Category	Examples
Antibiotics	Penicillin and penicillin analogues, β-lactam antibiotics, cephalosporins, tetracyclines, erythromycin
Nonsteroidal anti-inflammatory drugs	Salicylates, ibuprofen, indomethacin
Narcotic analgesics	Morphine, codeine, meprobamate
Local anesthetics	Procaine, lidocaine, cocaine
General anesthetics	Thiopental
Muscle relaxants	Suxamethonium, tubocurarine, pancuronium
Blood products and antisera	Red blood cell, white blood cell, and platelet transfusions; gamma globulin; rabies, tetanus, diphtheria antitoxin; snake and spider antivenom
Diagnostic agents	Iodinated radiocontrast agents
Foods	Eggs, milk, nuts, legumes (peanuts, soybeans, kidney beans), fish, shellfish
Venoms	Bees, wasps, hornets, fire ants, scorpions, snakes
Enzymes and other biologic agents	Acetylcysteine, pancreatic enzyme supplements, chymopapain
Extracts of potential allergens used in desensitization	Pollen, food, venom extracts
Chemotherapeutic agents	Cisplatin, cyclophosphamide, daunorubicin, methotrexate
Insulin	Pork, beef, and human insulin
Other drugs	Protamine, chlorpropamide, parenteral iron, iodides, thiazide diuretics

Immune-mediated IgE-dependent or IgE-independent and non-immune-mediated mast cell degranulation-mediated anaphylactic reactions have similar clinical features. Agents capable of producing direct mast cell degranulation include NSAIDs, opiates, ciprofloxacin, and physical factors, (cold, heat, exercise). Patients who are taking beta blockers or ACE inhibitors may develop severe anaphylaxis to an inciting agent and are less likely to respond to first-line agents.3–6

In idiopathic anaphylaxis, the pathophysiology and triggering events are unknown. Idiopathic anaphylaxis is a diagnosis of exclusion. It is mostly seen in adults and adolescents. About half these patients have concomitant atopic disease. They respond to treatment with corticosteroids and antihistamines.7,8 Special testing like serum tryptase, C4 levels may be necessary to exclude conditions such as systemic mastocytosis, hereditary angioedema, and acquired C1 inhibitor deficiency.

Factitious anaphylaxis is a type of Munchausen syndrome. Patients with this disorder typically have an acute crisis that resembles anaphylaxis because of intentional self-exposure to an allergen. These reactions may be attributed to an unknown allergen or a well-defined allergen such as bee venom.

Anaphylaxis may progress to shock, multiple organ failure, and death. Early recognition and rapid implementation of treatment is lifesaving. It is essential that patients with anaphylaxis be accurately diagnosed so that management can proceed as quickly as possible. Because these severe reactions may continue despite appropriate treatment, and because a recurrence of symptoms after an initial favorable response may occur, patients with severe life-threatening anaphylaxis should be admitted to the hospital or intensive care unit (ICU) for continued monitoring.

History and Incidence

Allergic emergencies have been described in humans since ancient times.9–11 At the turn of the twentieth century, a more detailed description of these events was reported by two French physiologists, Portier and Richet.¹² They coined the term anaphylaxis, which originates from the French word anaphylactique, which means “reverse protection.” It was believed that these reactions were in contrast to the attenuated or tachyphylactic reactions that commonly protect subjects from reintroduced antigens such as viruses. More recent research defining the role of IgE; the interactions between IgE, antigen, mast cells, basophils, and eosinophils; and the biochemical mediators from these cells has clarified the events leading to clinical anaphylaxis.^2,13–15

The true incidence of the various types of anaphylactic reactions is difficult to determine because these reactions are often spontaneous and unpredictable and are clinically similar to other acute reactions. Lifetime prevalence of anaphylaxis due to all triggers is estimated to be 0.05% to 2%.¹⁶ Estimates of the incidence of the most commonly reported episodes are possible, however. In the United States, penicillin alone probably accounts for several hundred fatalities each year.^17–19 Anaphylaxis to the cephalosporins also is commonly reported.²⁰ It has been estimated that among patients with an allergic reaction to a penicillin, there is a 3% to 7% rate of allergic reaction to a cephalosporin. Reports of anaphylactic reactions to the newer β-lactam antibiotics are accumulating.²¹

