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InFocus: No Hard Evidence for Anaphylactic Interventions, but They're Still Standard Fare

Roberts, James R. MD

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doi: 10.1097/01.EEM.0000443913.23359.54
    The best place to inject IM epinephrine for anaphylaxis is into the muscle of the lateral mid-thigh. The subcutaneous route is inferior.

    Emergency physicians are often faced with patients symptomatic from acute allergies, ranging from minor skin rashes to overt life-threatening anaphylaxis. It's a relatively easy diagnosis, although the cause is not always evident, even on further investigation.

    Anaphylaxis is a serious allergic reaction that is rapid in onset, and may cause death. Treatment protocols have remained essentially unchanged since I was a resident many years ago, but a few recent articles have addressed the subject. It is my conclusion that the current triad of epinephrine, glucocorticoids, and antihistamines will remain in place even though evidence for their efficacy is anecdotal, experiential, and uncontrolled.

    It appears to be unethical to withhold current standard anaphylactic interventions even though scant factual evidence supports their use. Death from anaphylaxis usually results from asphyxiation because of upper airway edema, respiratory failure from bronchial obstruction, and less commonly, from cardiovascular collapse. Probably the best evidence for continuing with current practice is clinical experience that demonstrates a sharp turnaround in anaphylactic symptoms, particularly with epinephrine.

    Management of Anaphylaxis: A Systematic Review

    Dhami S, Panesar SS, et al


    Nov. 20, 2013; DOI:10.1111/all.12318

    These European authors attempted to evaluate evidence for the effectiveness of interventions for acutely managing anaphylaxis by searching seven databases for systematic reviews, randomized trials, and other supporting literature, including case series. They found no robust studies investigating the effectiveness of epinephrine, H1-antihistamines, or systemic glucocorticoids to manage anaphylaxis. They did, however, find evidence regarding the optimum route, site, and dose of epinephrine. An evaluation of fatality register studies suggested that a failure or delay in administering epinephrine may increase the risk of death, and the most effective route is IM injection. Injecting the middle of vastus lateralis muscle is optimal treatment.

    Figure. E
    Figure. E:
    pinephrine is the first drug used for anaphylaxis, and it is likely the only medication that will effectively treat anaphylaxis. It is available in two containers, and each contains 1 mg of the drug. A small 1 ml glass vial (break-off top, used for asthma) contains 1 mg of drug, so 0.1 ml contains 0.1 mg of epinephrine (1:1000). This is the preferred mixture and it is injected IM as a 0.3 to 0.5 ml or mg dose. Using a 1 ml syringe simplifies the injection. The cardiac arrest vial of epinephrine contains 10 ml of fluid, for a total of 1 mg of epinephrine (1:10,000). One ml contains 0.1 mg of the drug, and this may be used IV in very small doses for the patient in extremis. Epinephrine is best used as an infusion in severe anaphylaxis, and 0.1 mg (1 ml of the 1:10,000 cardiac vial) can be given slowly by IV (60-90 seconds) in life-threatening situations.

    These authors define anaphylaxis as a severe life-threatening generalized or systemic hypersensitivity reaction. They stated that it is difficult to predict initially the severity of a reaction, and death may occur within minutes of onset. The effectiveness of emergency management is not in question, but a review of 55 eligible studies concluded that the medical literature was lacking in firm scientific support of commonly used current therapeutic medications.

    Epinephrine: The authors identified 15 studies addressing the effectiveness of epinephrine, although these were only systematic reviews and case series, no randomized controlled trials. Epinephrine is considered the quintessential first-line intervention, but about a fifth of children experiencing anaphylaxis needed more than one dose of this drug. A review of a fatality register found it was difficult to predict the severity of subsequent reactions, risk factors for fatality, or underuse, delayed use, or incorrect use of epinephrine. Importantly, occasional deaths occurred even if epinephrine was used properly.

