7 Things to Consider When Epinephrine Doesn't Help Anaphylaxis
It’s 4 pm and just as you’re about to take a bite of your ice-cold grilled cheese sandwich that was supposed to be lunch, the pager goes off again: It’s a 37-year-old female at a public park with multiple ant bites and a known allergy. The park is 12 miles from your station and after an agonizing 17 minutes, your BLS unit arrives. The patient is in a tripod position, her stridor can be heard from 10 feet away, her radial pulse is gone, and her skin is grey and wet. She barely lifts her shirt to show you the red marks all over her stomach: insect bites and a spreading rash.
She nods when you ask her if she’s allergic but doesn’t even attempt to speak.
“She forgot her epi pen today,” explains her boyfriend.
You understand that early IM epinephrine is the most important treatment for this patient.1 You confirm the epinephrine isn’t expired. In Snohomish County, Washington, you draw up 0.5 milliliters, containing 0.5 milligrams of epinephrine with efficient, practiced motions.2 You pull up the side of her shorts, sanitize the area, inject it into her thigh and press the plunger down. You hold it in for a few extra seconds to ensure the medication was delivered, withdraw and place the needle in a sharps bin.
And ... nothing. She continues to gasp for air and fails to show signs of improvement.
While epinephrine begins to work immediately, it can require as many as 15 minutes to take full effect.1 Most systems' procedures say to repeat the epi injection after three to five minutes. You allow five minutes to go by while you bag your patient and prepare your second dose. She isn’t improving at all.
7 Things to Consider Now:
1. A second injection of epinephrine is needed.
It’s possible that one shot wasn't sufficient due to the size of the patient or the amount of allergen the patient was exposed to. If your patient doesn’t respond to two injections of epinephrine of at least 0.3 mg each, she is now considered to have “refractory anaphylaxis.” This is very rare (one study showed that it was only 42 of 11,596 cases) but also fatal more than 25% of the time.3
2. The epinephrine never made it into the patient.
If your agency uses auto-injectors, this could be due to a failure to hold the pen against the injection point for at least 10 seconds before you withdraw it, so all the medication goes in.
If your agency uses syringes to draw up the medication from a vial, withdraw the remaining liquid in the epinephrine vial.1 If the provider didn’t invert the vial while drawing up with the medication, it is possible that the patient was only injected with air. This is a surprisingly common error, especially with very new providers or ones who rarely give injections. This problem can be ruled out with some simple math.
The vial initially contained 1 mL of liquid. If it contains 0.5 mL of liquid, then you did give the patient the medication (as 1 minus 0.5 is 0.5). If it still contains 1 mL, then you accidentally injected the patient with air. Immediately re-draw the drug, properly inverting the vial and gently press on the plunger until some medication drips out of the top of needle. Inject the patient again, with actual epinephrine, and see if you get different results.
3. The injection was subcutaneous instead of intramuscular.
If your patient has deep adipose tissue over their lateral thigh, it’s possible that the needle you used wasn’t long enough. Many IM needles are only 1.25” long and plenty of patients have an adipose layer over their thigh that’s thicker than that. You may have injected the epinephrine into fat instead of muscle. This tissue has a lot less blood flow to it, causing injected medications to need extra time to enter the bloodstream. It could even cause the epinephrine not to work at all.1
Therefore, if your anaphylaxis patient is significantly overweight, inject the epinephrine into the deltoid (lateral shoulder) instead. There’s a lot less adipose tissue there and standard needles are almost certain to reach muscle.
4. Some medications interfere with epinephrine.
Try and get a medical history. There are several kinds of drugs that could possibly decrease the effectiveness of epinephrine. One is beta blockers. These are often prescribed, and common ones include Metoprolol, Carvedilol, Atenolol, and Propanolol. Generally, drugs in this class will have a “-lol” ending though there are exceptions.4
The beta pathway of the body controls our fight or flight reactions, causing the airway to widen, the heart to beat harder and faster, and the veins to constrict.1 Epinephrine, whether produced by the body or injected by a provider, activates this pathway. However, many patients with heart problems or even severe anxiety are put on beta blockers. These drugs inhibit this fight or flight pathway, preventing the heart from speeding up too much in response to stress or strain in a patient for whom this would be dangerous.
