Treating Severe Allergy And Acute Anaphylaxis: Epinephrine Injection, Antihistamines | 2015 EB Medicine

Allergy And Anaphylaxis: Principles Of Acute Emergency Management

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Table of Contents
Table of Contents
  1. Abstract
  2. Case Presentations
  3. Introduction
  4. Critical Appraisal of the Literature
  5. Epidemiology, Etiology, And Pathophysiology
    1. Epidemiology
  6. Differential Diagnosis
  7. Prehospital Care
  8. Emergency Department Evaluation
    1. Initial Stabilization
    2. History
    3. Physical Examination
  9. Diagnostic Studies
  10. Treatment
    1. Secure And Monitor The Airway
    2. Address Breathing And Monitor Respiratory Rate
    3. Ensure Adequate Circulation
      1. Route Of Epinephrine Administration
      2. Epinephrine Dosing
        • Intramuscular Epinephrine Administration
        • Intravenous Epinephrine Administration
        • Epinephrine Infusion
    4. Antihistamines As Second-Line Medications
    5. Corticosteroid Use In Anaphylaxis
    6. Fluid Resuscitation
  11. Special Circumstances
    1. Refractory Anaphylaxis
  12. Controversies And Cutting Edge
  13. Disposition
    1. Admission And Length Of Observation Period
  14. Summary
  15. Risk Management Pitfalls In Management Of Allergy And Anaphylaxis
  16. Time- And Cost-Effective Strategies
  17. Case Conclusions
  18. Clinical Pathway For Management Of Allergy And Anaphylaxis In The Emergency Department
  19. Tables and Figures
    1. Table 1. Common Etiologies Of Anaphylaxis
    2. Table 2. Gell And Coombs Classification Of Hypersensitivity Reactions
    3. Table 3. Differential Diagnosis Of Anaphylaxis
    4. Table 4. Clinical Criteria To Diagnose Anaphylaxis
    5. Table 5. Frequency Of Occurrence Of Signs And Symptoms Of Anaphylaxis
    6. Table 6. Awake Intubation Technique
    7. Table 7. Dosing Options For Antihistamines
    8. Figure 1. Mechanisms Underlying Human Anaphylaxis
  20. References


Allergic reactions and anaphylaxis are potentially life-threatening processes that present with a variety of clinical symptoms. Emergency clinicians must be able to recognize these presentations and make prompt clinical decisions regarding management of a patient’s airway, treatment options, and disposition of a patient who improves after initial presentation. Furthermore, emergency clinicians may be faced with patients who have atypical presentations or require special consideration, such as high-risk patients with comorbid conditions and patients who do not respond to first-line treatments. An increasing number of patients in the United States carry allergy diagnoses, and it is expected that this subset of the population will continue to seek care in the emergency department. This review assesses the research and evidence on the diagnosis, etiology, and treatment of anaphylaxis, as well as the utilization of epinephrine, both in and out of the hospital setting.

Case Presentations

A 55-year-old man with no significant medical history presents to the ED after breaking out in an “itchy” rash on day 3 of using an antibiotic for a sinus infection, but he can't recall the name of the medication. He has no other recent exposures or food allergies. His girlfriend once had a similar reaction to a medication, and just prior to arrival she gave the patient her epinephrine auto-injector to use. The patient reports abdominal cramping and wheezing, and he states that he feels a tingling in his lips, although there is no lip swelling, and he is breathing without difficulty. He notes that the rash seems to be spreading to different parts of his body, and resolves in one place only to reappear somewhere else. He denies any history of allergy to medications in the past, and says he has taken many different types of antibiotics without untoward effects. His vital signs are: temperature, 37°C; blood pressure, 130/80 mm Hg; heart rate, 90 beats/min; and respiratory rate, 12 breaths/min. The patient also took diphenhydramine 25 mg by mouth 30 minutes prior to arrival in the ED, and he notes that the rash and itching seem to be improving, although he has residual abdominal cramping and mild wheezing. The patient wants to go home, and you wonder if that’s a good idea.