Insects, especially those of the Hymenoptera order, which includes bees, wasps, hornets, and fire ants, account for numerous immediate hypersensitivity reactions. About 3% of adults and 1% of children are affected and the anaphylaxis can be fatal at the first sting. About 50 people experience fatal reactions to insect stings every year in the United States, and about half of them do not have a prior sting exposure.22–24 Fire ants are aggressive insects from South America that now reside in the southern United States. In some areas, they have been known to sting 58% of the residents yearly and account for serious allergic reactions.²⁵

Snake bites account for probably a dozen or so anaphylactic deaths per year in the United States. Snake bites may be associated with typical anaphylactic symptoms and other problems related to the enzymes, proteins, and peptides in venom. Local tissue necrosis, coagulation problems, hemolysis, and neurologic transmission defects have been described. In the United States, most anaphylactic reactions to snake bites are caused by pit vipers. These snakes include rattlesnakes, water moccasins, and copperheads.26,27

Food-induced anaphylaxis is probably the most common cause of anaphylaxis and accounts for 30% of fatalities. Peanuts (legumes) and typical nuts from trees account for 90% of fatal cases. Additional common food antigens include fish, soybeans, egg whites, and shellfish.²⁸ Biphasic reactions are much more common in food-induced anaphylaxis than in other types of anaphylaxis and have been reported in 25% of fatal cases.^29–31

Iodinated contrast agents account for approximately 125 deaths per year ³² and lead to clinical symptoms similar to anaphylaxis. Life-threatening reactions are extremely rare, with an incidence of 0.1%.^33,34 With the advent of low osmolar iodinated contrast agents, the risk of anaphylaxis to contrast agents has decreased drastically.³⁵

Latex, used in surgical gloves, balloons, condoms, rubber bands, and many other products, may produce anaphylaxis.36,37 The use of universal precautions as a result of the acquired immunodeficiency syndrome epidemic has increased the number of reactions to latex in health care workers. Children with spina bifida and genitourinary tract abnormalities are especially susceptible to latex-induced anaphylaxis because of frequent exposure to latex-containing bladder catheters and other products.

Anaphylactic reactions during anesthesia have been described and typically are associated with hypotension and cardiopulmonary arrest. One review suggests that most cases of intraoperative anaphylaxis are from muscle relaxants (e.g., suxamethonium, tubocurarine, pancuronium).³⁸ Latex, protamine, and blood products also may cause intraoperative anaphylaxis.

Anaphylaxis and other types of IgE-mediated allergic reactions tend to occur in susceptible, genetically predisposed individuals. The reason for the genetic inheritance of sensitivity to the antigens that produce anaphylaxis continues to be speculative. A popular theory is that type I reactions, when confined to an area of parasitic invasion (e.g., intestinal tract), facilitate the killing and removal of parasites and confer a survival advantage to individuals capable of mounting a type I response. Various clinical and laboratory observations support this view.39–41 The sites of IgE synthesis in laboratory subjects correspond to the sites of entry of many parasites. These sites include the lymphoid tissue of the respiratory tract, the gastrointestinal tract, and the skin. Eosinophils, cells that migrate to the site of antigen introduction in anaphylaxis, elaborate mediators that are toxic to the outer parasitic covering.

When type I reactions to antigen are no longer restricted to local areas because of genetically determined or acquired factors, the release of mediators becomes generalized. Problems typical of a systemic response include increased microvascular permeability, loss of intravascular volume, abnormal vascular reactivity (especially vasodilation), and impaired pulmonary gas exchange. Local IgE-mediated reactions become decompensatory when systemic involvement ensues.

Pathogenesis and Pathophysiology

Immunologic Mechanisms Leading to Mast Cell and Basophil Activation and Mediator Release

When an antigen to which an individual has previously been sensitized is reintroduced, a sequence of events is initiated that leads to mediator release (Fig. 28.1). At least several weeks are required between the initial exposure to antigen and a subsequent exposure for clinical manifestations of anaphylaxis to occur. The antigen may be introduced through the skin, respiratory tract, or gastrointestinal tract. Antigen also may be introduced intravenously, usually in association with drug administration. Although most venoms are injected subcutaneously, some may access the circulation through an intravascular route.

