Anaphylaxis: 36 Practical Pointers for Reducing the Risk of Reaction

Paul Steinberg, MD

Steinberg P. Anaphylaxis: 36 practical pointers for reducing the risk of reaction. Consultant. 2017;57(10):588-595.


ABSTRACT: Practical measures can prevent most episodes of anaphylaxis. For example, display information about previous adverse reactions prominently in the medical record. If a patient reports allergy to a medication, use an alternative. Whenever possible, give antibiotics orally rather than parenterally. Always keep the medications and equipment necessary to treat anaphylaxis on hand. Warn patients not to withhold anaphylaxis treatment when needed, and urge them to discard any unused medication or foods that caused the reaction. Children’s thighs need to be fixed during epinephrine injection, and the autoinjector must be held in place for the recommended number of seconds.

KEYWORDS: Anaphylaxis, hypersensitivity reaction


The World Allergy Organization (WAO) has published a consensus definition of anaphylaxis as being “a severe life-threatening generalized or systemic hypersensitivity reaction.”1 The reaction is due to release of bioactive mediators from mast cells and basophils.2 The WAO recommends that, if the reaction is immunologically mediated involving immunoglobulin E (IgE), immunoglobulin G, or immune complex activation of the complement system (eg, to peanuts, penicillin, bee venom, blood products, natural rubber latex), the term allergic anaphylaxis should be used. If nonimmunologic reactions are involved (eg, to exercise, aspirin/nonsteroidal anti-inflammatory drugs [NSAIDs], radiocontrast agents), the WAO recommends using the term nonallergic anaphylaxis. The use of anaphylactoid, the older term for nonallergic anaphylaxis, is no longer recommended. Because signs and symptoms of allergic and nonallergic anaphylaxis may be identical, meeting 1 of 3 criteria for diagnosis has been suggested (Table 1).3


Anaphylaxis usually uniphasic, but it may be biphasic (recurrent) usually within 12 hours, rarely up to 72 hours. It has an incidence of up to 21% in all ages and 15% in children.2

Why one shock organ reacts preferentially over another is unknown. Fatalities most commonly have been associated with angioedema of the upper airway, followed by hypotension and associated arrhythmias. Because the definition of anaphylaxis has varied from study to study, the lifetime prevalence is unknown; the best estimate in industrialized countries is approximately 0.5% to 2% of the population.4

It is estimated that 7 to 10 nonfatal cases of anaphylaxis occur per 1000 doses of penicillin, with 1 fatal reaction per 50,000 doses,5 and that 8 nonfatal cases occur per 1000 stings from bees, wasps, hornets, and fire ants (40-50 annual US deaths).6

Once a diagnosis of anaphylaxis has been established by a temporal relationship (usually < 1 hour) between an event (eg, medication or radiocontrast administration, food ingestion, venomous sting) and the subsequent clinical manifestations, excellent treatment protocols are available.2 An elevated serum or plasma total tryptase level can support the clinical diagnosis of anaphylaxis, ideally obtained 15 minutes to 3 hours after onset, but the tryptase level may remain elevated for 6 hours, and a normal value does not rule out the diagnosis.7

The following are 36 suggestions to avert the largely preventable syndrome of anaphylaxis.

1. Always take a complete history of all adverse reactions to any diagnostic or therapeutic agent or to latex or any food.

The authors of a classic study of anaphylactic fatalities reported to have occurred after penicillin administration found that in 50% of cases, no information about previous reactions had been recorded, and it was unclear whether a question about penicillin allergy had ever been posed to the patients.5

The standard question, “Do you have any drug allergies?” is not sufficient. Many patients do not consider over-the-counter (OTC) medications to be drugs and may be unsure of what an allergic reaction is. A better question is, “Have you ever had an allergic reaction or a bad reaction to a prescription medicine (such as penicillin), an OTC medication (such as aspirin), a vaccination, an anesthetic, an x-ray dye, rubber, a blood product, an insect sting, or food?”