A 40-year-old woman with a history of hypertension who takes 100 mg a day of metoprolol is brought to the ED by EMS after experiencing a sensation of throat tightening and dizziness about 10 minutes into her normal indoor exercise routine on a treadmill. She has no other medical problems and no significant family history. In an effort to eat more healthfully, she has been consciously increasing her intake of green vegetables lately, and consumed 16 ounces of a juice comprised of celery and kale 1 hour prior to exercise. She denies chest pain or pressure, and the initial ECG from EMS shows sinus tachycardia at 120 beats/min, without any other concerning changes for acute coronary syndromes. En route to the ED, she developed a diffuse, pruritic rash and received diphenhydramine and methylprednisolone from EMS, but does not appear better. Her vital signs are: temperature, 37.2°C; blood pressure, 90/60 mm Hg; heart rate, 120 beats/min; and respiratory rate, 16 breaths/min. Her physical examination is remarkable for a diffuse rash, expiratory wheezing, and uvula and posterior oropharyngeal mucosal swelling. Although she adamantly denies any food and drug allergies and has not had exposure to any new medications, you proceed to treat her for an anaphylactic reaction and administer 0.5 mg of a 1:1000 solution of intramuscular epinephrine to the anterolateral thigh. However, soon after the administration of epinephrine, you note that she is no better, and, in fact, her heart rate has now increased to 140 beats/min, and her blood pressure has dropped to 80/50 mm Hg. Your nurse and medical student look a bit concerned, and your student asks why this is happening when epinephrine is the first-line drug for anaphylaxis. The medical student wonders out loud whether there is anything else you might give this patient to help her, and whether you could be missing a cardiac event...


Allergic reactions occur when hypersensitivity to a foreign protein or antigen that normally would not be deleterious is acquired. On the spectrum of allergic responses, anaphylaxis is a profound reaction. Historically, anaphylaxis has lacked a standard, universally accepted definition, which has hampered the ability to consistently diagnose it. The National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network consensus defines anaphylaxis clinically as a continuum of a constellation of acute symptoms affecting multiple systems in the body after exposure to an allergen. Anaphylaxis is probable when any of the following criteria are met: (1) the presence of skin signs or symptoms together with respiratory involvement or signs of organ dysfunction or hypotension; (2) the involvement of at least 2 organs or systems after recent exposure to an allergen; or (3) signs of organ dysfunction or hypotension after exposure to a known allergen.1 The areas of organ dysfunction are skin and mucosal tissue, as well as respiratory, neurologic, and vascular systems.

Anaphylaxis is caused by an immediate hypersensitivity response mediated by immunoglobulin-E (IgE) that releases inflammatory mediators from mast cells in tissues and from basophils into circulation. This IgE-mediated response follows a previous exposure to an allergen and sensitization to it, and it results in a rapid, potentially life-threatening reaction.

An anaphylactoid reaction is an immediate systemic reaction that, similar to an anaphylactic reaction, also releases inflammatory mediators via the stimulation of mast cells and basophils. However, unlike anaphylaxis, it is not IgE-mediated and, because the formation of IgE is not a prerequisite, an anaphylactoid reaction may occur on the initial exposure to an allergen. Clinically, anaphylactoid reactions are often indistinguishable from anaphylaxis. For this reason, the World Allergy Organization has suggested abandoning use of this terminology and referring to anaphylactic and anaphylactoid reactions as IgE-mediated anaphylaxis and nonallergic anaphylaxis, respectively.2 Some triggers of anaphylaxis include radiocontrast dye, ethanol, N-acetylcysteine, and opioids.3

Angioedema is localized, nonpitting edema of the subcutaneous and submucosal tissues, resulting from mast cell mediators or bradykinin. It may be the result of a hereditary or acquired defect modulating bradykinin-related peptides and complement activation, as a result of a C1-esterase inhibitor deficiency. Furthermore, it may occur secondary to drugs, especially angiotensin-converting enzyme (ACE) inhibitors, or via an allergic/IgE-related mechanism.

