All About Epinephrine: What It Does in a Reaction, How Long It Lasts, When It Gets Hot or Cold
Allergic Living magazine and Gina Clowes at AllergyMoms.com reached out to Dr. Julie Brown, an emergency medicine physician at Seattle Children’s Hospital, for her expertise on anaphylaxis and epinephrine. In this article she answers frequently asked questions on how to know when to administer an Epi-Pen©, how it works, when to give a second dose, expiration dates, and what happens to epinephrine when subjected to significant heat or cold exposure.
By Allergic Living
January 9, 2020
One of the nerve-racking parts of living with severe allergies is having to make the call about if and when an allergic reaction is anaphylaxis. A shot of epinephrine can save a life but having to inject ourselves or our child with a needle is something we did not sign up for.
However, mistakes in the critical areas of recognizing and responding to anaphylaxis can mean the difference between life and death. Plus, studies are showing that prompt administration of epinephrine can simply reduce the chance that a food allergy reaction moves from relatively mild to severe anaphylaxis.
Over the years, Allergic Living readers have raised many questions related to epinephrine: from when to give it, to when a person needs a second dose, to issues such as how much heat or cold an epinephrine auto-injector can take, whether antihistamines mask anaphylaxis symptoms and more.
We asked Gina Clowes, the nationally known food allergy educator and parenting coach and consultant at AllergyMoms.com, to help us create a go-to epinephrine resource with answers to these vital questions.
Gina reached out to Dr. Julie Brown, an emergency medicine physician at Seattle Children’s Hospital, for her expertise on the topic. Dr. Brown works closely with the food allergy community and has a continuing research interest in epinephrine, auto-injectors and anaphylaxis. As Gina says, “We’re so grateful to Dr. Brown for agreeing to answer common epinephrine questions. I find her insights and answers fascinating, and know they’ll be helpful to a lot of people.”
Following you will find written answers about epinephrine in a handy Q&A format.
Allergic Living’s Epinephrine Q&A
To get us started, what does epinephrine do in the body in a severe allergic reaction?
Dr. Brown explained that epinephrine is adrenaline, the same hormone that is formed in the body in the fight or flight response. “But it also has a very important role, probably by design, in turning off allergic reactions.
In the allergy context, she says epinephrine acts on a number of different receptors on cells in the body, and “seems to reverse fairly pointedly all of the things that are happening in allergic reactions.”
Why is the advice to give epinephrine promptly in an allergic reaction when there is more than one mild symptom? Why not wait to see if symptoms progress?
“The reason is, the earlier you give epinephrine, the better outcomes are,” says Dr. Brown. The longer one waits, the more likely the reaction is to progress and require multiple doses of epinephrine.
If we wait, we’re “more likely to get sicker and have much more significant symptoms,” she says. “We are more likely to need multiple doses of epinephrine or need to stay in the hospital.”
She reminds us that “patients can start off having very mild symptoms, and then turn very quickly to getting very sick. What we want to do is to treat before things get serious.” Sadly, most patients who have died from anaphylaxis had delayed treatment with epinephrine.
How long should you wait before giving a second dose, if it seems like the symptoms aren’t improving or if they seem to be coming back?
Dr. Brown generally recommends between 5 and 15 minutes as a reasonable timeframe between doses to determine if the epinephrine has taken effect. However, she cautions that “if you have someone who looks like they are not breathing, they are turning blue, they are passed out, you would shorten the time window.”
In such a case she says it may be reasonable to give a second dose, “just to make sure that you’ve got a good amount of epinephrine circulating” while awaiting an ambulance.
If you’re giving a second dose, do you recommend giving it in the same thigh or the other thigh from the first dose?
After the death of a U.K. teenager, whose case involved getting two injections of epinephrine in the same thigh, there was some suggestion that a second dose should have been given in the opposite thigh.
The suggestion was that this might increase the circulation of epinephrine in the body. However, Dr. Brown does not see a concern with injecting a second dose in the same thigh. As this is such a large muscle, she says you are highly unlikely to inject in the exact same location.
However, she agrees that there is no problem with injecting a second dose in the opposite thigh (to the first dose) if there is no barrier to doing so.
Should the patient be lying down with legs elevated during anaphylaxis?
In a severe anaphylactic reaction, Dr. Brown says there is a lot of fluid leakage from the blood vessels internally, which makes it hard for your body to pump enough blood through your heart. It’s often helpful for a person to lie down with feet elevated when suffering from a serious reaction.