2. Don’t bury vital written information about previous reactions.

Prominent display of adverse reactions is particularly important when one health care provider who is substituting for another is not as familiar with the patient’s history. Consider placing stickers on the bed of inpatients with latex allergy. Each chart or electronic medical record should contain an adverse reaction form listing the following facts:

  • The date or, if it is unknown, the approximate year of the reaction
  • The provoking substance (eg, medication, contrast agent, food)
  • The nature and severity of the reaction
  • The name of the person entering the information

Details such as a patient’s mild upset stomach from an antibiotic need not be listed. Still, when in doubt, record.

3. Always believe the patient who tells you about having had an adverse reaction.

In one study, 70% of patients who died after a penicillin injection had previously received the antibiotic, and one-third of them previously had experienced sudden allergic reactions to it.5 This means that a significant number of patients had told the health care providers about their penicillin allergy—but were given it anyway!

4. When a patient tells you about an adverse reaction to a medication, always use an alternative unless a reliable, safe test is available to rule out allergy.

A substitute is almost always available for any medication that a patient reports having caused an adverse reaction. If the offending medication must be used, either seek allergy consultation or use a desensitization protocol (see No. 8). Although hypersensitivity may wane with time, the introduction of even micrograms may cause anaphylaxis in a sensitized person.

Skin-testing protocols are available only for selected IgE-mediated allergic reactions, such as those caused by penicillin. Experience has shown that careful pretesting with penicillin G and benzylpenicilloyl polylysine can detect 90% to 95% of persons who are sensitized and thus have the potential for an anaphylactic reaction.8 To date, no fatalities have been reported among history-positive, skin-test–negative patients who subsequently received penicillin.8

Skin testing with other antibiotics has not been sufficiently studied to accurately assess the risk of adverse reaction in skin-test–positive patients.8 If you must use one of these agents because it is potentially lifesaving, but the patient’s history suggests allergy, a desensitization protocol (with the oral route being safer than the parenteral route) in an intensive-care unit is recommended (see No. 8).

5. Know about potential medication cross-reactivity.

The use of skin testing with cephalosporin has been reported, but negative test results do not exclude the risk of immediate allergic reactions.9 Approximately 2% of patients with skin-test–proven sensitivity to penicillin react to cephalosporins.8 However, the package insert for every cephalosporin cautions that cross-hypersensitivity among β-lactam antibacterial drugs has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy.

Current recommendations for administration of cephalosporins in patients with a history of penicillin allergy are as follows9:

  • For patients with a negative penicillin skin-test result, it is safe to give a cephalosporin.
  • For patients with a positive penicillin skin-test result, 2% may react, some with anaphylaxis, so it is best not to use a cephalosporin or, if one is necessary, to use a desensitization protocol similar to that used with penicillin.
  • If skin testing is not available and a cephalosporin is necessary, use a desensitization protocol.

NSAIDs pose a high risk in patients who have had an adverse reaction to aspirin and vice versa. Reactions to aspirin or NSAIDs are not thought to be IgE-mediated but rather to result from blockade of the cyclooxygenase pathway, since these drugs inhibit prostaglandin synthetase.10 Consequently, no skin or in vitro tests are available to confirm the diagnosis, and administering a test dose of an NSAID is not recommended. Indications for aspirin desensitization include the following:

  • Heart disease requiring the antiplatelet effect of aspirin
  • Nasal polyposis resistant to medication or surgery
  • Arthritis and other inflammatory conditions requiring aspirin or NSAIDs

Highly successful desensitization protocols have been published for patients who have had asthmatic and/or sinusitis reactions to aspirin.11

In patients with sulfa allergy, published evidence suggests that using sulfa medications that do not contain an arylamine group (such as oral hypoglycemic agents, diuretics, and NSAIDs such as celecoxib) is safe.8

6. If the antibiotic is available in oral form, consider administering it orally or via a nasogastric tube rather than parenterally.

Each year, between 400 and 800 persons per year die from antibiotic-related anaphylaxis worldwide, and 97% of these deaths are related to β-lactams.5 Since penicillin has been in use, the vast majority of fatalities have resulted from parenteral administration.5

7. If you must give an antibiotic parenterally, consider trying a preliminary oral dose.

The risk of provoking fatal anaphylaxis with oral penicillin is dramatically lower than with parenteral use. Consider giving the first dose orally, if available, and observing the patient for at least 30 minutes before giving it parenterally.12

8. If a patient needs urgent treatment with an antibiotic known to have caused anaphylaxis, desensitize the patient—preferably via the oral route.

