Anaphylaxis Guidlns

Posted on Jun 14, 2011 in Articles | 6 comments

Improving the Diagnosis and Treatment of Anaphylaxis: Updated Clinical Guidelines

 

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CME Information

Learning Objectives

After participating in this educational activity, participants should be better able to

• Implement guideline-based strategies for the accurate diagnosis of anaphylaxis, including identification of patient-specific risk factors
• Identify patients who are appropriate candidates for an epinephrine auto-injector and develop emergency action plans to prepare patients for self-management in the event of an emergency

Introduction

Anaphylaxis is an acute, life-threatening systemic reaction that can occur by either immunologic or nonimmunologic mechanisms (Figure 1). The clinical manifestations of anaphylaxis, and their severity, result from the sudden release of mediators from mast cells and basophils.[1] Typically, reactions are unpredictable since exposure to inciting substances can occur at any time and be of known or unknown (idiopathic) causes. Anaphylaxis is more readily defined as one of the following three emergent scenarios: 1) the acute onset of a reaction (minutes to hours) involving the skin, mucosal tissue, or both, and at least one of the following: respiratory compromise, reduced blood pressure, or symptoms of end-organ dysfunction; 2) two or more of the following that occur rapidly after exposure to a potential allergen including involvement of the skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated symptoms, and/or persistent gastrointestinal symptoms; or 3) reduced blood pressure after exposure to a known allergen.[1]

The incidence of anaphylaxis appears to be increasing, particularly in children, adolescents, and young adults.[2-6] Anaphylaxis places approximately 40 million U.S. residents at risk for a life-threatening medical emergency with patients incurring an estimated 30,000 emergency department (ED) visits annually.[7,8] Anaphylaxis due to insect stings or food can cause anywhere from 40 to 200 or more deaths each year in the United States.[9,10] Food allergies are becoming increasingly more prevalent in the United States, with an estimated 12 million Americans affected and growing.[8] Problems with underdiagnosis, underreporting, and miscoding contribute to the lack of accurate estimates as well as the inadequate treatment of anaphylaxis.

Injectable epinephrine therapy is the globally recognized choice of therapy for anaphylactic events, but remains underutilized by healthcare providers and patients. Data clearly show that fatalities related to anaphylaxis occur more often when patients are away from home and are associated with either not using epinephrine or with a delay in the use of epinephrine.[11,12] High rates of underdiagnosed patients have been noted, which leaves many high-risk patients with no immediate access to epinephrine.

Injectable epinephrine is the globally recognized choice of therapy for anaphylactic events, but remains underutilized by healthcare providers and patients.

Additionally, several misconceptions persist that compromise guideline-recommended care, specifically the use of injectable epinephrine.[13] These misconceptions include—

1. A severe attack will always be preceded by an earlier, milder warning reaction
2. There is always time to get medical attention, so patients do not have to worry about administering epinephrine quickly
3. Medications, especially epinephrine, will always work when needed, even if use is delayed by patients who wait and see whether they really need it

In fact, milder warning attacks do not necessarily come before a near-fatal or fatal reaction, and even when epinephrine is used in a timely manner, it is not always effective in cases of severe anaphylaxis. There is very clear evidence that delays in treatment or failure to treat patients with epinephrine contribute strongly to many of the fatal reactions to insect stings and food. In the United States, death from insect sting anaphylaxis occurs in 40 to 50 individuals per year and some data suggest that death from food-related anaphylaxis occurs in 150 to 200 individuals per year.[9,10,12]

Very recently, several new sets of evidence-based guidelines, in collaborative efforts, have been implemented to aid clinicians in the recognition, diagnosis, and treatment of anaphylaxis. They include the Joint Task Force on Practice Parameters’ The Diagnosis and Management of Anaphylaxis Practice Parameter: 2010 Update, the 2011 World Allergy Organization (WAO) Guidelines for the Assessment and Management of Anaphylaxis, as well as the 2010 National Institute of Allergy and Infectious Diseases (NIAID) Guidelines for the Diagnosis and Management of Food Allergy.[1,14,15] These new evidence-based clinical guidelines have prompted a re-evaluation of current practice and provide support for clinical decisions critical to the care of patients at risk for anaphylactic reactions.

