Kyle R. Copeland , PharmD

Educational Objectives

Upon completion of this educational activity, participants should be able to:

• Describe the pathophysiology of and risk factors for anaphylaxis.
• Discuss the different treatment options available for the treatment of anaphylaxis and detail when they are appropriate.
• Counsel and educate patients on anaphylaxis and how to use the different epinephrine auto-injector kits.

In 1902, scientists Charles Robert Richet and Paul Portier described an unexpected hypersensitivity reaction in dogs immunized with jellyfish toxin. The animals tolerated the first injection with no problems, but experienced the rapid onset of bronchospasm, cardiac arrest, and death when exposed to a smaller, repeat dose 14 days later. They would go on to name the reaction "l'anaphylaxie," derived from the Greek words a- (against) and -phylaxis (immunity). This discovery resulted in a Nobel Prize for them in 1913.1

Epidemiology and Incidence

Nearly 100 years later, there is still debate about the exact definition of "anaphylaxis." Some clinicians describe it in broad terms, whereas others use very narrow requirements and try to sort it into classifications. A good working definition of anaphylaxis is a severe, multisystem allergic reaction that is rapid in onset and may result in death.2 It is important to note that anaphylaxis is often confused with anaphylactic shock. Anaphylaxis is a much broader term, and the goal is to prevent the progression of the reaction to a state of shock by rapid recognition and treatment.

The exact incidence of anaphylaxis is difficult to estimate because it is not a reportable disease and there are wide variances in definition as noted above. Most of the available data have been derived from hospital databases, which do not include those reactions that are treated on an outpatient basis. Even in those cases that present to the emergency department, miscoding often occurs when anaphylactic reactions are called acute allergic reactions and acute hypersensitivity reactions. In one study, 57% of likely reactions associated with food allergies were not reported as anaphylaxis.3 This results in a potentially fatal disease that it is both underreported and undertreated. Reviews estimate the incidence is between 50 and 2000 cases per 100,000 people, with a lifetime incidence from 0.05% to 2%.4 The greatest concern is that the majority of deaths are preventable with appropriate care.

Pathophysiology

The term anaphylaxis has traditionally been reserved for immune-mediated reactions and the term "anaphylactoid reaction" has been used to describe those reactions that do not involve the immune system. In 2004, the World Allergy Organization proposed changing the classification to "immunologic" and "nonimmunologic."5 This is because immunologic anaphylaxis can include reactions mediated by immunoglobulin E (IgE), immunoglobulin G (though not identified in humans), and immune-complex, complement-mediated reactions. Nonimmunologic anaphylaxis is precipitated by any agent that induces sudden and massive mast cell or basophil degranulation in the absence of immunologic mediators. Regardless of classification, the clinical course and treatment for both types of reactions are identical.

In immune-mediated anaphylaxis, exposure to an antigen (allergen) results in the stimulation of IgE antibodies from B-cells. These antibodies attach to receptors on inflammatory cells, such as mast cells and basophils. Unattached IgE antibodies remain free in the bloodstream. When the patient is reexposed to the allergen (even at a lower dose), it interacts with any surface-bound IgE that is specific for that allergen. Cross-linking occurs when the allergen is able to interact with 2 or more receptors on the surface of the cell, resulting in intracellular signaling. This, in turn, can result in activation of the mast cell or basophil and the release of chemical mediators, such as histamines, prostaglandins, and leukotrienes. It also results in a cascading of initiation on other mast cells and basophils, leading to a vicious cycle.6

Signs and Symptoms

Although there are more than 40 signs and symptoms of anaphylaxis, they can be broadly divided into 4 categories: skin and mucosal, respiratory, cardiovascular, and persistent gastrointestinal symptoms.7

Generalized urticaria and angioedema are the most common cutaneous symptoms, occurring in more than 90% of anaphylactic episodes, though they may be delayed in onset.1 Respiratory compromise (shortness of breath, wheezing, choking, coughing) is also very common. Cardiovascular signs include hypotension, dizziness, tachycardia, and collapse. Gastrointestinal symptoms are less dramatic. In general, the faster the onset of symptoms the more severe the reaction will be.3

Patient-Specific Risk Factors
There are several comorbidities and medications that may interfere with the recognition of triggers and/or symptoms of anaphylaxis. These include existing impairment of vision or hearing, neurologic disease, psychiatric disease, sedatives, hypnotics, ethanol, and recreational drugs.2 Although not increasing the risk of anaphylaxis, pulmonary (asthma, chronic obstructive pulmonary disease) and cardiovascular disease are more likely to be associated with a fatal anaphylactic event.7

