Anaphylaxis: 36 Commonsense Ways to Reduce the Risk

Key words: anaphylaxis,
hypersensitivity reaction

In 2000, the World Allergy Organization (WAO) published a consensus definition of anaphylaxis as a severe, life-threatening generalized or systemic hypersensitivity reaction.¹ The reaction is caused by the release of bioactive mediators from mast cells and basophils.²

The WAO recommends that if the reaction is immunologically mediated- involving IgE, IgG, or immune complex activation of the complement system-the term “allergic anaphylaxis” should be used (examples: peanuts, penicillin, bee venom, blood products, natural rubber latex). If nonimmunological reactions are involved, the organization recommends the term “nonallergic anaphylaxis” (examples: exercise, aspirin and NSAIDs, cold). Anaphylactoid, the older term for nonallergic anaphylaxis, is no longer recommended. Since the signs and symptoms of allergic and nonallergic anaphylaxis may be identical, the presence of 1 of 3 criteria for diagnosis has been suggested (Table 1).

Why one “shock organ” reacts preferentially over another is unknown. Fatalities have been most commonly associated with angioedema of the upper airway, followed by hypotension/
arrhythmias. Since the definition of anaphylaxis has varied from study to study, the prevalence is unknown. Possibly the best estimate is that about 1% of the population have been given an outpatient prescription for epinephrine.³ It is estimated that there are 7 to 10 nonfatal cases of anaphylaxis per 1000 parenteral doses of penicillin (1 fatal reaction per 50,000 doses) and 8 nonfatal cases per 1000 venomous stings from bees, wasps, hornets, and fire ants (40 to 50 deaths in the United States per year).^4,5

Once a diagnosis of anaphylaxis is established by a temporal relationship (usually less than 1 hour) between an event (eg, administration of a medication or an x-ray dye, ingestion of a food, or a venomous sting) and the usual clinical manifestations, excellent treatment protocols are available.²

In this article, I suggest 36 ways to avert the largely preventable syndrome of anaphylaxis. An Wang, founder of Wang Laboratories, once said, “Success is more a function of consistent common sense than it is of genius.” Most of the strategies suggested here are little more than that.

1. Always take a complete history of all adverse reactions to any diagnostic or therapeutic agent or to rubber or food.
A classic paper on fatal penicillin reactions states that in 50% of the deaths, no information about previous reactions was available in the medical records. It appears that no question about penicillin allergy was ever posed.⁴

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

2. Don’t bury vital written information about previous reactions.
Prominent display of adverse reactions is particularly important when one physician substituting for another is not as familiar with the patient’s history. In addition to pasting stickers on chart fronts or if possible on the bed of inpatients, I recommend that each chart contain a standardized Adverse Reaction Form listing these facts:

• Date or, if unknown, approximate year of reaction.

• Provoking substance(s).

• Nature of reaction.

• Name of person who is entering the information.

Details such as mild upset stomach from an antibiotic need not be listed. However, when in doubt, record. A future standardized electronic medical record should keep vital information “unearthed.” 

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 drug; one-third of them had previously experienced sudden allergic reactions to it.⁴

In truth, a significant number of patients had told the physician they were allergic to penicillin-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 skin test is available to rule out allergy.
A substitute is almost always available for the medication the patient claims caused an adverse reaction. If the offending medication must be used, either seek allergy consultation or use a desensitization protocol (see No. 26). Although hypersensitivity may wane with time, the introduction of even micrograms may cause anaphylaxis in a sensitized patient.

Skin-testing protocols are available only for select IgE-mediated allergic reactions, such as those caused by penicillin. Experience has shown that careful pretesting with penicillin G and benzylpenicilloyl polylysine (PPL) can detect 90% to 95% of persons who have the potential for an anaphylactic reaction. To date, no fatalities have occurred among history-positive, skin test–negative patients who subsequently received penicillin.⁶ Unfortunately, commercial PPL testing material was removed from the market several years ago; currently, risk assessment by skin testing is available only in research facilities where the reagent can be prepared.