Confirming a Diagnosis of Anaphylaxis

Prompt assessment and recognition of the signs and symptoms of anaphylaxis are recommended in current guidelines for the management of anaphylaxis.[1,14] However, a thorough evaluation may not always be performed, which can limit a practitioner’s view about appropriate treatment at the time of an event and of potential risk of future events. The following questions are recommended for practitioners to consider when assessing anaphylaxis:

1. What was the patient’s activity and food consumption in the last six hours?
2. Were there cutaneous manifestations, particularly flush, pruritus, urticaria, and angioedema?
3. Was there any sign of airway obstruction in either the upper or lower airways?
4. Were there gastrointestinal symptoms (nausea, vomiting, or diarrhea)?
5. Were syncope or presyncopal symptoms present?

To ensure appropriate diagnosis and treatment, recognition of key clinical symptoms is essential to patient care. Once the patient reports his or her symptoms and/or events leading to the acute event, the practitioner can evaluate whether the patient is anaphylactic or not based on what the practitioner knows. The common clinical manifestations of anaphylaxis and their relative frequencies are described in Table 1.

The likelihood of true anaphylaxis is based on the time of onset and combination of these symptoms. In practice, the way symptoms manifest in patients is diverse and may not always provide a clear view of what is an “expected” anaphylactic reaction. Therefore, it is important that clinicians consider clinical criteria that lend themselves to the likelihood of anaphylaxis. Table 2 describes the criteria present in typical patients with anaphylaxis that are necessary to make an accurate diagnosis of anaphylaxis.[14] Evaluating the patient’s systemic response to an allergen can also help confirm the diagnosis, and can be made by checking serum tryptase and plasma and urinary histamine levels. However, due to the half life of these metabolites, the values are only useful if the patient is seen within the first hour of the onset of the reaction. If unknown, the identification of a specific cause of anaphylaxis may require the use of skin prick tests, serum IgE levels, and/or challenge tests (eg, food).[1] The history of anaphylaxis may be strongly associated with a particular allergen, but if it is not, then identification of the specific allergen becomes important for the development of avoidance strategies as a part of the patient’s anaphylaxis action plan.

Differential Diagnosis
A differential diagnosis must be considered when the history is taken, even in patients with a previous history of anaphylaxis.[1] In the absence of confirmed exposure to a known allergen, specific attention should be given to differentiating asthma, vocal cord dysfunction, panic attacks, vasovagal reactions (symptoms including hypotension, pallor, weakness, nausea, vomiting, and diaphoresis, but can frequently be distinguished from anaphylaxis due to a lack of skin involvement), flushing episodes such as those caused by drugs and ingestants including niacin, nicotine, catecholamines, angiotensin-converting enzymes (ACE) inhibitors, and alcohol. Reactions to monosodium glutamate following a meal can also mimic anaphylaxis. Other conditions that may cause flushing such as rosacea, gastrointestinal and thyroid tumors, carcinoid syndrome, pheochromocytoma, hyperglycemia, postmenopausal flush, alcohol-induced flushing, and the ‘‘red man syndrome’’ due to the administration of vancomycin should also be considered.[1]

Anaphylaxis Treatment

For anaphylaxis, injectable epinephrine is the most appropriate first-line treatment.[1,14] The steps for basic anaphylaxis management developed by the WAO are described[14] in Table 3. At the present time, there is no evidence contrary to recommend any therapy other than epinephrine for an acute episode.[16] More so, epinephrine delivered intramuscularly is universally recommended as first-aid treatment for anaphylaxis.[17] The rationale for this is based on studies that show the onset of cardiac arrest from a reaction to be as quick as five minutes, and that individuals have difficulty administering epinephrine from premeasured ampules in real world scenarios.[18] The most efficient way to deliver lifesaving medication, in this case epinephrine, to a patient in an emergency is to inject the recommended dose into the mid-anterolateral aspect of the thigh via an auto-injector. Furthermore, biphasic reactions can occur in 23% of adults receiving an epinephrine injection for anaphylaxis, and more than one epinephrine injection is needed; therefore, consider prescribing two or more epinephrine auto-injectors.[14]

Other therapies such as antihistamines, sublingual isoproterenol, inhaled epinephrine, and corticosteroids without epinephrine do not prevent or relieve severe anaphylactic reactions.[11,19] Therefore, it is inappropriate to use them for the first-line treatment or primary prevention of anaphylaxis. For example, the time to 50% suppression of a histamine-induced flare with oral antihistamine therapy is on the order of 80 minutes. As mentioned previously, cardiac arrest can occur in as little as 5 minutes. The appropriate use of epinephrine, however, is sometimes limited by misconceptions and by reluctance of some patients and practitioners to use this medication.