In infants, it can be hard to recognize anaphylaxis, because many of the symptoms mimic other benign signs, such as flushing, spitting up, and loose stools. In children and teenagers, inconsistent behavior and a lack of concern about severity may result in exposure to triggers and/or not carrying epinephrine autoinjectors on a regular basis. Anaphylaxis during pregnancy is generally associated with very poor outcomes for the fetus. During labor and delivery, exposure to beta-lactam antibiotics is the most common trigger. In elderly patients, the presence of multiple, concomitant diseases results in an increased risk of fatality.3

Certain food allergies are associated with a higher incidence of anaphylaxis. In one study in the United States, peanuts and tree nuts were responsible for 94% of fatal cases.1 Other common IgE-dependent triggers include venoms (insect stings), latex, medications (especially beta-lactam antibiotics), and occupational allergens. Patients with hyper-IgE syndrome and multiple allergies to different substances are also more likely to experience anaphylaxis.8 Allergen immunotherapy (skin testing and desensitization) are rarely associated with anaphylaxis.

Nonimmunologic triggers include mostly physical factors (intense exercise, cold, heat), medications (such as opiates), and ethanol. Some triggers are associated with both immunologic and nonimmunologic mechanisms. Idiopathic anaphylaxis is diagnosed when no specific trigger can be identified. Any food, medication, or venom can induce anaphylaxis, and new allergen triggers are constantly being reported.3

Table 1 presents examples of common anaphylaxis triggers.

Prevention

The primary method of preventing anaphylaxis is identification and strict avoidance of patient-specific triggers. Written, personalized information should be provided to each patient with known triggers, listed along with probable cross-reactive triggers. Patients are often referred to an allergist for specific testing; when identified, certain IgE-mediated reactions may be treated with potentially curative immunotherapy.2 

For many medication-induced reactions, standardized desensitization protocols have been published. These introduce the allergen in slowly increasing doses over several hours. Once the full dose of the medication has been given, the patient maintains desensitization by strictly adhering to a regular administration schedule. Unfortunately, such tolerance is not permanent, and if the medication is stopped, the patient will rapidly return to their previously allergic state. These protocols should only be considered in health care facilities with experience in desensitization.9

Treatment-Epinephrine

Early provision of appropriate doses of epinephrine remains the cornerstone of all treatment regimens for anaphylaxis and is a life-saving intervention. Epinephrine results in vasoconstriction through its effect on alpha-adrenergic receptors, increasing peripheral vascular resistance, improving blood flow and coronary perfusion, reversing peripheral vasodilation, and reducing angioedema. It is also a direct cardiac stimulant through positive inotropic and chronotropic effects on the beta1-receptors of the myocardium. Finally, it stimulates beta2-adrenergic receptors, leading to bronchodilation and reductions in the release of inflammatory mediators from mast cells and basophils.10 

Intramuscular injection into the front, outer thigh is the first-line route of injection regardless of age, as it results in faster and higher plasma concentrations than subcutaneous injection. Intravenous injection should be reserved for patients with unresponsive anaphylaxis or circulatory collapse, because it has been associated with fatal cardiac arrhythmias and myocardial infarction.11

Several reviews have demonstrated the importance of early self-administration of epinephrine with significant reductions in mortality.10 Therefore, patients with a history of anaphylaxis should be prescribed an epinephrine auto-injector, counseled on its use, and reminded to carry at least 1 with them at all times.

Availability of Current Auto-Injectors

The delivery system for auto-injectors was originally developed for military use. It allowed medication to be predrawn and easily injected, which is of great importance in times of high stress, such as during an anaphylactic episode. Recent innovations have led to 2 independent delivery systems, the syringe and the cartridge delivery systems.10

The syringe delivery system is primed by the thumb after the removal of the needle safety cap. Activation releases a spring, driving the contents of the syringe through a needle via a piston rod that simultaneously pierces the tissue. There are a few inherent disadvantages to this design. The first is that the medication may start being delivered while the needle is still piercing the skin, which can alter the final dose received. Additionally, the glass syringe design limits the force that can be applied to deploying the needle, resulting in reduced penetration through clothing and skin. Available syringe-based injectors include TwinJect, Adrenaclick, and generic epinephrine auto-injectors. TwinJect was the first device to contain 2 doses of epinephrine. The first dose is injected via the auto-injector. The second dose is accessed by unscrewing the needle and removing the syringe, and is injected in a traditional syringe/needle fashion. Due to technical issues, Shionogi Pharma, the company that makes TwinJect, repurposed the product as Adrenaclick, which provides only 1 dose of epinephrine. There are 2 generic epinephrine autoinjectors considered by the FDA to be interchangeable with Adrenaclick.