It can also stop the effects of epinephrine in some cases. The receptors the epinephrine would need to bind to may be entirely blocked by a pill the patient took this morning.
Epinephrine can also be rendered ineffective by alpha blockers, which are generally given to treat high blood pressure such as Doxazosin and Prazosin.4
Another class of drugs that can interfere with epinephrine is ergot alkaloids, which are prescribed to treat migraines. These drugs have generic names that end in “-amine” or trade names that sound like they belong in Lord of the Rings, like Ergomar, Trudhesa, and Migergot.
There are a couple of possible drug interactions: One is that the epinephrine won’t work. The other is that you’ll precipitate a dangerous hypertensive crisis. It’s important to remember that a hypertensive crisis is still much safer for your patient than not having an airway.
If a patient is on any of these drugs, ALS providers can try 3 mg of Glucagon and fluids to treat hypotension and Ipratropium to treat any breathing difficulty.5 BLS providers can immediately pass on that a patient has a history of using these medications to their ALS rendezvous.
Norepinephrine and dopamine are also beta agonists and therefore likely to be similarly inhibited by similar drugs, but if you have nothing else, there’s little harm in trying.
5. The patient is continuing to be exposed to their allergen.
If they ingested the allergen, there’s little to be done for that in the field. However, it could be that a bee stinger is still in and injecting venom. If the allergen is topical, such as latex or a medication patch, this could also still be in contact with the patient. Do a thorough physical exam and see if you can assess your way out of this.
6. The patient's condition isn't anaphylaxis.
It’s entirely possible to mistake another cause of shortness of breath and hemodynamic collapse, such as congestive heart failure with cardiac wheezing, as anaphylaxis.
7. If all else fails, as always, ask for help.
Call medical control, another high level provider, or ask for another unit for assistance. One of the best things about prehospital medicine is that it’s a team sport; we never face any problem truly alone.
You ask for the ETA of the ALS unit over the radio, knowing this request will convey how desperate you are for their help.
You draw up and administer a second dose of epinephrine. Your patient is only slightly overweight, perhaps 200 pounds at 5’6”, but this time you inject in the deltoid just to make sure your bases are covered. You inspect the original vial of epinephrine and find it half empty: she did get the first dose. Her boyfriend doesn’t think she takes any medications, but he’s not sure. This must be anaphylaxis; no other diagnosis makes any sense.
Ten minutes have now gone by, and she no longer has the strength to sit up.
Valuing your patient’s life over her modesty, you strip all of her clothes off and ... there. Dozens of ants are still physically on her left leg, biting her repeatedly. You were treating her on top of the ant’s nest she’d stepped in. You move her and then rinse them away with a bag of saline
The ALS crew starts a line and begins an epinephrine drip. Now that she isn’t constantly being re-exposed to her trigger, she begins to stabilize. She is discharged from the hospital without complications two days later.
Works Cited
1. Sicherer, S. H., Simons, F. E., Mahr, T. A., Abramson, S. L., Dinakar, C., Fleisher, T. A., Irani, A.-M., Kim, J. S., & Matsui, E. C. (2017a). Epinephrine for first-aid management of anaphylaxis. Pediatrics, 139(3). https://doi.org/10.1542/peds.2016-4006
2. Prehospital Care Treatment Guidelines, Protocols, and Procedures. Snohomish County EMS Agency | Protocols. (2025, January). https://snocountyems.unionactive.com/?zone=%2Funionactive%2Fview_article.cfm&HomeID=931981&page=202420Protocols
3. Francuzik W, Dölle-Bierke S, Knop M, Scherer Hofmeier K, Cichocka-Jarosz E, García BE, Lang R, Maris I, Renaudin JM, Worm M. Refractory Anaphylaxis: Data From the European Anaphylaxis Registry. Front Immunol. 2019 Oct 18;10:2482. doi: 10.3389/fimmu.2019.02482. PMID: 31749797; PMCID: PMC6842952.
4. Brewer, A. (2023, August 20). EpiPen and interactions: Other drugs, supplements, and more. Healthline. https://www.healthline.com/health/drugs/epipen-interactions#epi-pen-and-alcohol
5. McLendon, K. (2023, January 26). Anaphylaxis. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK482124/