    Two studies found that maximum plasma concentrations occur more quickly with intramuscular injection than subcutaneous administration. One study found the proximal thigh in the vastus lateralis muscle was the optimal site. Whether the drug is totally safe in patients with a cardiac history has not been addressed in the literature, but it did not support eschewing epinephrine in patients over 55 who had no history of coronary artery disease.

    Glucocorticoids: The authors were unable to make any literature-based recommendations on the use of glucocorticoids because of the lack of investigation in the literature. Methylprednisolone 125 mg IV is a common dose. Glucocorticoids are usually given empirically, and may prevent biphasic anaphylaxis.

    Antihistamines: No suitable randomized controlled trials demonstrated the value of H1- or H2-antihistamines as an intervention for acute allergic reactions. They did find evidence that a combination of the two was superior to H1-antihistamines alone for treating urticaria but not angioedema. Pruritus was controlled better by H1-antihistamines, while a combination of H1- and H2-antihistamines offered no advantage. Antihistamines do not relieve stridor, shortness of breath, wheezing, gastrointestinal symptoms, hypotension or shock, and should not be substituted for epinephrine. Diphenhydramine 50 mg IV and Ranitidine 50 mg IV are common empiric doses.


    Prophylactic interventions: Interventions have been studied to prevent anaphylaxis from snake bite antivenin and IV iodinated contrast media. Prophylactic epinephrine was effective in reducing the risk of anaphylaxis snake antivenin, but the other interventions were not. The literature failed to demonstrate that commonly suggested premedication with glucocorticoids and H1- or H2-antihistamines prevented anaphylactoid symptoms triggered by contrast media. Such premedication will likely persist.

    Good evidence does support the use of epinephrine for the emergency management of anaphylaxis, particularly by injecting it into the lateral aspect of the thigh. Epinephrine was anecdotally supported in the literature, and researchers recommend giving it early in the course of anaphylaxis, but no medical literature existed upon which to base recommendations for commonly used fluid replacement, oxygen, glucocorticoids, antihistamines, or bronchodilators. Their conclusion was that epinephrine should be the first drug of choice for acutely managing anaphylaxis, and it should be administered IM into the lateral aspect of the mid-thigh.

    Comment: I think most EPs would give epinephrine, steroids, and antihistamines to any patient manifesting signs of an acute allergic reaction, including hives, hypotension, and outright anaphylaxis. I have frequently administered epinephrine to treat severe urticaria. It is imperative to give this first with anaphylaxis. Epinephrine does make many patients a bit jittery and occasionally slightly hypertensive, but it works well and appears to short-circuit urticaria quickly. Epinephrine is also routinely used for treating snake antivenin and contrast material reactions, but I doubt if anyone administers epinephrine prophylactically to such patients at risk. Dye reactions are actually related to anaphylactoid rather than the IgE-mediated anaphylaxis; contrast material hypersensitivity is treated the same as anaphylaxis from penicillin or food.

    I could find no report of problems or worse outcome when epinephrine was used to treat anaphylaxis in patients with cardiac history. Reports in the literature support epinephrine for the elderly with asthma before the use of inhaled bronchodilators, and older physicians used it frequently in all comers with anaphylaxis or asthma. I think it is reasonable to conclude that there are no contraindications to epinephrine for acute anaphylaxis.

    Given this, it appears that epinephrine is standard fare for any patient with anaphylaxis. The standard dose is likely 0.3 mg IM; those with more severe reactions may be given 0.5 mg IM. This can be repeated every five to 10 minutes, but once is often enough. It's important to avoid the use of IV epinephrine in all but the most egregious cases. Cardiopulmonary arrest obviously requires IV epinephrine in the 1 mg cardiac dose. I have occasionally given a very small IV epinephrine dose to patients who still have a blood pressure, albeit low, when they appear to be at risk for deterioration. I would suggest slowly administering no more than 0.1 mg IV, perhaps occasionally repeating it, if that route is chosen and the patient still has a blood pressure and pulse. You should administer it over 60-90 seconds, diluted in saline. It's unlikely that it would cause a problem, but someone with severe coronary artery disease or labile hypertension may be at risk. A slow continuous infusion of epinephrine is likely the best tactic, but the dose and logistics are difficult to memorize. I see no downside to giving glucocorticoids or antihistamines, even the H1 and H2 combinations, but the first drug chosen should always be epinephrine.