“You are helping them to circulate their blood the best if they’re lying down,” she says. “And after you’ve given epinephrine, you’re helping to circulate that epinephrine the best if they’re lying down.”
She discussed U.K. research into cases of patients who had died from anaphylactic shock. Some patients worsened after they stood up quickly or were propped up during their extreme reactions. The lack of blood flow to the heart may have led to a heart attack, which contributed to the fatal outcome.
Dr. Brown recommends that patients experiencing active anaphylactic symptoms should lie down, if possible. However, “I certainly see lots of kids who are sitting comfortably for hours in our emergency department and they don’t all need to be lying down.” She says this recommendation is probably most important when a patient feels faint or light-headed or early in a reaction that is progressing rapidly.”
Importantly, she says, “not everybody is going to be best off lying down.” Dr. Brown gives the example of someone who’s having respiratory distress as a symptom. “If it’s upper airway difficulty, with what we call stridor – the kind of noise where you’re having trouble breathing in – that person often needs to be sitting up and leaning forward. This is a position that allows your airways to be the most open.”
In addition, she says that individuals who are vomiting should be lying on their side to reduce the chances of choking.
Is there danger in having a person walking around while they’re having a serious allergic reaction?
This is an issue of concern particularly in schools. “The teacher should never send a kid in school on their own to the nurse’s office,” says Dr. Brown. “You don’t know how the disease is going to progress between the classroom and the nurse’s office.”
She recommends sending someone with the student, at a minimum, so they can monitor and advocate for the child or teen if needed. If the child is feeling faint, then help should be brought to the child, rather than sending the child to get help.
How long does a dose of epinephrine last?
According to Dr. Brown, studies have shown there is “epinephrine in your system for at least 6 hours. It’s at a higher level for about an hour, and it peaks around 5 minutes. There’s a pretty decent amount [circulating] for 40 minutes.”
Why do some people say, “Epinephrine only lasts for 15 minutes?”
She says people often think epinephrine only lasts 15 minutes “because that’s when you’re suggested to take a second dose if needed. But it doesn’t mean that there isn’t medication still on-board from the first dose.”
Evidence shows most people only need one dose of epinephrine, says Dr. Brown. One reason is that it lasts for the duration of most reactions. A second reason is that epinephrine stabilizes mast cells, making them less “twitchy,” an effect that may last even after the epinephrine is gone.
She says a third factor is that, even for patients who don’t get epinephrine, “a lot of these reactions will burn out on their own. Thank goodness for that, because everybody [with food allergies] has a first reaction where they aren’t carrying epinephrine!” she says. “Of course, you never want to count on it burning out on its own, so you should always treat anaphylaxis early with epinephrine.”
Let’s talk about caring for epinephrine devices. What happens if I leave an auto-injector in the cold overnight in my car?
The good news is: “There are a number of studies that have looked at what happened to epinephrine when you freeze it. They’ve shown that both refrigerating and freezing epinephrine does not degrade epinephrine. So it maintains high levels of epinephrine.”
Dr. Brown and colleagues have further investigated what happens to auto-injector devices when frozen. Dr. Brown was senior author of a study [by Alex Cooper et al] in which 104 Epi-Pens were frozen for 24 hours, then thawed while their mates [from EpiPen 2-Pak cartons] were left at room temperature. The frozen-then-thawed devices fired a similar amount of epinephrine to their never-frozen paired device. When another 104 frozen-thawed devices were opened unfired, there was no damage to the syringes or other device parts.
This research “didn’t find any evidence of adverse effects to the device of having been frozen for 24 hours. It looks like freezing has pretty minimal effects on Epi-Pens,” said Dr. Brown. She cautions that this research looked only at Epi-Pens, not other auto-injectors, and the impact on other devices could be different.
What happens if the auto-injector gets too hot, for example, left in the sun or overnight a hot car?
Dr. Brown explains that heat is “much more problematic” than cold. Previous research has shown that “you can definitely see the degradation of epinephrine itself with high heat.” She says temperatures in a car on a hot, sunny day can exceed 194 degrees F, and a device exposed to this sort of heat could have degradation of the epinephrine.
The device itself can also be negatively impacted by heat. Her team’s ongoing research [lead investigator Samuel Agosti] is examining the impact of high heat and exposing Epi-Pens© and Epi-Pen Jrs© to 183 degrees F for 8 hours. In this study, Dr. Brown reports, “we’re seeing differences in the amount of epinephrine fired from heated-then-cooled devices compared with their unheated pairs [from Epi-Pen 2-Paks]. We are also having trouble getting some devices out of the cases.”
