Anaphylaxis is a serious allergic reaction, with a rapid onset; it may cause death and requires emergent diagnosis and treatment. Consensus clinical criteria have been developed to provide consistency for diagnosis (Table 14-1).^1,2,3

The terms anaphylactic and anaphylactoid were previously applied to immunoglobulin E (IgE)-dependent and IgE-independent events, respectively. Because the final pathway in both events is identical, anaphylaxis is the term now used to refer to both.⁴ Hypersensitivity is an inappropriate immune response to generally harmless antigens, manifesting a continuum from minor to severe manifestations. Anaphylaxis represents the most dramatic and severe form of immediate hypersensitivity.

Foods, medications, insect stings, and allergen immunotherapy injections are the most common provoking factors for anaphylaxis, but any agent capable of producing a sudden degranulation of mast cells or basophils can induce anaphylaxis (Table 14-2).^5,6 Latex hypersensitivity is increasing in prevalence in the general population, with a resultant risk for anaphylaxis. In addition, a significant number of anaphylaxis cases have no identified cause, termed idiopathic anaphylaxis.⁷ The lifetime individual risk of anaphylaxis is estimated to be 1% to 3%, but the prevalence of anaphylaxis may be increasing.⁸ Although allergic reactions are a common cause for ED visits,⁹ anaphylaxis is likely underdiagnosed.^10,11

Anaphylaxis, for the most part, arises from the activation of mast cells and basophils through a mechanism involving crosslinking of IgE and aggregation of the high-affinity receptors for IgE.⁶ Upon activation, mast cells and/or basophils quickly release preformed mediators from secretory granules that include histamine, tryptase, carboxypeptidase A, and proteoglycans. Downstream activation of phospholipase A₂, followed by cyclooxygenases and lipoxygenases, produces arachidonic acid metabolites, including prostaglandins, leukotrienes, and platelet-activating factor. The inflammatory cytokine, tumor necrosis factor-α, is released as a preformed mediator and also as a late-phase mediator with other cytokines and chemokines. These mediators are responsible for the pathophysiology of anaphylaxis. Histamine stimulates vasodilation and increases vascular permeability, heart rate, cardiac contraction, and glandular secretion. Prostaglandin D₂ is a bronchoconstrictor, pulmonary and coronary vasoconstrictor, and peripheral vasodilator. Leukotrienes produce bronchoconstriction, increase vascular permeability, and promote airway remodeling. Platelet-activating factor is also a potent bronchoconstrictor and increases vascular permeability. Tumor necrosis factor-α activates neutrophils, recruits other effector cells, and enhances chemokine synthesis. These overlapping and synergistic physiologic effects contribute to the overall pathophysiology of anaphylaxis.⁶

The classic presentation of anaphylaxis begins with pruritus, cutaneous flushing, and urticaria. These symptoms are followed by a sense of fullness in the throat, anxiety, a sensation of chest tightness, shortness of breath, and lightheadedness. A complaint of a “lump in the throat” and hoarseness heralds life-threatening laryngeal edema in a patient with symptoms of anaphylaxis. These major symptoms may be accompanied by abdominal pain or cramping, nausea, vomiting, diarrhea, bronchospasm, rhinorrhea, conjunctivitis, and/or hypotension. As the cascade progresses, respiratory distress, decreased level of consciousness, and circulatory collapse may ensue. In severe cases, loss of consciousness and cardiorespiratory arrest may result.

Signs and symptoms begin suddenly, often within 60 minutes of exposure, in most patients. In general, the faster the onset of symptoms, the more severe is the reaction—one half of anaphylactic fatalities occur within the first hour. After the initial signs and symptoms abate, patients are at a small risk for a recurrence of symptoms caused by a second phase of mediator release, peaking 8 to 11 hours after the initial exposure and manifesting symptoms and signs 3 to 4 hours after the initial clinical manifestations have cleared. The late-phase allergic reaction is primarily mediated by the release of newly generated cysteinyl leukotrienes, the former slow-reacting substance of anaphylaxis. The incidence of this biphasic phenomenon has been reported to vary widely up to 20%, but prospective studies specifically searching for clinically important biphasic events report an incidence of 4% to 5%.^12,13

The diagnosis of anaphylaxis is clinical. Consider anaphylaxis when involvement of any two or more body systems is observed, with or without hypotension or airway compromise (Table 14-3).^1,14 The diagnosis is easily made if there is a clear history of exposure, such as a bee sting, shortly followed by the multisystem signs and symptoms described above. Unfortunately, diagnosis is not always easy or clear, because symptom onset may be delayed, symptoms may mimic other presentations (e.g., syncope, gastroenteritis, anxiety), or anaphylaxis may be a component of other diseases (e.g., asthma).