The cartridge delivery system, in contrast, is activated after removal of the safety cap by pressing the tip of the injector directly into the tissue until a click is heard. A spring is released and both cartridge and needle are moved to their end position. The needle pierces the skin and the remaining force of the spring causes the cartridge to burst and deliver its contents. This means the medication will not be delivered until the needle is fully deployed, resulting in maximal levels achieved in the intramuscular region. Because there is no preactivation, there is 1 less operational step. The use of the cartridge design also allows for a stronger spring mechanism, allowing the needle to more easily penetrate through clothing and skin. The only available cartridgebased injectors are the EpiPen series.12-15 Recently, Dey Pharma, manufacturer of EpiPen, updated their product line and made both strengths available as a "2-Pak." Additionally, the EpiPen injectors now have an automatic orange safety guard that extends over the needle once it is removed from the thigh to prevent accidental needle sticks.13
 

BX Rating

Confusion arises on the part of patient, pharmacist, and physician because epinephrine auto-injectors carry a BX rating from the FDA. When a patient presents with a prescription for a particular brand of epinephrine auto-injector, the pharmacist, by law, must dispense the named product and not substitute one of the other injectors.16
 

Dosing

There are only 2 available doses of epinephrine in auto-injectable form, 0.15 and 0.3 mg. This can present some difficulty when prescribing, as the recommended dose is 0.01 mg/kg, up to a maximum of 0.3 mg in children and 0.5 mg in adults.12 The prescribing information for EpiPen states that the 0.15-mg injector is suitable for children weighing less than 30 kg (66 lb). The possibility of an under- or overdose must be weighed against the need for standard doses to minimize confusion.15 The only alternative is the use of an ampule, syringe, and needle, which is prone to error even in nonurgent settings. Although 0.3 mg is an appropriate first dose for children weighing over 30 kg and adults, it may be necessary for these patients to use more than 1 auto-injector, depending on the severity and timing of symptoms,3 though the proper number of injectors to dispense has not been determined. Careful consideration of severity, cost, and expiration dating must be discussed between patient and prescriber. Most practitioners recommend access to at least 2 injectors.

Antihistamines

Traditional antihistamines (H1-receptor blockers) are slow in onset of action and primarily reduce severity of itching, redness, and angioedema. For oral therapy, the second-generation antihistamines are preferred, as they are less likely to cause sedation and other side effects. As they are not available intravenously, if needed, diphenhydramine may be given at an intravenous (IV) dose of 25 to 50 mg, repeated to a maximum of 400 mg in adults (1 mg/kg to a maximum of 50 mg in children). Although there is minimal evidence to support their use, H2-antagonists (such as ranitidine) have been studied in conjunction with H1-blockade with increased efficacy in experimental models. These medications should be used routinely; however, they are not a substitute for prompt administration of epinephrine.3

Bronchodilators

Inhaled beta-agonists are useful in patients with severe bronchospasm unrelieved by epinephrine. Because they do not relieve mucosal edema (targeted by the alpha1-adrenergic effects of epinephrine), they are adjunctive treatment only.3

Glucocorticoids

In recent reports, glucocorticoids were noted to be administered more frequently than epinephrine in emergency departments. The effectiveness of these medications has never been established in clinical trials. They may help reverse the late onset of bronchospasm and cutaneous effects of anaphylaxis. The delay in onset of action relegates their usefulness to potential reductions in the risk of biphasic and protracted anaphylaxis. Despite this, there have been documented cases of biphasic reactions in patients administered corticosteroids as part of their initial drug therapy. If given, methylprednisolone at a dose of 125 mg/day IV for adults (1 mg/kg for children) or prednisone 50 mg/day orally in adults (1 mg/kg for children) is generally adequate. The medication can be stopped after 3 days without a taper, as the risk of biphasic reactions beyond that point is very low.17