More than one epinephrine injection is needed in 23% of adults receiving an epinephrine injection for anaphylaxis; therefore, consider prescribing more than one epinephrine auto-injector.[14]

Some of the reasoning for the underuse of epinephrine auto-injectors also has to do with accessibility. Although epinephrine is an essential medication for the treatment of anaphylaxis, not everyone has access or can afford auto-injectors. Injectable epinephrine is only available by prescription as either spring-loaded self-injectable devices (EpiPen®, Dey Laboratories; Adrenaclick®, Shionogi Pharma, Inc.) or as preloaded syringes (Ana-Kit®, Bayer Laboratories). The spring-loaded auto-injector device contains a single dose of epinephrine, but may be preferred because of its ease of use. Without comparative randomized trials, which are very difficult to design, control, and are ethically challenging for anaphylaxis, features of a given auto-injector may take precedence over rigorous randomized trial data. Ease and other facets of use become important since recent evidence has shown that auto-injectors are sometimes improperly used by patients, caregivers, and practitioners.

For example, accidental needle injections and the “lost-dose hazard” is an issue with certain devices. Preventing the complete loss of the epinephrine dose during a time of crisis is critical. The result of improper use of an epinephrine auto-injector is not only partial or complete waste of a therapeutic dose needed in an urgent situation, but further injury is possible. Additionally, preventing unintentional injections into fingers, thumbs, and hands by patients is important. Auto-injectors with improved design, including needle protection features, may be an advantage for patients in this regard.[20]

Furthermore, there are data suggesting that the effectiveness of epinephrine may be compromised in patients receiving beta-blockers. The patient may be refractory to epinephrine or the reaction itself may be more severe.[1] However, for patients treated with these medications for hypertension or underlying cardiovascular disease, there is no absolute contraindication to the use of epinephrine. If epinephrine appears ineffective for anaphylaxis in patients taking beta-blockers, administration of both glucagon and intravenous isotonic crystalloid solution may be necessary in these patients.[1]

There is also another growing concern among patients as well as the medical community about the availability of generic epinephrine auto-injectors.[21] Currently, the U.S. Food and Drug Administration (FDA) has given a BX rating to all available instruments. What this means, for example, is that since the EpiPen has received a BX rating from the FDA, there is insufficient evidence to allow any other branded or generic auto-injector to be used as a substitute (ie, they are not “therapeutically equivalent”) for the EpiPen. The same is true for the Twinject and Adrenaclick (and its generic version labeled as an epinephrine auto-injector) auto-injectors. Therefore, one auto-injector should not be substituted for another and, in fact, it may be unlawful to dispense a substitute that has not been rated by the FDA as a suitable substitute for a particular auto-injector. From a practical perspective, once a patient is trained on a particular device, making a substitution for another device may cost the patient valuable time in the event the patient experiences an anaphylactic episode. Clinicians and patients need to be vigilant that their prescribed auto-injector is not substituted at the pharmacy.

MYTH: Epinephrine auto-injectors are substitutable.

FACT: There is insufficient evidence to suggest that available epinephrine auto-injectors are therapeutically equivalent and can be substituted for any other available epinephrine auto-injector.

Case Study: Laura, 19-year-old Female Patient

History
Laura is a 19-year-old college student who, about three weeks ago, had an allergic reaction approximately 20 minutes following a meal with her friends. During the meal she ate mozzarella sticks, pizza, and a piece of cherry pie. In the six hours preceding the reaction, Laura had not done anything strenuous or exercised and the only medication she took was acetaminophen for a headache. Her notable medical history includes perennial allergies that worsen seasonally and positive skin prick tests for dust mite allergen, penicillin, and timothy hay. She was also previously diagnosed with intermittent asthma a few years ago. She currently lives 50 miles from her doctor’s office.

Acute Symptomatology

• Urticaria
• Breathing impairment
• Dizziness

Once this event resolved naturally, she visits her doctor at the next available appointment the office had in the evening after her classes. The clinician reviews her history noting her emergent symptoms at the time of the reaction, her activities, and the food she consumed that day. Her known allergies are reviewed and Laura is asked about any other suspicious reactions. She admits to an episode of hives with nausea and cramping pain earlier this year, but she dismissed them at the time since it was during her menstruation. Her clinician suspects that ground tree nuts in the pie crust she ate may be the inciting allergen in this case.