Skin testing with other antibiotics has not been evaluated in as many patients as penicillin has been. Risks associated with administration of other antibiotics to history-positive, skin test–negative patients are unknown.⁷ If you must use one of these because it is potentially lifesaving and the history suggests allergy, a desensitization protocol (oral route safer than parenteral route) in an ICU is recommended (see No. 26).

5. Know about potential cross-reaction between medications.
The risk of administering a first-generation cephalosporin to a patient with penicillin allergy is not negligible. For higher-generation cephalosporins, the risk is thought to be lower⁸; however, the package insert for every cephalosporin states caution in use, since “cross-hypersensitivity among β-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy.” If a cephalosporin is the treatment of choice over antibiotics that do not contain a β-lactam ring, the safest approach is a desensitization protocol (by the oral route if preparations are available). Use a protocol similar to that of penicillin, beginning with 0.05 mg for oral or 0.01 mg for intravenous administration.

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; rather, they may be caused by blockade of the cyclooxygenase pathway, because these drugs inhibit prostaglandin synthetase.⁹ Consequently, there are no skin or in vitro tests to confirm the diagnosis, and giving a test dose is not recommended. Highly successful desensitization protocols are available for patients who have had asthmatic and/or sinusitis reactions to aspirin.¹⁰

In patients who are allergic to sulfa, it appears from the literature that using non-arylamine–containing sulfa medications (examples: oral hypoglycemics, diuretics, and NSAIDs such as celecoxib) is safe.⁸

6. Know how to handle previous adverse reactions to vaccines.
If a patient reports an “allergic” reaction to a vaccine, withhold and follow 1 of these 3 strategies:

• For patients with a future vaccine need, skin test with the vaccine (this requires training and the use of proper skin testing controls) or give the vaccine in a graded-dose protocol and be prepared to treat anaphylaxis.²

• For those with an uncertain need, check antibody levels to see if they are protective. If they are, withhold the vaccine; if not, proceed with the need strategy.

• For those with no need of the vaccine in the future, document the reaction and withhold. Protocols are available for immunotherapy with tetanus toxoid on a need basis; however, these protocols take 10 to 20 weeks to complete.¹¹

7. Know which vaccines contain egg residues and know which ones can be given to egg-allergic patients.
Vaccines against influenza are grown in chick extra-embryonic allantoic fluid; yellow fever in chick embryos; and single-virus rubella, mumps, rubeola, rubella/rubeola, rubella/mumps, rubella/rubeola/ mumps, and rabies in chick embryo fibroblasts.¹¹ Measles-mumps-rubella (MMR) and purified chick embryo rabies vaccines can be given safely, even in egg-allergic patients; however, the safety of other vaccines has not been established.^12,13

Before you give vaccines other than MMR or rabies, ask all patients whether they can eat eggs without any adverse reaction and withhold the vaccine if the reaction was anaphylactic. Use of influenza (killed and attenuated live) or yellow fever vaccines in patients with previous nonanaphylactic reactions to eggs is not recommended unless skin testing can be done to assess risk. Use of rabies vaccine in a patient with any previous significant adverse reaction to egg requires immediate allergy consultation. If consultation is not available, proceed with vaccination and be prepared to treat anaphylaxis.

8. Consider the oral rather than the parenteral route when giving antibiotics.
The statistics are frighteningly clear: between 400 and 800 patients per year die of antibiotic-provoked anaphylaxis, and 97% of these deaths are caused by β-lactams. Since penicillin has been in use, the vast majority of fatalities have resulted from parenteral administration.¹⁴

9. If you need to 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 (about 6 fatalities from orally administered penicillin have been reported). Consider giving the first dose orally and observing the patient for at least 30 minutes before you give the antibiotic parenterally.¹⁵

10. Always tell the patient which medication you plan to give just before injecting it.
Saying directly, “I am going to give you penicillin,” can sometimes cause a few synapses to reconnect and previous problems recalled.

11. Give injections distally when possible.
If an anaphylactic reaction follows an injection, it may be helpful to place a tourniquet above the injection site. You can inject the site with a small amount of 1:1000 epinephrine. In truth, though, the advantages of tourniquets have not been proved.