Figure 28.1 The sequence of events leading to mediator release starts with sensitization (initial introduction of a bivalent antigen) and synthesis of antigen-specific IgE. IgE then reversibly binds to mast cells or basophils. When antigen is reintroduced, two cell-bound IgE molecules are linked by the bivalent antigen in a process called cross-linking. Cross-linking facilitates the approximation of Fc surface receptors on the mast cell and basophil and initiates a sequence of intracellular biochemical reactions that culminate in mediator release. ECF-A, eosinophil chemotactic factor of anaphylaxis; NCF, neutrophil chemotactic factor; PAF, platelet-activating factor; PGs, prostaglandins; SRS-A, slow-reacting substance of anaphylaxis.

In most cases of anaphylaxis, when antigen is reintroduced into the host, it encounters IgE, previously synthesized by plasma cells in response to a previous introduction of antigen. IgE, similar to other immunoglobulins, is composed of two heavy chains and two light chains linked by disulfide bonds. Two portions of the molecule have well-defined functions. The Fab portion of the molecule recognizes and binds antigen. The Fc portion of the molecule binds reversibly to receptors on the surface of mast cells and basophils (Fig. 28.2).

Figure 28.2 In immune-mediated IgE-dependent anaphylaxis, each molecule consists of four polypeptide chains. Two are heavy chains (epsilon [ε]) and are unique to the IgE class of immunoglobulins. Light chains are either kappa (κ) or lambda (λ) chains and may be found in other types of immunoglobulins.

The combination of reintroduced antigen with antigen-specific IgE sets the stage for a sequence of biochemical and cellular events that produce the clinical syndrome of anaphylaxis. The bivalent antigen cross-bridges two IgE molecules (see Fig. 28.1). Cross-bridging facilitates the approximation of Fc surface receptors on mast cells and basophils, triggering the release of mediators from intracellular granules and membrane-based phospholipids. The systemic release of these mediators leads to the pathophysiologic changes that produce the clinical manifestations of anaphylaxis.

Clinical reactions similar to anaphylaxis mediated by immunoglobulins of the IgG class have been described. IgG molecules may combine with antigens, producing an antigen-antibody complex that activates complement. Activation of complement generates C3a and C5a, also known as anaphylatoxins because they stimulate mediator release from mast cells and basophils. IgG-mediated reactions are considered type III reactions according to the classification of Gell and Coombs or may be referred to as Arthus reactions. These reactions may characterize IgA-deficient individuals who exhibit sudden reactions to blood transfusions. These individuals may develop an antibody of the IgG class to the IgA in the transfused blood product.42,43 This combination of IgG and IgA antibody activates complement, generates C3a and C5a, and produces a sudden reaction typical of anaphylaxis. Because approximately 1 in 700 individuals is IgA deficient, numerous people are susceptible to this type of blood transfusion reaction.⁴³ The anaphylactic responses to protamine may be IgG-, IgE-, or non-immune-mediated.^44–46

Nonimmunologic Events Leading to Mediator Release

The mediators released during nonimmune reactions originate from mast cells and basophils and are identical to the mediators of immune-mediated anaphylaxis. The direct activation of surface receptors on mast cells and basophils by antigen may be responsible for mediator release in these reactions. Iodinated contrast agents, opiates, and highly charged polyionic antibiotics seem to activate surface receptors directly. Physical stimuli, including heat, cold, and hyperosmolar stimuli, also are capable of stimulating mast cells and basophils. Exercise-induced anaphylaxis may be associated with the stimulation of mast cells through cooling of the airways. Other possible mechanisms include complement activation without immune complex mediation (old preparations of propafol with cremophor diluent),⁴⁷ direct mast cell degranulation (merperidine),⁴⁸ and direct activation of the kinin-kallikrein pathway, resulting in the generation of bradykinin, C3a, and C5a (oversulfated chondroitin sulfate in heparin products).⁴⁹

Cellular Characteristics of Anaphylaxis

Despite the release of similar mediators during anaphylaxis, mast cells and basophils differ in several ways. Mast cells are more abundant than basophils and generally reside in the connective tissue of subcutaneous and submucosal areas. Basophils characteristically circulate in the blood.⁵⁰ Despite these differences in location and number, functional differences between the two cell types have not been clearly identified. Both types of cells have receptors for the Fc portion of IgE, and both have granules that bind basic dyes. In addition, the granules of both cells contain histamine and various other mediators that participate in the anaphylactic response.