She recommends replacing a device that has had significant heat exposure. She cautions if “it feels hot to the touch, I would say that’s pretty suspect that the device is not reliable anymore. There’s a risk there.”
In Europe, there’s an auto-injector with a higher epinephrine dose and a longer needle. Do you think we need an option like this as well?
Dr. Brown doesn’t think so. She says that in the United States, “we have safe devices that have really maximized needle lengths for serving a wide range of population and different-sized people.” Longer needles might be more suitable for some extremely large patients, but those longer needles might be long enough to reach bone in many normal-weight patients.
She notes that the goal is to get the medicine into the thigh muscle, and the device mechanism that pushes the drug out also plays a role. So needle length isn’t the only factor. Although there will always be challenges to meet every patient’s needs, Dr. Brown believes the options available the devices in the U.S. “are probably doing a reasonable job,” all things considered. She notes there is even a third dose option now, the Auvi-Q device for infants.
Do you have any concerns about putting auto-injectors through the scanners at airport security?
Dr. Brown had no concerns about airport scanners. She’s not aware of any specific research in this area but doubts an airport scanner would have “any ability to impact your dose of epinephrine or the functioning of the device.”
What about if an epinephrine auto-injector goes through the washing machine?
Her team [led by investigator Andrew McCray] has researched this easy mistake to make – and the news is not good for an EpiPen that has gone through the laundry. While prescribing information does not address what to do if the device is submerged in water, the EpiPen website says the carrier tube is not waterproof and that a submerged device should be replaced. However, Dr. Brown said: “I still thought that they would do pretty well because it looks like a robust device that was based on a design developed for the military. But our results are not encouraging.”
She reports that water gets lodged in the outer layer of the device, and more importantly “the amount of drug that fires appears to be impacted.” She recommends following the advice to replace an auto-injector that has gone through the washing machine.
If an individual for some reason was not able to access an unexpired auto-injector, how long can you reasonably use an expired device?
Epinephrine devices do continue to maintain a high level of the labeled dose of epinephrine as they age. While Dr. Brown recommends keeping current, unexpired devices whenever possible, she has little concern about the four-month expiration date extension that the FDA issued on certain lot numbers during periods of shortage.
However, as Dr. Brown explains, “the amount of epinephrine is only part of the story. There are epinephrine metabolites that occur as the medication ages. The safety or toxicity of these metabolites in the body in expired medication is unknown. While the theoretical risk of these metabolites shouldn’t prevent use of a potentially life-saving medication in an emergency, it is a good reason to keep a current device on hand.”
She’s aware that many allergy families keep older auto-injectors in case of emergency, but cautions that the level of epinephrine is getting pretty low after two years, and the level of metabolites is probably getting fairly high. “Two years is probably a reasonable limit for keeping back-up devices. After that, it’s really time to just toss them in your med recycling bin.”
If the epinephrine inside the device is still clear, does that mean it is still potent and safe to use?
With heat, light exposure or over time after expiration, epinephrine is degraded and metabolites begin to increase. Epinephrine metabolites can exceed FDA recommended levels well before the medication shows any discoloration, says Dr. Brown. However, some pharmacists still perpetuate the notion that as long as the medication is clear, it’s OK to use.
“If the epinephrine has been exposed to heat, it can have a fairly significant increase in epinephrine metabolites and not be discolored. You can’t rely on color tell you whether or not your device is safe to use,” she cautions.
“If it is discolored, it is unsafe. But if it was exposed to heat and is clear, it could still have significant degradation.”
Can Benadryl or another antihistamine mask symptoms of anaphylaxis?
Although Dr. Brown acknowledges the concern of Benadryl masking anaphylaxis, she says “that is giving antihistamines way more power than they have in allergic reaction.” Her view is that if a reaction is going to be an anaphylactic one, an antihistamine won’t stop it. There is no argument that epinephrine is the drug of choice to treat anaphylaxis, a life-threatening allergic reaction. But for a mild symptom, such as a mild runny nose or slight rash, she says “it’s fine to give an antihistamine. You’re not going to mask anything. As long as you’re still keeping a watchful eye for symptom progression.”
She shares two caveats, though. Dr. Brown is among a growing number of experts who prefer a non-sedating antihistamine, such as Zyrtec, rather than Benadryl, as the latter is more sedating. She recommends this to avoid confusion between drowsiness from the medication and drowsiness related to anaphylaxis.