12. Have patients wait 20 or 30 minutes after any injection.
Since most anaphylactic reactions occur within 30 minutes after an injection (antibiotics, vaccines, allergy shots, etc), tell patients who have been given anything by injection that a half-hour wait is office policy. The absence of a previous adverse reaction does not guarantee an anaphylactic reaction will not occur. If the patient cannot or will not wait, ask him or her to sign a form releasing you from medical responsibility.

13. Warn patients, particularly teenagers, not to withhold anaphylaxis treatment when it is indicated.
Patients may think “I’ll see what happens” or “I can tough this out” or “I can make it through” and not use their epinephrine syringe when clearly needed. Teenagers are prone to this attitude and fatalities have resulted.¹⁶

14. Be extremely careful with patients who are allergic to natural rubber latex.
Anaphylactic reactions to natural rubber latex are becoming more common-especially among health care workers, rubber industry workers, and children with spina bifida or urogenital abnormalities. These children have had multiple exposures to latex for most of their lives because of examinations, surgical procedures, and fecal disimpactions.¹⁷

Skin contact with gloves, tourniquets for blood drawing, blood pressure cuffs, disposable draping, ECG pads, and adhesive bandages may cause anaphylaxis. Use vinyl or “synthetic” gloves. “Hypoallergenic” labeling is meaningless and has been removed from most medical products. Medical devices now should state whether they contain natural rubber latex. If there is any question about whether an older product such as a blood pressure cuff or tourniquet contains natural rubber latex, place a cloth towel underneath.

15. Urge patients to discard any unused drug or food they have reacted to.
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 a challenge. Less likely, but still possible, is pharmacy mislabeling.

Many patients have an impaired memory and may inadvertently ingest the medication or food again if on hand-a frequent problem with aspirin and NSAIDs. Have the patient or a family member go through the medicine cabinet and drawers, food cabinets, and refrigerator to discard the offending food or medications.

16. 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, an ingredient in many over-the-counter cold medications. Emphasize to patients that label reading is essential, and if there is any question about the safety of an item, they should not ingest it.

17. Warn patients not to become cavalier about known food allergies.
Patients may have the urge to try eating foods that previously caused allergic reactions, reasoning “I probably outgrew this” or “It won’t happen to me” or “How could such a small amount hurt me?” Fatalities have been reported, principally among teenagers with a cavalier attitude about eating foods they knew to be risky.¹⁶

18. Remove a honey bee’s stinging apparatus from the skin wound. The stinging apparatus (“stinger”) is a muscular bag filled with venom that is connected to a hollow barbed apparatus.¹⁷ 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.

19. Refer all patients with anaphylactic reactions to Hymenoptera (wasp, bee, yellow jacket, hornet, fire ant) stings to an allergist.
Refer children younger than 16 years who have generalized reactions (cardiovascular and/or respiratory, not cutaneous only) and patients 16 years or older with generalized reactions (cutaneous, cardiovascular, and/or respiratory) to an allergist for venom skin testing and possible desensitization. Large local reactions are of no concern.¹⁸

An interesting study revealed physicians in the St Louis emergency departments were not appropriately referring such patients. There is no reason to believe other health care facilities are different.¹⁹

20. Prescribe an epinephrine syringe for patients at risk.
Epinephrine, not antihistamines or corticosteroids, is the initial medication of choice for treatment of anaphylaxis, and there are no known contraindications. It appears that the risk of not using it, even in older patients with cardiovascular disease, is greater than using it.² When prescribed, it must be immediately available at all times in all places.

Patients at risk include those who have experienced anaphylactic reactions to:

• Hymenoptera venom and have not yet been desensitized.

• Food or food additives and cannot control their diets.

• Natural rubber latex.

• Exercise.

• “Idiopathic anaphylaxis.” Recommended adult dosing is 0.3 to 0.5 mL of 1:1000 solution (0.3 to 0.5 mg); for children, 0.01 mg/kg (maximum, 0.3 mg). Doses can be repeated 2 to 3 times at 5 to 15 minute intervals.²

Spring-loaded, temperature-stabilized epinephrine injectors can be prescribed, and they may be carried in a pocket, backpack, “fanny pack,” or small bag. Temperature extremes in a car or glove compartment or the sun’s heat outdoors may cause significant product deterioration.