Risk Assessment
Potential issues that put this patient at risk for a second episode and poor outcome

• History of atopic conditions including allergies and asthma
• Dismissed an earlier suspicious reaction this year
• As of yet, unidentified allergen that may not be able to be avoided
• Does not carry an epinephrine auto-injector

Management
After careful consideration of Laura’s risks and previous history, her clinician decides to manage Laura by—

• Ensuring that her allergies are appropriately managed and her asthma is well controlled
• Ordering a new panel of skin prick tests to include tree nuts (a common ingredient in pie crust)
• Prescribing epinephrine auto-injector(s)
• Providing training on the appropriate use of auto-injector
• Providing patient education on allergen avoidance
• Developing a personalized emergency action plan so she is prepared to self-manage in the event of an emergency

 

Mitigating Future Risk and Preventing Anaphylaxis in the Community

With life-threatening allergic reactions are on the rise, the need to recognize and effectively manage anaphylaxis in a way that is adherent to current guidelines has become more readily apparent. Risk assessment should be periodic in nature and risk reduction will inevitably be a long-term proposition that includes a personalized strategy.[22,23] History of atopy, age, presence of cardiovascular disease, underlying mastocytosis, and medications are important attributes to consider in an assessment of a patient’s risk for anaphylaxis since a specific attribute may predispose an individual to having a reaction. Avoidance of triggers including food, stinging and biting insects, medications, and other allergens including occupational/environmental exposures should be employed, otherwise, utilizing allergen immunotherapy, desensitization, and preventive medications for patients who know they will be exposed to an allergen may be necessary strategies.

Foods including cow’s milk, egg, and peanuts account for the majority of anaphylactic reactions in young children, while peanuts, tree nuts (eg, pecans, walnuts, cashews, Brazil nuts, pistachios), and seafood (eg, fish, crustacean shellfish) account for the vast majority of reactions in teenagers and adults.[24] Therefore, when allergens are known, patients can adapt to their own respective needs for prevention. It is generally assumed that most food allergies wane over time, or that a child “grows out of them.” In the case of milk allergy, this may not necessarily be true. Recent evidence suggests that children with cow’s milk allergy still need to be vigilant about their exposure through their teen years.[25] There is still a risk of anaphylaxis that generally goes unrecognized since patients, family members, and even healthcare practitioners sometimes assume that the patient has or will soon grow out of that particular allergy. In fact, a recent study investigated the occurrence of cow’s milk or cow’s milk products in foods and found that even though there are only trace amounts of milk in many packaged foods, evidence suggests that low milligram amounts are sufficient to cause mild allergic reactions.[26] Most importantly, accidental exposures to cow’s milk are very common and taking note of every way that either cow’s milk or cow’s milk products are expressed on labels is exhaustive. These considerations should be part of a patient’s risk assessment and addressed accordingly.

The most common triggers of anaphylaxis in the community include stinging insects (honey bees, yellow jackets, and paper wasps), biting insects (mosquitoes, ticks, and flies), foods (peanuts, tree nuts, fish, shellfish, and cow’s milk), and drugs (β-lactams, NSAIDs, and infusional biologic therapies).

Medication-triggered anaphylaxis is particularly common in middle-aged and older adults, with penicillin as the most common cause of drug-induced anaphylaxis. The second most common cause of drug-induced anaphylaxis is with nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen and aspirin.[24]

In addition to preventing anaphylactic episodes, the ultimate clinical goal is to prevent unnecessary deaths. Practitioners need to confirm patients’ triggers for anaphylaxis with a thorough clinical history and composite view of the anaphylactic episode as well as any laboratory tests, if deemed appropriate. Risk should be evaluated on a case by case basis.[20,23,27]

Anaphylaxis Action Plans

Anaphylaxis is a medical emergency and having an action plan for preparedness, including recognition of symptoms and appropriate questioning, and emergency management is essential for successful outcomes in community settings. Even with proper avoidance strategies, patients at risk may still experience an anaphylactic episode, so they need to be prepared to self-manage the event if medical resources are not readily available. This includes developing an emergency response plan, receiving training on the use of self-injectable epinephrine, and education that conveys the inappropriate nature of using certain medications, including oral antihistamines or an asthma metered-dose inhaler, for anaphylactic reactions.[22,23] Finally, since anaphylactic reactions are unpredictable, information on emergency management of anaphylaxis should be made available in public places for patients at risk, their families and caregivers (eg, such as schools and restaurants).