The usual setting is a penicillin-allergic patient with a life-threatening infection (eg, meningitis, endocarditis) who is receiving a different antibiotic that is not effective, putting the patient at risk of dying from overwhelming infection. In this situation, giving penicillin is probably less life-threatening than withholding it. Desensitization is then recommended rather than giving a test dose.

Detailed penicillin desensitization protocols have been published for the recommended safer oral approach and for the riskier parenteral approach.13 Desensitization protocols for sulfa medications also are available.13

9. Always tell the patient which medication you plan to give just before administering it.

Saying directly, “I am going to give you penicillin,” can sometimes jog a patient’s memory and help a patient recall having had a previous problem.

10. Know how to handle patients’ previous adverse reactions to vaccines.

Allergic reactions to vaccines are rarely caused by the infectious agent but rather by the other ingredients such as egg, gelatin, yeast, latex, milk, or preservatives.14

If a patient reports having had an “allergic” reaction to a vaccine, strategize as follows:

  • For patients with a vaccine need, skin test with the vaccine (this requires training and the use of positive and negative skin-testing controls) or give the vaccine in a graded-dose protocol and be prepared to treat anaphylaxis.14
  • For patients with an uncertain need, check antibody levels to see whether they remain protective; if so, withhold the vaccine, and if not, proceed with the need strategy.
  • For patients with no need for vaccination, document the reaction and withhold the vaccine.

Protocols are available for patients with a need for vaccination with tetanus. However, 10 to 20 weeks are necessary to complete the protocol.15

11. Know which vaccines contain egg and are contraindicated in egg-allergic patients.

Many influenza vaccines are prepared in chick extraembryonic allantoic fluid; the yellow fever vaccine is prepared in chick embryos; and the rabies vaccine and single-virus and combination vaccines for measles, mumps, and rubella (MMR) are prepared in chick embryo fibroblasts.14 All influenza, MMR, and purified chick embryo cell rabies vaccines can be given safely to egg-allergic patients with a recommended 30-minute wait after administration. However, the safety of other vaccines has not been established in patients with egg allergy.16,17

Before administering vaccines other than influenza, MMR, or rabies, ask all patients whether they can eat eggs without any adverse reaction, and withhold the vaccine if their reaction was anaphylactic.

12. Give injections distally when possible.

If an anaphylactic reaction follows an injection, placing a tourniquet above the injection site may be helpful, although not of proven benefit. The site can be injected with a small amount of 1:1000 epinephrine to retard absorption, but this also is not of proven benefit.

13. Have patients wait in the office for 30 minutes after an injection.

Because most anaphylactic reactions occur within 30 minutes after an injection (eg, antibiotic, vaccine, allergy shots, etc), tell patients who have received any injection that a half-hour wait is office policy. The absence of a previous adverse reaction does not guarantee that an anaphylactic reaction will not occur. If a patient cannot or will not wait, ask him or her to sign a form releasing you from medical responsibility.

14. Warn patients not to withhold anaphylaxis treatment when it is indicated.

Patients, especially teenagers, may think, “I’ll see what happens,” or “I can tough this out,” or “I can make it through,” and not use their epinephrine autoinjector when it is clearly needed, possibly resulting in fatality.18 Epinephrine is the only proven treatment for anaphylaxis, but it is underutilized across all age groups.18

15. Be extremely careful with patients who are allergic to natural rubber latex.

In the past, anaphylactic reactions to natural rubber latex had been common, especially among health care workers and among children with spina bifida or urogenital abnormalities, who have frequent exposure to latex during examinations, procedures, and fecal disimpactions.19 Such reactions have become less common since gloves and other medical supplies causing latex sensitization have been largely removed from the clinical setting.

Skin contact with gloves, tourniquets, blood pressure cuffs, disposable draping, electrocardiography electrode pads, adhesive bandages, and elastic on clothing may cause sensitization or even anaphylaxis. Before administering injectable medication to latex-allergic patients, ensure there is no latex in syringe plungers, needle covers, and multidose bottle stoppers. Use vinyl or nitrile gloves. The term hypoallergenic is meaningless and has been removed from most medical product labels. Medical devices, even adhesive bandages, now should state whether they contain natural rubber latex. If any question exists about whether an older product such as a blood pressure cuff or tourniquet contains natural rubber latex, place a cloth towel underneath.

