse
- Hypoxic brain injury or death due to inadequate oxygenation
- Prolonged recovery and hospitalization
- Biphasic anaphylaxis where symptoms recur hours later
Up to 44% of anaphylactic deaths are associated with no administration of epinephrine despite previous allergy diagnosis and prescription. Delayed epinephrine due to failure to recognize anaphylaxis symptoms is also associated with poor outcomes.[11]
Experts emphasize that epinephrine has an excellent safety profile and the benefits far outweigh any risks when used appropriately for anaphylaxis. Withholding epinephrine confers substantial preventable risk.
What is the role of observation without epinephrine?
Observation without epinephrine administration is not recommended in anaphylaxis and goes against expert guidelines. However, observation may have a limited role in certain contexts:
- To monitor for symptom progression AFTER epinephrine is given. Patient should receive close monitoring to ensure no biphasic or recurrent symptoms occur.
- If allergen exposure is suspected but no symptoms have YET developed. Brief observation without epinephrine is reasonable to determine if anaphylaxis symptoms manifest and require treatment.
- In mild cutaneous-only reactions to determine if symptoms progress beyond skin, necessitating epinephrine. Observation period should be brief (under 20 minutes) with epinephrine immediately available.
In all situations, the observation period should be brief and epinephrine must be administered at the first sign of respiratory, cardiovascular, or gastrointestinal symptoms, or rapid symptom progression.
Conclusion
Anaphylaxis is an unpredictable, rapidly progressive condition requiring immediate intervention with epinephrine to halt life-threatening complications. Withholding epinephrine based on initial mild symptoms confers significant risk given the potential for reactions to quickly worsen and become fatal. Exceptions exist for brief observation periods and extra-cautious management of mild cutaneous symptoms ONLY. However, experts strongly advise prompt injection of epinephrine as first-line treatment for any suspected anaphylactic reaction to interrupt rapid progression and avoid negative outcomes. No other medication comes close to epinephrine’s effectiveness and safety profile in reversing the multisystem effects of anaphylaxis. While further studies on natural history would be ethically difficult, currently available evidence clearly validates epinephrine as the only first-line anaphylaxis treatment that directly targets the underlying pathophysiology. With this in mind, anaphylaxis should never be expected to reliably resolve without timely administration of lifesaving intramuscular epinephrine.
References
- Sampson HA, Muñoz-Furlong A, Bock SA, et al. Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol. 2005;115(3):584-591. doi:10.1016/j.jaci.2005.01.009
- Lieberman P, Nicklas RA, Randolph C, et al. Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol. 2015;115(5):341-384. doi:10.1016/j.anai.2015.07.019
- Simons FER, Ardusso LRF, Bilo MB, et al. International consensus on (ICON) anaphylaxis. World Allergy Organ J. 2014;7(1):9. doi:10.1186/1939-4551-7-9
- Turner PJ, Worm M, Ansotegui IJ, et al. Time to revisit the definition and clinical criteria for anaphylaxis? World Allergy Organ J. 2019;12(10):100066. doi:10.1016/j.waojou.2019.100066
- Westfall TC, Westfall DP. Adrenergic agonists and antagonists. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011.
- Simons FER. Anaphylaxis. J Allergy Clin Immunol. 2010;125(2):S161-S181. doi:10.1016/j.jaci.2009.12.981
- Prince BT, Mikhail I, Stukus DR. Underuse of epinephrine for the treatment of anaphylaxis: Missed opportunities. J Asthma Allergy. 2018;11:143-151. doi:10.2147/JAA.S150072
- Song TT, Lieberman P. Treatment of food-induced anaphylaxis in the community. Front Immunol. 2020;11:2101. doi:10.3389/fimmu.2020.02101
- Järvinen KM, Sicherer SH, Sampson HA, Nowak-Wegrzyn A. Use of multiple doses of epinephrine in food-induced anaphylaxis in children. J Allergy Clin Immunol. 2008;122(1):133-138. doi:10.1016/j.jaci.2008.04.031
- Sampson HA. Anaphylaxis and emergency treatment. Pediatrics. 2003;111(Supplement 3):1601-1608. doi:10.1542/peds.111.S3.1601
- Pumphrey RSH, Gowland MH. Further fatal allergic reactions to food in the United Kingdom, 1999-2006. J Allergy Clin Immunol. 2007;119(4):1018-1019. doi:10.1016/j.jaci.2007.01.021