    Sheikh recently reviewed evidence for the effect of glucocorticoids in treating and preventing anaphylaxis. (Current Opin Allergy Clin Immunol 2013;13[3]:263.) A Cochrane systematic review failed to identify any randomized controlled trials or even quasi-randomized controlled trials investigating the effectiveness of glucocorticoids for treating anaphylaxis. Routine prophylaxis was found to be of questionable value even when the glucocorticoids were given to those at risk for contrast media or snake antivenin reactions. Antihistamines for preventing immunotherapy-triggered anaphylaxis also yielded mixed results. They concluded that glucocorticoids should be regarded at best as second-line agents ED anaphylaxis management. Routinely administering steroids to patients receiving iodinated contrast materials or snake antivenin therapy is unlikely to confer clinical benefits. Most hospitals still require antihistamines and steroids before contrast dye in patients at high risk for contrast reactions.

    Emergency Department Anaphylaxis: A Review of 142 Patients in a Single Year

    Brown AF, McKinnon D, Chu K

    J Allergy Clin Immunol


    These authors investigated all presentations of patients in the ED with allergic reactions, describing the clinical features, management, and other approaches. A total of 162 ED patients had acute allergic reactions; 142 were considered to have anaphylaxis. Anaphylaxis was severe in 60 patients, and one patient died. The clinical features for those with life-threatening anaphylaxis are outlined in the table.

    Cutaneous features were present in 94 percent of patients with anaphylaxis, and 35 percent of those with severe anaphylaxis had dizziness/syncope before hospital presentation. About 25 percent had laryngeal edema, and 22 percent had systolic hypotension on presentation. The etiology of the anaphylaxis was found in about 73 percent of cases, and most commonly was a drug, insect, venom, or food. Epinephrine and antihistamines were used in the prehospital phase of this Australian study in about 20 percent of cases. Definitive care was given entirely in the emergency department alone for 94 percent of cases, but only 43 percent of those with severe anaphylaxis were referred for follow-up. About a third of patients were discharged directly from the ED after a median 6.5 hours of monitoring (range 4-9 hours). Admission into the ED observation unit occurred in 61 percent, and three percent were admitted to the ICU.

    These authors conclude that anaphylaxis is more common than apparently recognized. It occurred in one of 439 ED cases, and half of those patients were categorized as being severe.

    First-line treatment included epinephrine, oxygen and IV fluids, and these authors also reported the use of H1-antihistamines and steroids. Interestingly, 27 of 39 patients received epinephrine IV in the hospital, but the majority of patients with severe anaphylaxis received epinephrine in the prehospital phase. Lack of follow-up care was considered to be an area that needed improvement.

    Comment: The prehospital use of epinephrine, even by IV, is rather common in Australia, but it's only rarely used by paramedics in my patient population. It's also rare for us to see a patient who used an auto-injector. Prescribing an auto injector for epinephrine is a common intervention in the ED. I don't know exactly how many patients actually get the prescription filled or have the courage to use it if they have another reaction, but referring them to their doctor for this or giving them a prescription makes sense to me.