Two devices are available in the US market: EpiPen and Twinject. The EpiPen delivers 0.3 mL of 1:1000 epinephrine for adults. For children who weigh 15 to 30 kg (33 to 66 lb), the EpiPen Jr is available; this device delivers 0.3 mL of 1:2000 epinephrine. A unit with 2 EpiPens is called the EpiPen 2 Pak.

The Twinject contains either 0.3 mg of epinephrine per dose for adults or 0.15 mg per dose for children who weigh 15 to 30 kg (33 to 66 lb) in the autoinjector device, combined with a separate similar dose of a self-injecting syringe (note that with Twinject 2 injection techniques are needed; see No. 21).

Epinephrine dosing in children who weigh less than 15 kg (33 lb) is discussed in an article by Sicherer and Simons.²⁰

21. 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 an epinephrine syringe. During an evolving anaphylactic reaction is hardly the time for the patient to read the package insert to learn how the device works. The EpiPen manufacturer will supply written information and practice trainers at no expense (www.epipen.com). The manufacturer of Twinject has an interactive Web site (www. twinjecttraining.com).

Injecting epinephrine into the lateral thigh is recommended because it has been shown to raise blood levels faster and higher than subcutaneous arm or intramuscular deltoid placement.¹

After epinephrine is administered, the patient should preferably be transported by a second party to an emergency facility. If alone, the patient should call 911 for assistance. Transport patient in a supine position and elevate legs if light-headed or unconscious.

The patient should stay at the emergency facility for 4 to 6 hours. Provide patients with a written “action plan” that explains how and when to use the epinephrine syringes. Examples can be downloaded from the Web site of the American Academy of Allergy, Asthma, and Immunology (www.aaaai.org). Try to educate at least one family member, caregiver, or friend about epinephrine use in case the patient cannot self-administer.

22. Assess the need to use larger doses of epinephrine as the patient gets older, and check expiration dates.
For both autoinjector devices, review patient weight annually and increase the dose to the higher levels as recommended. Current recommendations are to use the adult-size EpiPen or Twinject 0.3 mg for weight greater than 30 kg, although some experts recommend it for weight greater than 25 kg.²⁰

Use of outdated syringes is not recommended, but research has shown outdated syringes contain some epinephrine. In an emergency, they should be used if they are the only treatment available.²¹

23. Consider prescribing more than 1 epinephrine injection.
Although no consensus guidelines are available, most specialists prescribe 2 or more. Considerations for more than 1 injection include:

• Previous anaphylactic reaction that required more than 1 injection.

• Very obese child or adult.

• Concerns about a “biphasic” anaphylactic reaction occurring 4 to 6 hours later (the incidence in published studies varies from 8% to 35%²²) for patients who cannot get to an emergency facility.

• Concerns about travel time to an emergency unit (the World Health Organization and Anaphylaxis Canada [www.anaphylaxis.org] recommend 1 dose per 10 to 20 minutes of travel time).

 24. Recommend that all patients at risk for anaphylaxis wear identification jewelry, which can be purchased from most pharmacies, or jewelry that is registered (MedicAlert, 800-432-5378, www.medicalert.org), or carry a wallet card.
At-risk persons should consider wearing a bracelet or necklace or carry a wallet card with the proper information about the offending diagnostic or therapeutic agent, rubber, food, exercise, or other potential cause of anaphylaxis.

25. Do not premedicate patients who have had a previous IgE-mediated reaction and then challenge with medication.
Although pretreatment protocols have demonstrated protection in non–IgE-mediated reactions (eg, radiocontrast media²³), there is no evidence that these protocols will protect against IgE-mediated anaphylaxis from penicillin, natural rubber latex, and other causes.