16. Urge patients to discard any unused drug or food to which they have reacted.

If an outpatient medication is thought to have caused an anaphylactic reaction, check the contents against the label. Patients may put multiple medications in the same container or reuse older containers, making identification of the culprit a challenge. Pharmacy mislabeling is less likely but is possible.

Patients with impaired memory may inadvertently ingest a medication or food again if it remains available—a frequent problem with aspirin and NSAIDs. Have the patient or a family member or visiting nurse go through the patient’s medicine cabinet and drawers, kitchen pantry, and refrigerator and discard the offending foods or medications.

17. Educate patients to avoid exposure to provoking agents.

Certain foods such as peanuts may be particularly difficult to avoid, since they may be disguised in cookies or other prepared foods. Another example is aspirin, which is an ingredient in many OTC cold preparations. Emphasize to patients that reading labels is essential, and if there is any question about the safety of an item, they should not ingest it.

18. Warn patients not to become cavalier about known food allergies.

Patients may have the urge to try foods that previously had caused allergic reactions, reasoning that “I probably outgrew this,” or “It won’t happen to me,” or “How could such a small amount hurt me?” Instead, encourage them to get tested, and explain that anaphylaxis, once it has begun, may not be able to be controlled. Fatalities have been reported, principally among teenagers with a cavalier attitude about eating foods they knew to be risky.18

19. Remove a honeybee’s stinging apparatus from the skin wound.

The honeybee’s stinger is a muscular bag filled with venom that is connected to a hollow, barbed apparatus.20 Remove the 1- to 2-mm–wide bag by pinching it off, flicking it off with your finger, or breaking it off by scraping along the skin with a knife.

NEXT: Tips 20-36 

20. Refer all patients with anaphylactic reactions to Hymenoptera stings (eg, wasps, bees, yellow jackets, hornets, fire ants) to an allergist.

Refer patients who have a generalized reaction (cutaneous, cardiovascular, and/or respiratory involvement) to an allergist for risk assessment. Large local reactions are characterized by increasing size over 24 to 48 hours, swelling of greater than 10 cm in diameter contiguous to the sting site, and resolution in 3 to 10 days. These local reactions generally do not require consultation, only symptomatic treatment.20 Nevertheless, they are a form of allergy, and although patients who have these local reactions usually do not need immunotherapy, they do require epinephrine, because they have an anaphylaxis risk that is higher than the general public.

One group of authors’ survey revealed that emergency department health care providers in Saint Louis were not providing appropriate avoidance instruction, a prescription for epinephrine, or referral to an allergist to patients who presented with stinging insect anaphylaxis.21 There is no reason to believe that other health care facilities are different.

21. Prescribe an epinephrine self-injecting syringe for patients at risk.

Epinephrine, not antihistamines or corticosteroids, is the initial medication of choice and is the only proven treatment of anaphylaxis. There are no absolute contraindications—it appears that the risk of not using epinephrine, even by older patients with cardiovascular disease or by pregnant women, is greater than the risk of using it.20,22 When prescribed, it must be immediately available at all times in all places.

Patients at risk include all those who have experienced anaphylaxis, including from Hymenoptera venom, foods, natural rubber latex, and exercise, or with no known cause (idiopathic anaphylaxis).

The recommended adult dosing is 0.3 to 0.5 mg of 1:1000 solution (0.3-0.5 mg intramuscularly [IM]; subcutaneous injection is no longer recommended).2 For children, the recommended dosing is 0.01 mg/kg (maximum, 0.3 mg IM). Doses can be repeated 2 to 3 times at 5- to 15-minute intervals.2

Spring-loaded, temperature-stabilized epinephrine autoinjectors can be prescribed for patients to carry in a pocket, backpack, or small bag. Temperature extremities in a car (eg, glove compartment) or outdoors from the sun’s heat may cause significant product deterioration and should be avoided. Several devices are available on the US market as 2 packs, including the EpiPen and its generic version (0.3 mg for adults), the EpiPen Jr and generic version (0.15 mg for children weighing 15-30 kg), the Adrenaclick and its generic equivalent (0.3 mg for adults or 0.15 mg for children weighing 15-30 kg), and AUVI-Q, a more compact device with talking instructions (0.3 mg for adults or 0.15 mg for children weighing 15-30 kg). Sicherer and Simons discuss epinephrine dosing for children weighing less than 15 kg.23