The second caveat is that if an antihistamine has been given for a single symptom, such as hives, you would still count that symptom as one system affected, even if the symptom resolves. She explains that “if you’ve treated hives with an antihistamine and they’ve improved, but half an hour later you go on to start vomiting, now you’ve hit two systems. According to most care plans, you would meet criteria for using epinephrine.”
After epinephrine, what role do other drugs have in anaphylaxis?
Interestingly, research shows conflicting benefits of corticosteroid medication in anaphylaxis. First, Brown explains there is a misconception that steroids take a long time to work, but “there’s some evidence that steroids actually can work within 30 minutes.”
However, research from Canada suggests that steroids given prior to admission into the hospital increased intensive care admissions. She notes that “it’s unclear if that truly was an effect of the steroids,” or if perhaps steroids were being used instead of epinephrine.
There is also a notion that steroids decrease the risk of a biphasic or secondary reaction. But a review of cohort studies suggests that steroids are not having an impact on biphasic reactions. Brown concludes that “there’s really not a lot of great evidence to support that steroids are doing anything in anaphylaxis.”
There are many other drugs and supports that can help a patient recover from an anaphylactic reaction such as fluids, oxygen, antihistamines, albuterol and other asthma medications. The additional drugs and monitoring available are why it is so important to seek medical care during an anaphylactic reaction.
Why might there be a different protocol for when to give epinephrine at home versus the ER?
“The first thing to remember is that [patient emergency anaphylaxis] care plans have a very low threshold for giving epinephrine. Often you are giving epinephrine because you meet this two-system criteria for giving epinephrine,” Dr. Brown explained.
That threshold for using epinephrine by a lay person, who is not in a medical setting, is lower than it would be in a hospital. In the emergency department Brown notes:
“The physician has the advantage of having you on monitors, of knowing your vital signs, what your exam is like, what kind of a timeframe we’re talking about. Time is very important in anaphylaxis, and that’s not something that is incorporated into emergency care plans. The doctors will incorporate all that information into the decision-making about whether or not it’s appropriate to give more epinephrine at that time, whether or not they want to do something else, or whether they just want to watch further.”
“All of those may be safe and appropriate options in the emergency department setting, while you might make very different decisions if you’re in the community and following your care plan.”
What is a co-factor, and why might a co-factor make an allergic reaction worse?
Dr. Brown cautions that it’s important to understand that “there is no rhyme or reason to food allergy reactions and that any reaction can become the bad reaction. You can have had very mild reactions all of your life, and then your next one can be really severe.”
At the same time, it is wise to be aware that “if you’ve had very life-threatening reactions in the past, then that may increase your chance of having one again,” she says.
While our individual histories are things we can’t necessarily change or impact, co-factors are things that we can be aware of. Dr. Brown explains that co-factors are “things like exercise, heat, alcohol consumption, illness and menstruation. All of those can exacerbate your allergic reaction.”
“So if you’re having a mild allergic reaction and you go out for a jog, that may really flare up that reaction. Or if you’re having a bit of a reaction and you go take a hot shower, that may really activate all your masts cells and you may come out of the shower just covered in hives. Some people are exacerbated by cold, so they might go out on a very cold day and find that that sets them off. Illness certainly decreases people’s threshold for reaction. So they may find that they can tolerate a food pretty well most of the time, and then when they are ill have a decreased threshold for reacting to that food. Some women find around their menstruation they’re much more likely to react to certain foods,” she says.
What’s a parting piece of advice you’d like to share with allergic parents and patients?
“Don’t be afraid of epinephrine. It is unfortunately so hard for so many people to get past the mental idea of giving themselves [or a child] a shot, but it invariably makes you feel so much better when you’re having an allergic reaction,” says Dr. Brown. “It only does good things; it only keeps you safe. It really is a wonder drug in anaphylaxis.”
She puts it succinctly: “Don’t be afraid to use it yourself. Don’t be afraid to use it for your child. You’re only going to make things better.”
Allergic Living and Gina Clowes extend our appreciation to Dr. Julie Brown for her generous time in helping to create this go-to resource for the food allergy community. Dr. Brown is an emergency medicine physician and co-director of emergency medical research at Seattle Children’s Hospital, with study interests in epinephrine, auto-injectors and anaphylaxis. Gina is the founder of AllergyMoms.com.