26. If a patient needs urgent treatment with an antibiotic known to have caused anaphylaxis, desensitize the person-preferably by the oral route.
The usual setting is a penicillin-allergic patient with a life-threatening infection (eg, meningitis or endocarditis) who is receiving a different antibiotic and dying of 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 protocols have been published for the recommended safer oral approach and for the more risky parenteral approach.²⁴ Protocols for sulfa are also available.²⁴

27. If a patient needs a radiocontrast medium for an x-ray 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 by using such protocols. Since the incidence of severe reactions (dyspnea, sudden hypotension, cardiac arrest, and/or loss of consciousness) is lower with low osmolar nonionic media,²⁵ some authors strongly recommend the use of such media along with pretreatment protocols in patients who have had previous immediate reactions. Table 2 provides a pretreatment protocol recommended by Greenberger and colleagues.²⁶

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.²⁷ 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. Although most reactions to local anesthetics are vasovagal or caused by epinephrine, it is wise to perform a provocative testing protocol with the desired agent.²³ Anesthetics have been arbitrarily divided into 2 groups:

• Group 1 agents contain a cross-reacting para-aminophenol group (eg, procaine).

• Group 2 agents do not contain this cross-reacting group (eg, lidocaine or mepivacaine).

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 one in group 1 or a different group 2 agent.²⁸

30. Use a desensitization protocol if the patient has had an anaphylactic reaction to human insulin.
Single-component insulins (ie, beef or pork) have been removed from the US market. If a patient has had an anaphylactic reaction to human insulin, skin testing and desensitization protocols are indicated.²³

31. Use a pretransfusion protocol for all patients with previous significant transfusion reactions. Obtain a hematology or allergy consultation for patients who have had significant previous transfusion reactions. Pretransfusion protocols similar to those for radiocontrast media are recommended.²⁹

32. Do not give heterologous serum (eg, horse-derived) to a patient who has had a significant previous reaction to horse protein.
A common scenario is the patient who may need horse serum antitoxin for a snakebite (antivenin) but has had a significant previous reaction to horse-derived antitoxin or to eating horse meat or is allergic to horses. Theoretically, skin testing and/or desensitization is advised; however, after a snakebite, the risk of withholding antivenin may be greater than giving it. In patients with possible allergy to horse protein, give the antivenin in an ICU and treat anaphylaxis early and vigorously if it occurs.

In some countries, horse serum–derived tetanus antitoxin is still available. Do not administer it to at-risk patients when a human-derived tetanus antitoxin is available.

33. Avoid giving -adrenergic blocking medications to patients at risk for anaphylaxis.
Patients who take β-blockers may not respond to epinephrine, which can result in fatal anaphylaxis. In patients at risk for anaphylaxis from foods, venom, natural rubber latex, or other causes, use alternatives to β-blockers for hypertension or arrhythmia. Allergy immunotherapy (“allergy shots”) is contraindicated for patients receiving β-adrenergic blockers orally, parenterally, or topically (eg, eyedrops). ² 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. Sedating medications, alcohol, and recreational drugs may cloud a patient’s judgment about the severity of a reaction or when to treat.

34. Warn patients with exercise anaphylaxis not to exercise alone.
Counsel such patients to always carry an epinephrine syringe if they wish to exercise. Instruct them to always work out with a partner who is familiar with use of the syringe.³⁰

35. Withhold routine allergy immunotherapy (allergy shots) in patients at high risk for anaphylaxis.
There appears to be a dangerous synergistic effect between uncontrolled asthma and development of anaphylaxis after an allergy shot. Injections should also be withheld:

• When the patient has just exercised vigorously.

• If a fever or other illness has recently developed; a mild upper respiratory tract infection without fever is not a contraindication.

• If the patient is receiving β-adrenergic blockers.

• If the patient has severe symptoms of allergic rhinoconjunctivitis.

36. Always have the medications and equipment ready to treat an anaphylactic reaction.
Most reactions can be detected early and can be stopped quickly by properly used epinephrine and antihistamines. In any office where you give injections (eg, medication, vaccinations, or allergy shots), keep a variety of items for treatment of anaphylaxis on hand (Table 3).

Editor’s note:
Dr Steinberg wrote on the prevention of anaphylaxis for CONSULTANT in April 2000; he has expanded and updated his discussion here.

References:

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