The emergency clinician must confidently identify anaphylaxis and allergic reactions, and implement definitive and rapid interventions. Delays in treatment and inadequate treatment may have dire consequences. This issue of Emergency Medicine Practice presents a review of the current evidence that guides the evaluation and treatment of anaphylaxis and allergy, and focuses on the clinical scenarios that are most often seen in common practice.

Critical Appraisal Of The Literature

A literature search was performed using PubMed and Ovid MEDLINE® with the search terms anaphylaxis, allergy, and hypersensitivity. The search focused on English-language articles limited to humans that included systematic reviews, clinical trials, multicenter studies, or meta-analyses. References pertinent to emergency treatment were selected, and used for additional manual literature searches. Due to the plethora of literature on allergy and anaphylaxis, the search focused on literature from 1986 to 2014, including clinical diagnosis in the emergency setting and on prehospital and hospital diagnosis and treatment. In addition, a search of the National Guideline Clearinghouse (, using these refined search terms, produced guidelines and practice parameters from 2010 and 2011. A review of the Cochrane Database of Systematic Reviews yielded approximately 13 reviews on the general category of allergy and anaphylaxis. Several of these were specific to emergency management and covered the following topics: H1 antihistamines in anaphylaxis, glucocorticoids and heliox use in allergy and asthma, epinephrine auto-injectors, and an emergency action plan for people at risk of anaphylaxis. Overall, approximately 550 articles were reviewed, and 104 of these are included here for reference.

Due to the ethical challenges of randomized placebo-controlled trials of treatment for anaphylaxis, most studies are retrospective or based on clinical observations. Although a preponderance of the literature is from the field of allergy and immunology, a smaller number of references were found in the emergency medicine and pediatric emergency care literature.