Other Treatment Considerations

Hypotensive patients should receive adequate hydration, preferably with a crystalloid or colloid. Patients who are currently taking beta-blockers may have a poor response to epinephrine due to loss of beta-adrenergic stimulation. Treatment with glucagon (1-5 mg in adults, 1 mg maximum in children) should be considered, as its positive cardiovascular effects are independent of beta-blockade, and it results in endogenous release of epinephrine and norepinephrine.3

Biphasic and Protracted Anaphylaxis

Biphasic reactions are characterized by a normal reaction (generally appropriately treated) with resolution of symptoms for a brief period of time and subsequent reactivation of symptoms without further exposure to an allergen. There are several proposed mechanisms, but none fully explain this phenomenon. There are no clear predictors of biphasic reaction; however, there is some evidence that oral ingestion of an allergen, delays in epinephrine administration, suboptimal epinephrine dosing, and requirements of large doses of epinephrine are all correlated with increased possibility of a biphasic reaction. It must be noted that a biphasic reaction can occur in any individual, from any allergen, and in both immunologic and nonimmunologic reactions. Outcomes can range from relatively mild symptoms to fatal reactions, with at least one third of the secondary reactions being more severe than the initial response. In general, biphasic reactions occur within the 8 hours after exposure to an allergen, though the time ranges from 1 to 78 hours.18

Protracted reactions last for several hours (possibly days) without completely resolving. There are very few case reports of this type of reaction, and treatment options are similar to biphasic reactions.

Those patients with protracted reactions require prolonged observation. Given the risk of biphasic reactions, it seems prudent that most patients be observed for 12 hours prior to discharge after successful treatment of an anaphylactic reaction. This should be increased to 24 hours or longer in those with delayed onset of initial symptoms, presence of severe initial symptoms, delay of more than 60 minutes for initial treatment with epinephrine, slow response to initial therapy, those with a history of cardiovascular disease, and those with a previous biphasic reaction. Should patients be discharged sooner, it is recommended to supply them with an epinephrine auto-injector and ensure that they are comfortable with its use. They should also be counseled on the potential for return of symptoms in the next 3 days.3

Pharmacist/Patient Education

The role of the pharmacist in patient education cannot be stressed enough. In studies, less than 44% of patients were able to demonstrate correct self-administration technique with epinephrine auto-injectors. Even more disconcerting is the study that showed 79% of health care professionals who teach the use of these devices were unable to demonstrate correct use. Given these statistics, it would be ideal for all pharmacists who dispense these products to familiarize themselves with the individual steps for proper utilization of the autoinjectors. The manufacturers of EpiPen, Adrenaclick, and TwinJect all have training injectors that do not contain a needle or active ingredient. Additionally, videos and printed material are available for the individual products as well.13-15

Patients should be counseled not only on the proper technique for epinephrine administration, but also about when to use their auto-injectors (Table 2). Prompt administration is key. In one study of 27 patients, all those treated within 30 minutes of onset survived, compared with 2 deaths in those with delayed treatment.10 Certain symptoms, especially with exposure to known allergens, should prompt immediate use of the auto-injector. Additionally, they should be used when symptoms are mild, but the patient is in a remote location; the symptoms are progressing; if the patient or health care provider is uncertain about the severity of the reaction; and when there is a known exposure to an allergen that previously caused a severe reaction, even if no symptoms have developed. Once epinephrine is administered, the patient should call 911 and proceed to the nearest emergency department, taking the used injector(s) with them.

Personalized anaphylaxis management plans are being used more frequently, because the majority of reactions occur in the absence of a health care professional. Such written plans, when used with proper education and training, reduce anxiety and increase confidence with treatment options. Although there is no standardized, universal management plan, experts agree that they should all contain information regarding recognition of symptoms, treatment with epinephrine, and emergency contact information. Plans should be personalized for each patient and include known triggers, concomitant disease states, and current medications. Plans should also be updated on a regular basis (at least yearly when auto-injectors are replaced). A freely available plan can be downloaded from the American Academy of Allergy, Asthma, and Immunology at www.aaaai.org/members/resources/anaphylaxis_toolkit/action_plan.pdf.4,19

It is recommended that those at risk for anaphylaxis carry identification (ID), such as medical alert jewelry or wallet card, so health care practitioners can quickly recognize and treat anaphylaxis. When purchasing medical ID jewelry, patients will want to find a company that provides access to a patient-specific registry service, so that their information is readily available. Wallet cards can be ordered in packs of 100 for distribution to patients from www.aaaai.org.4,19

Summary

Anaphylaxis is a medical emergency requiring immediate diagnosis and treatment. The medication of choice is intramuscular epinephrine (0.15-0.3 mg per dose). Patients should immediately call 911 and go to the nearest emergency department. Other treatment adjuncts, such as antihistamines and corticosteroids, should be routinely used once the patient has been stabilized with epinephrine and aggressive fluid provision. 