The differential diagnosis of anaphylactic reactions is extensive, including vasovagal reactions, myocardial ischemia, arrhythmias, severe acute asthma, seizure, epiglottitis, hereditary angioedema, foreign body airway obstruction, carcinoid, mastocytosis, vocal cord dysfunction, and non–IgE-mediated drug reactions. The most common anaphylaxis imitator is a vasovagal reaction, which is characterized by hypotension, pallor, bradycardia, diaphoresis, and weakness, and sometimes by loss of consciousness.

Laboratory investigations are of minimal utility.¹⁵ Serum histamine levels, elevated for 5 to 30 minutes after reaction, are unhelpful because they are typically normal upon ED presentation. Tryptase is a neutral protease of unknown function in anaphylaxis that is found only in mast cell granules and is released with degranulation. Serum tryptase levels are elevated for several hours and have been proposed for later confirmation of a suspected anaphylactic episode, but this test has poor sensitivity; about one third of patients with an acute anaphylaxis episode have a normal serum tryptase level upon ED arrival,¹⁶ and some patients experience severe anaphylaxis without elevated tryptase levels.¹⁷

Triage all acute allergic reactions at the highest level of urgency because of the possibility of sudden deterioration.¹⁰ Current treatment recommendations are derived from the clinical experience of experts as professed in consensus statements and guidelines.^15,18,19,20

FIRST-LINE THERAPY

Emergency management starts with airway, breathing, and circulation. Assess vital signs and pulse oximetry. Initiate IV access, oxygen administration, and cardiac rhythm monitoring in patients with severe symptoms. The first-line therapies for anaphylaxis (airway protection, oxygen, decontamination, epinephrine, IV crystalloids) have immediate effect during the acute stage.^19,20,21,22

Airway and Oxygenation

In severe anaphylaxis, securing the airway is the first priority. Examine the mouth, pharynx, and neck for signs and symptoms of angioedema: uvula edema or hydrops, audible stridor, respiratory distress, or hypoxia. If angioedema is producing respiratory distress, intubate early, because delay may result in complete airway obstruction secondary to progression of angioedema. Provide sufficient oxygen to maintain arterial oxygen saturation >90%.

Decontamination

If the causative agent can be identified, termination of exposure should be attempted. Gastric lavage is not recommended for foodborne allergens and may be associated with complications (i.e., aspiration) and delays in the administration of more effective treatments (e.g., epinephrine). In insect stings, remove any remaining stinging remnants because the stinger continues to inject venom even if it is detached from the insect (see chapter 211, “Bites and Stings”).

Epinephrine

Epinephrine is a mixed α₁– and β-receptor agent. The α₁-receptor activation reduces mucosal edema and treats hypotension, β1-receptor stimulation increases heart rate and myocardial contractility, and β₂-receptor stimulation provides bronchodilation and limits further mediator release.¹⁵ Epinephrine is the treatment of choice for anaphylaxis.^15,18,23,24 However, observational studies indicate that it is underused, often dosed suboptimally, and underprescribed upon discharge for potential future self-administration.^9,11 Most of the reasons proposed to withhold epinephrine are flawed, and the therapeutic benefits of epinephrine exceed the risk when given in appropriate routes and doses.²³

In patients without signs of cardiovascular compromise or collapse, administer epinephrine IM (Table 14-4).²⁵ Repeat every 5 to 10 minutes according to response or if relapse occurs. Injections into the thigh are more effective at achieving peak blood levels than injections into the deltoid area.²⁵ IM dosing is recommended because it provides higher, more consistent, and more rapid peak blood epinephrine levels than SC administration.^25,26 For convenience and accurate dosing, many EDs have adopted the use of EpiPen® (0.3 milligram epinephrine for adults; Dey, L.P., Napa, CA) and EpiPen Junior® (0.15 milligram epinephrine for children <30 kg; Dey, L.P.).