Risk Management Pitfalls In Management Of Allergy And Anaphylaxis

  1. “The patient had an intravenous catheter in place, so I thought it seemed reasonable to give epinephrine through the intravenous line rather than to stick the patient again with an intramuscular injection.”
    Expert guidelines recommend administering epinephrine via the intramuscular route. It has a fast time of onset, and there is a lower likelihood of adverse arrhythmias from intramuscular administration versus intravenous administration of epinephrine. If a patient is not reacting appropriately to repeated doses of intramuscular epinephrine or has cardiovascular collapse, consider intravenous epinephrine at that time, and attempt to determine the causes of the refractory response (such as chronic use of beta blockers).
  2. “The patient has urticaria and wheezing after eating a cookie with nuts, but he looks good and is not hypotensive, so I won’t give epinephrine yet. I’ll try albuterol and an antihistamine first. Besides, he is 60 years old, and who knows if he has undiagnosed cardiac disease?”
    Nothing should delay the administration of epinephrine in an anaphylactic reaction. Doing so increases the likelihood of a biphasic reaction and increases mortality. There are also no absolute contraindications to epinephrine use. The benefits of giving it in this situation outweigh the risks, as the adverse effects from hypotension and decreased filling pressure in anaphylaxis may actually worsen underlying ischemia.
  3. “My 21-year-old patient had a syncopal episode with bradycardia. It had to have been a vasovagal episode and not anaphylaxis. Besides, she didn’t even have a rash.”
    Patients having an anaphylactic reaction who present with syncope generally have an accompanying tachycardia due to distributive shock and fluid extravasation. However, less frequently, patients may present with bradycardia-associated syncope, although there is some conjecture about the precise mechanism. Also, patients taking chronic beta blockers may not be able to mount a tachycardic response and may appear with a relative bradycardia. Even children and young adults may be prescribed these medications for a variety of reasons, and glucagon may be needed in such cases if they are refractory to first-line epinephrine. Furthermore, 10% to 20% of patients with anaphylaxis do not have urticaria or cutaneous findings on examination. Isolated hypotension or syncope after being exposed to a known allergen is sufficient to qualify the reaction as an anaphylactic one.
  4. “It’s really busy tonight, so I will send the patient back to the allergist to get a prescription for an EAI in the morning. He seems perfectly stable.”
    All patients should be discharged from the ED with an EAI and guidance on how to self-administer it, even if their symptoms have resolved in the ED. Biphasic reactions can occur in 5% to 20% of patients, and auto-injectors can be effective in saving lives in the prehospital setting.
  5. “EMS already gave epinephrine to the patient. I just need to observe.”
    Severe anaphylaxis may necessitate more than one dose of intramuscular epinephrine. Though the first dose may be enough to abate the initial allergic reaction, it may not be sufficient to quell the multitude of symptoms. If the patient still manifests hemodynamic compromise, redosing of epinephrine is a necessity. In refractory cases, an epinephrine intravenous push or via infusion may be needed.
  6. “I’m writing a prescription for an EAI and sending the patient home. That should prevent another visit.”
    Patients who have a serious allergic reaction are more prone to recurrent or more-severe subsequent reactions. It is crucial that patients are not only in possession of EAIs, but that they also have a clear understanding of how and when to use them. There are data to support the fact that patient instruction labels are becoming more useful; however, this should not replace concomitant teaching in the ED, which should be a part of any discharge plan.
  7. “The patient with the severe allergic reaction is crashing, so I’ll perform RSI. That should secure her airway.”
    Careful consideration must be taken when approaching airway management in anaphylaxis. In patients requiring orotracheal intubation, attention should be paid when giving paralytics in RSI. If the intubation attempt is unsuccessful, these patients may be difficult to effectively ventilate via bag-valve mask because of oropharyngeal edema and laryngeal constriction. Awake intubation, fiberoptic intubation, and delayed-sequence intubation offer alternatives to RSI. The emergency clinician may choose to involve an anesthesiologist in these procedures depending upon his or her degree of experience with these advanced airway techniques.
  8. “The patient had been taking his ACE inhibitor for years without a problem. I just treated his reaction in the ED and sent him home.”
    ACEIIA is a special circumstance of bradykinin-mediated (nonallergic-mediated) angioedema that may not be responsive to epinephrine and standard treatments. Airway management and fresh-frozen plasma may be indicated, and immediate cessation of the ACE-inhibitor is always necessary. Most ACE-inhibitor reactions occur in the weeks following the start of therapy; however, some patients develop symptoms years after being on the medication.
  9. “I did not give the patient epinephrine because his oropharyngeal edema pointed toward a diagnosis of angioedema.”
    Just because angioedema is present, an allergic-mediated etiology should not be ruled out. Angioedema is a physical sign, and it may be a manifestation of anaphylaxis or an allergic reaction, as well as a symptom in nonallergic, bradykinin-mediated pathways. If the history points toward such an allergic episode, angioedema is responsive to epinephrine, and it should be employed in treatment.
  10. “EMS is calling in for medications en route to the ED for a 27-year-old woman who has pruritus, wheezing, and low oxygen saturation after taking NSAIDs. They are only 5 minutes away so I would rather use my judgment and take a look at her myself before I order epinephrine. I’ll just tell them to give antihistamines and steroids for now.”
    There should never be a delay in administering epinephrine, the undisputed first-line medication, for what appears to be anaphylaxis. Studies have shown that epinephrine admin-istration in the field by EMS personnel is safe and used appropriately in the overwhelming number of situations. Continued efforts must be focused on increasing its use in the early phase of anaphylaxis.

Tables and Figures

Table 1. Common Etiologies Of Anaphylaxis

Table 2. Gell And Coombs Classification Of Hypersensitivity Reactions


Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study will be included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the authors, will be noted by an asterisk (*) next to the number of the reference.

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Publication Information

Elizabeth Singer, MD, MPH, FACEP; David Zodda, MD;

Publication Date

August 1, 2015

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