All patients with anaphylaxis should be discharged with a prescription for epinephrine auto-injectors. The proper number of injectors to dispense is not known; however, some cases will require more than 1 injection for proper management of the reaction. Patients should be counseled on the proper injection technique, when to give the medication, and what to do after injecting the medication. Additionally, an individualized anaphylaxis management plan should be developed in collaboration with the patient. Finally, the patient should be encouraged to carry proper medical alert ID so proper interventions can be quickly provided by health care professionals.

Pharmacists should familiarize themselves with the currently available autoinjectors, including pertinent teaching aids, such as videos, DVDs, and practice injectors. Epinephrine auto-injectors are rated BX by the FDA and as such cannot be automatically substituted.

Educational Disclaimer:

Continuing professional education (CPE) activities sponsored by Pharmacy Times Office of CPE are offered solely for educational purposes and do not constitute any form of professional advice or referral. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the author(s) or they may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Participants are encouraged to refer to primary references or full prescribing information resources. 

The author(s), reviewer(s), and editor(s) have made extensive efforts to ensure that the information including treatments, drugs, and dosage regimens are accurate and conform to the standards accepted at the time of publication. However, health care professionals should always consult additional sources of information and exercise their best professional judgment before making clinical decisions of any kind. In particular, the reader is advised to check the product information provided by the manufacturer of a drug product before prescribing or administering it, especially if the drug is unfamiliar or is used infrequently.

References :

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2. Sampson HA, Munoz-Furlong a, et al. Second symposium on the definition and management of anaphylaxis: summary report – Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin Immunol. 2006;117:391-397.
3. Estelle R, Simons R. Anaphylaxis. J Allergy Clin Immunol. 2010;125:S161–S181.
4. Nurmatov U, Worth A, et al. Anaphylaxis management plans for the acute and longterm management of anaphylaxis: a systematic review. J Allergy Clin Immunol. 2008;122:353-361.
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7. Johnson RF, Peebles RS. Anaphylactic shock: pathophysiology, recognition, and treatment. Semin Respir Crit Care Med. 2004;25:695-703.
8. Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into its epidemiology. Arch Intern Med. 2001:161:15-21.
9. Ellis AK, Day JH. Diagnosis and management of anaphylaxis. CMAJ. 2003;169:307-312.
10. McLean-Tooke AP, Bethune CA, et al. Adrenaline in the treatment of anaphylaxis: what is the evidence. BMJ. 2003;327:1332-1335.
11. Tupper, Visser. Anaphylaxis – A review and update. Canad Fam Phys. 2010;56:1009-1011.
12. Frew AJ. What are the 'ideal' features of an adrenaline (epinephrine) auto-injector in the treatment of anaphylaxis? Allergy. 2010;Aug 17 [Epub ahead of print].
13. EpiPen [package insert]. Basking Ridge, NJ: Dey Pharma; 2010. 14. TwinJect [package insert]. Osaka, Japan: Shoinogi Pharma; 2010.
14. Adrenaclick [package insert]. Osaka, Japan: Shoinogi Pharma; 2010.
15. FDA: CDER Orange Book. www.accessdata.fda.gov/scripts/cder/ob/default.cfm. Accessed November 20, 2010.
16. Choo KJ, Simons E, Sheikh A. Glucocorticoids for the treatment of anaphylaxis: Cochrane systematic review. Allergy. 2010;65:1205-1211.
17. Tole JW, Lieberman P. Biphasic anaphylaxis: review of incidence, clinical predictors, and observation recommendations. Immunol Allergy Clin N Am. 2007;27:309-326.
18. American Academy of Allergy, Asthma, and Immunology. www.aaaai.org. Accessed November 20, 2010.

Kyle R. Copeland, PharmD is Clincal Pharmacist Specialist Parkwest Medical Center Pharmacy Knoxville, Tennessee Kyle R. Copeland, PharmD, has no relevant affiliations or financial relationships to disclose. The staff of Pharmacy Times Office of Continuing Professional Education has nothing to disclose relative to this activity.

(Source : pharmacy times)