22. If you prescribe epinephrine, you are obligated to teach the patient how and when to use it.

Health care providers, especially those in emergency departments, often fail to instruct patients in the proper use of epinephrine autoinjectors. During an anaphylactic reaction is hardly the time to read the package insert to learn how the device works. The device manufacturers supply written information and practice trainers at no expense; more information is available online at each device’s website (www.epipen.com, www.adrenaclick.com, www.auvi-q.com).

After epinephrine administration, a second party should transport the patient to an emergency facility. If alone, the patient should call 911 for assistance. If lightheaded or unconscious, the patient should be transported in the supine position. If the patient is unable to self-administer epinephrine, at least 1 family member, caregiver, or friend should be educated about how to use the epinephrine in case of reaction.

Injecting epinephrine into the lateral thigh is recommended, since it has been shown to raise blood levels faster and higher than subcutaneous arm or intramuscular deltoid placement.24

There are 2 very important new recommendations about the use of epinephrine autoinjectors. First, the prescribing information for the EpiPen and EpiPen Jr (but not the Adrenaclick or AUVI-Q devices) has been updated to note that only a 3-second hold in place is necessary instead of a 10-second hold. Second and more important is the need to fix the thigh of a child in place to avoid movement after injection, which could result in serious laceration and infection.25,26

Provide patients with a written action plan explaining when to use an epinephrine autoinjector. Examples in English or Spanish are available online at the website of the American Academy of Allergy, Asthma, and Immunology.27,28

23. Reassess the need to use larger doses of epinephrine as children get older, and check expiration dates.

With the use any of the available autoinjectors, review the child’s weight annually and increase the dose to adult levels for weight greater than 30 kg.23 The use of outdated autoinjectors is not recommended, but research has shown that outdated autoinjectors contain some epinephrine, and in an emergency, they should be used if they are the only treatment available.29

24. Make sure 2 injections are available to treat a reaction.

Although no consensus guidelines are available, at least 2 injections are strongly recommended in the following situations:

  • If a previous reaction had required more than 1 injection.
  • If concerns exist about a biphasic anaphylactic reaction occurring 4 to 6 hours later.30 Because of biphasic anaphylaxis potential, advise not separating the syringes in a 2 pack but keeping both available in all locations (eg, home and school).
  • In a very obese child or adult.
  • If concerns exist about travel time to an emergency facility. The World Health Organization recommends 1 dose per 10 to 20 minutes of travel time.31

25. Recommend that all patients at risk for anaphylaxis consider wearing identification jewelry or carrying a wallet card.

These can be obtained at most pharmacies. The jewelry or card should have the proper information about the offending diagnostic or therapeutic agent, rubber, food, exercise, or other potential cause of anaphylaxis.

26. Do not premedicate patients with previous IgE-mediated reactions and then challenge with medication.

Although pretreatment protocols have demonstrated protection in non–IgE-mediated reactions (eg, to radiocontrast media32), there is no evidence that these protocols will protect against IgE-mediated anaphylaxis from penicillin, natural rubber latex, and other causes. Furthermore, during testing or desensitizing, premedication may block a reaction that otherwise would have occurred at a lower dose.

27. If a patient needs a radiocontrast medium for a radiologic study and has had a previous anaphylactic reaction to it, use a pretreatment protocol.

The likelihood of a recurrent anaphylactic reaction to a radiocontrast medium can be dramatically reduced with the use of such protocols. Because the incidence of severe reactions (eg, dyspnea, sudden hypotension, cardiac arrest, loss of consciousness) is lower with low osmolar nonionic media, some authors strongly recommend the use of such media along with pretreatment protocols in patients who have had previous immediate reactions.32

Table 2 provides a pretreatment protocol as recommended by Grammer and Greenberger.33


28. Warn patients with cold-induced urticaria/angioedema not to swim in cold water above their knees.

These patients usually present with localized swelling of the hands, mouth, and face after exposure to cold water, cold beverages, or cold air.34 Total immersion in cold water may cause anaphylaxis, with possible loss of consciousness and drowning.