Most plans describe common signs and symptoms of anaphylaxis and emphasize the importance of using an epinephrine auto-injector promptly and calling 911 or emergency medical services. A patient’s personal management plan should be individualized to describe the patient’s own triggers, avoidance strategies, comorbidities, and medications the patient is taking, and a description of the epinephrine auto-injector and dose prescribed for the patient. In an emergency, for the patient who may be alone and not near a hospital, calling 911, administering epinephrine by auto-injector, maintaining a supine position so that the patient’s cardiovascular system has time to stabilize, and contacting family members are top priorities. For practitioners, an emergency action plan is outlined by the American Academy of Allergy, Asthma & Immunology. These plans need to be updated and discussed with the patient, and, if relevant, his or her caregivers, on a regular basis

Need for Community Education

When and where possible, support for education of the lay and professional public to promote the prompt availability and administration of epinephrine for the treatment of anaphylaxis is warranted. Accidental food ingestion can occur despite identification of specific triggers and avoidance measures. This frequently occurs in the school setting despite preventive measures engineered by parents, practitioners, teachers, and school nurses. Treatment should be immediately available for these emergencies. Treatment protocols need to be discussed with a practitioner and be focused on the portion of a child’s day when parental observation is at a minimum. The school staff should have written instructions from a child’s healthcare provider, which provide easy to follow steps for recognizing a reaction and administering medication.

Summary

The National Institutes of Health Consensus Development Conference remains the basis for existing guidelines that recognized everyone is a potential victim of anaphylaxis and that continued education of lay and professional populations on the recognition of symptoms and administration of injectable epinephrine at the site of an emergency is essential.[1,14,15] Furthermore, individuals at risk for anaphylaxis should be educated on avoidance precautions and trained on the use of prescription epinephrine auto-injectors. Epinephrine should also be made available in many first-aid situations for use by trained personnel who can rapidly evaluate the risk versus benefit of treatment with epinephrine in individual cases. These efforts could significantly reduce the annual death rate associated with insect sting and food anaphylaxis.

Despite substantial progress in the field of anaphylaxis and the recent update to existing clinical practice parameters, many clinical questions remain unaddressed. Recent trends suggest that the incidence of anaphylaxis is increasing, particularly in children, adolescents, and young adults.[28] It therefore has become increasingly important to understand patient-specific risk factors and comorbidities, such as severe asthma or cardiovascular disease, as well as concurrent medications that may contribute to an anaphylactic reaction. Furthermore, epinephrine auto-injectors provide life-saving first-aid treatment of anaphylaxis in the community but may be either under prescribed or underutilized depending on the circumstances. Available evidence from randomized studies and systematic reviews do not support the use of therapies such as antihistamines, corticosteroids, or anti-IgE. Recognizing patients who are at risk and providing them with education and device training are the most important steps in the prevention of anaphylaxis.

In summary, it is imperative that clinicians are familiar with current guidelines for the management of anaphylaxis. Outlined below are select tenets for timely diagnosis and treatment of anaphylaxis[29]:

• The presentation of anaphylaxis and its progression to death are unpredictable
• Injectable epinephrine is the first and most important drug to use in an acute allergic reaction
• Injectable epinephrine should be administered intramuscularly
• Anaphylactic reactions are biphasic as often as 23% of the time
• At least 40% of patients who have had allergic reactions after insect stings will have equally severe or worse reactions on resting; therefore, all patients who have anaphylaxis after an insect sting or any unknown or potentially unavoidable cause (eg, peanuts) should be prescribed an epinephrine auto-injector
• There is no absolute contraindication to the use of epinephrine in patients with heart disease who experience anaphylaxis, however, a thorough assessment of the risk of adverse events with epinephrine in patients with cardiovascular conditions vs not using epinephrine should be discussed based on a patient’s individual risk profile
• Patients on beta-blockers who experience anaphylaxis may have a hypertensive response to epinephrine and suboptimal clinical improvement, and may require 1 to 3 mg of IV glucagon once or glucagon by continuous infusion until anaphylaxis is controlled
• Rarely, anaphylactic reactions can be protracted over many hours. In such cases, patients may require large volume fluid resuscitation, treatment with vasopressors, or intra-aortic balloon pump therapy

 

Sean M. Gregory, PhD
Published on June 14, 2011

 

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