    The vast majority of patients with mild anaphylaxis can be adequately treated with six to eight hours of ED observation. I still support admission for those with initially severe symptoms, those who require a second round of treatment, or those who have hypotension or laryngeal edema even though it clears with treatment. These would make nice observation cases for a 24-hour period. I am not aware of a patient who had a recurrent anaphylaxis after being discharged from the hospital after prolonged observation, although sometimes anaphylactoid reactions do occur a few hours after IV contrast material. Biphasic anaphylaxis is defined as a recurrence of symptoms that develop following the apparent resolution of the initial anaphylactic episode, with no additional exposure to the trigger. Biphasic reactions have been reported to develop in up to 23 percent of anaphylactic episodes in adults. They typically occur within eight to 10 hours after resolution of the initial symptoms, although recurrences up to 72 hours later have been reported. Corticosteroids may prevent delayed recurrence of symptoms.

    Peanut allergy is high on the list as a cause of anaphylaxis, as are fish and antibiotics. Patients with acute allergies can become symptomatic with even minuscule exposure to the offending agent.

    The Cochrane Database was unable to find any relevant studies on using the commonly prescribed epinephrine autoinjector (EpiPen) for treating outpatient anaphylaxis. This is considered standard of care and is often suggested as an ED prescription, but the true benefit of such patient-used injectors will likely never be randomized in a trial because of ethical concerns. (Cochrane Database Syst Rev 2012;Aug 15;8:CD008935.)

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    Dr. Roberts: Thank you for your thoughts on oxygen. (“Think Twice Before Administering Oxygen,” EMN 2013;35[11]:12; I have a few questions for your counsel and consideration.

    When I have patients who come to the ED for acute exacerbation of pain issues (headache, back pain, fibromyalgia), I have a “cocktail” of several items: IV medications (mostly taken from this grouping: Benadryl, Reglan, Ofirmev, Toradol, Ativan, Zofran, Dilaudid, Solu-Medrol, and others), IV fluid (I usually give a liter or two of saline because most patients consume caffeine and are slightly dehydrated), and in the past year I have started adding 100% oxygen via mask for one hour (especially with smokers). The clinical response of “I feel much better” has been the goal, and it seems that the added oxygen has helped. What are your thoughts?

    When I have patients who arrive with “chest pain” as the complaint, I routinely add oxygen at 3L per nasal cannula. I think this moves them from breathing the usual 21% to breathing about 35% oxygen. Along with this, I give aspirin and one inch of nitropaste (if appropriate). It takes one to two hours to complete the ED workup of these patients who fall into one of three categories: Immediate transport to the cath lab (45 minutes or less), discharge home, and admit for further evaluation. I have considered the added oxygen a helpful therapeutic intervention given the admitting complaint. Maybe even more appropriate than going to an “oxygen bar” in an airport. What are your thoughts? Thank you for your time and consideration. — David Mayor, MD, MPH, Burr Ridge, IL

    Dr. Roberts responds: I don't think giving 100% oxygen for an hour would be in any way harmful to an otherwise healthy patient with pain. The placebo effect is likely beneficial, and it seems like you tailor your approach to such patients; good move.

    It has been proven that extra oxygen provides no benefit to an acute MI when oxygen saturations are normal, but that has been an intervention for decades. Again, I don't think that would be harmful at 3 L for a number of hours, but it is not “therapeutic.” The major concern with excessive oxygenation is the prolonged use of high concentrations given to ill patients for many hours, for the reasons outlined in my column.

    Dr. Roberts: In reference to your column on loop drainage for abscesses, I have considered a number of different items to use in making the loop drain. (“Loop Drainage for Cutaneous Abscess,” EMN 2013;35[2]:16;

    Penrose drains, “red robin” catheters, or silicone vessel tape are options yet sometimes are not readily available or are too large. Why not use the iodoform gauze we commonly utilize to pack abscesses to create a loop? It seems to keep abscesses actively draining when we pack them, is the right size, and is widely available. — Joshua Batt, DO, Colton, CA

    Dr. Roberts responds: I don't see why gauze wouldn't work, but the smooth guiding action of the silicone vessel loop described in the column allows for some daily manipulation by the patient to help keep the drainage holes open. Gauze might occlude the draining holes, but that's only speculation. Larger holes are also probably required for gauze, but give it a try, and let us know how it works.


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