29. Choose a different local anesthetic if patients report adverse reactions.

Most reactions to local anesthetics are vasovagal or caused by epinephrine. Anesthetics are categorized into 2 groups based on type IV hypersensitivity reactions. Group 1 anesthetics contain a cross-reacting para-aminophenol group (eg, procaine, benzocaine), whereas anesthetics in group 2 do not contain this cross-reacting group (eg, lidocaine, mepivacaine, bupivacaine).

If time does not permit a provocative testing protocol and the patient has had an adverse reaction to a group 1 anesthetic, then select an agent from group 2. If the patient has reacted to a group 2 anesthetic, then choose a group 1 agent or a different group 2 agent.2

30. Use a desensitization protocol if the patient has had an anaphylactic reaction to human insulin.

If a patient has had an anaphylactic reaction to human insulin, skin testing and desensitization protocols are indicated.35

31. Obtain consultation for all patients with previous significant transfusion reactions.

Obtain a hematologic or allergic consultation, since an anaphylactic reaction can have a variety of mechanisms (eg, anti-IgA antibodies).36

32. Be prepared to treat anaphylaxis when giving heterologous serum (e.g., horse-derived) to a patient who has had a significant previous reaction to horse protein.

A common scenario is the patient with a snakebite who needs horse serum antivenin but who has had a significant previous reaction to horse-derived antitoxin or to horsemeat or who is allergic to horses. Theoretically, skin testing and/or desensitization are advised, but after a snakebite, the risk of delaying antivenin may be greater than giving it.

In patients with possible allergy to horse protein, give the antivenin in an intensive-care unit, and treat anaphylaxis early and vigorously if it occurs.

In some countries, horse serum–derived tetanus antitoxin is still available. Choose human-derived tetanus antitoxin if it is available.

33. Avoid giving β-adrenergic blocking medications to patients at risk for anaphylaxis.

Patients taking β-blockers may not respond to epinephrine, resulting in fatal anaphylaxis. In patients at risk for anaphylaxis from foods, venom, natural rubber latex, or other causes, use alternatives to β-blockers. 

Allergy immunotherapy (allergy shots) is relatively contraindicated for patients receiving β-adrenergic blockers orally, parenterally, or topically (eg, eye drops); ideally, they should be temporarily stopped at least 24 hours in advance, then restarted 1 to 2 hours after the injection if no problems occur. α-Adrenergic blockers may also decrease the effects of epinephrine. Angiotensin-converting enzyme inhibitors and, to a lesser degree, angiotensin-receptor blockers may interfere with the patient’s own compensation to anaphylaxis; however, no current recommendation exist about stopping these agents. Sedating medication, alcohol, and recreational drugs may also cloud a patient’s judgment about the severity of a reaction or when to seek or initiate treatment.2

34. Warn patients with exercise anaphylaxis not to exercise alone.

Counsel such patients to always carry an epinephrine autoinjector when they exercise. Instruct them to always work out with a partner who is familiar with use of the device.37

35. Withhold routine allergy immunotherapy in patients at high risk for anaphylaxis.

Patients with uncontrolled or unstable asthma are at high risk for anaphylaxis; as such, immunotherapy is contraindicated in this population. Other situations in which to consider withholding immunotherapy injections include just after a patient has exercised vigorously, when a fever or other illness has recently developed in a patient, and when a patient has severe symptoms of allergic rhinoconjunctivitis or an acute exacerbation of chronic obstructive pulmonary disease.

36. Always have the medication and equipment ready to treat an anaphylactic reaction.

Most reactions can be detected early and stopped quickly with properly used epinephrine. In any clinical setting in which injections (eg, medications, vaccinations, allergy shots) are administered, having updated supplies on hand for the treatment of anaphylaxis is recommended (Table 3). 


Paul Steinberg, MD, is a consultant in allergy and immunology in the Department of Medicine at Bassett Healthcare in Cooperstown, New York, and a clinical professor of medicine at Columbia University College of Physicians and Surgeons in New York, New York.


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