Eosinophils are commonly identified in the tissues and plasma of patients with both immune- and non-immune-mediated anaphylactic reactions. These cells typically migrate to the site of antigen introduction. They are attracted by a variety of chemotactic factors, including factors derived from mast cells and basophils, antigen-antibody complexes, histamine, and complement. The granules of eosinophils stain with acidophilic dyes and contain a variety of biochemical mediators that are toxic to helminthic parasites. Substances that inactivate leukotrienes and histamines also are elaborated. Eosinophils function as modulators of the inflammatory response triggered by mast cell and basophil activation.51,52

Platelets and polymorphonuclear leukocytes also may be involved in the anaphylactic response. These cells respond to mast cell–derived and basophil-derived chemotactic factors and to tissue injury. They release a variety of mediators that may be responsible for recurrent and late-phase reactions (see the following discussion).

Biochemical Mediators of Anaphylaxis

The biochemical mediators of anaphylaxis are divided into primary and secondary mediators. Mediators directly released from mast cells and basophils are termed primary mediators (Table 28.2). Secondary mediators are released from other cell types in response to primary mediator release (Table 28.3). Primary mediators are subdivided further into preformed and newly synthesized mediators. Preformed mediators are formed and stored in the intracellular granules of mast cells and basophils. Newly synthesized mediators are derived from the metabolism of arachidonic acid, a phospholipid derived from cell membrane.

Table 28.2

Physiologic Effects of Primary Mediators of Anaphylaxis Derived from Mast Cells and Basophils

Table 28.3

Secondary Mediators of Anaphylaxis and Physiologic Effects

Mediator(s)	Physiologic Effect(s)
Neutrophil, platelet, and eosinophil-derived mediators	Permeability, coagulation changes, proteolysis
Activated complement system
C3a and C5a	Contract bronchial smooth muscle; increase vascular permeability; attract neutrophils, macrophages, and monocytes
C6-C9	Membrane damage
Activated coagulation cascade	Intravascular coagulation, permeability changes, tissue injury
Activated kinin system (bradykinin)	Increases vascular permeability

Histamine is a well-characterized primary mediator stored and released from the granules of mast cells and basophils. Histamine stimulates H₁ and H₂ receptors located on the surfaces of vascular and bronchial smooth muscle cells. Stimulation of H₁ receptors leads to precapillary arteriolar dilation, contraction of postcapillary venules, and formation of intracellular gaps between capillary endothelial cells. By increasing capillary hydrostatic pressure and permeability, these changes initiate the movement of plasma into the interstitial space. In the lung, H₁ receptor stimulation is associated with bronchial smooth muscle contraction. H₂ receptor stimulation leads to vasodilation, enhanced mucus secretion, increased heart rate and myocardial contractility, increased gastric acid secretion, and inhibition of T cells. The vasoactive and cardiac effects of H₂ receptor stimulation primarily contribute to the clinical manifestations of anaphylaxis.

The family of arachidonic acid metabolites known as leukotrienes consists of newly synthesized primary mediators that function as potent vascular permeability agents and bronchoconstrictors. Arachidonic acid metabolism via the cyclooxygenase pathways produces prostaglandins with bronchoconstrictive effects—prostaglandin D₂ and prostaglandin F₂. Other mediators that are released are tryptase, carboxypeptidases, and proteoglycans.

The primary mediator release from mast cells and basophils sets the stage for involvement by secondary mediators. Secondary mediators include products of enzyme-dependent cascading biochemical pathways. In addition, secondary mediators may be derived from other involved cells, such as neutrophils, platelets, and eosinophils.

Biochemical and Pharmacologic Regulation of Mediator Release

The biochemical regulation of mediator release provides a rationale for the pharmacologic therapy of anaphylaxis. The release of primary mediators is thought to be modified by intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) and calcium and other bivalent cations. Pharmacologic agents that affect the intracellular levels of these modulators and inhibit mediator release are often used in the treatment of anaphylaxis (Box 28.1).

β₂-Adrenergic agonists increase intracellular levels of cAMP by activating adenylate cyclase. This increase in cAMP subsequently inhibits the release of mediators. The methylxanthines aminophylline and theophylline also increase cAMP levels through the inhibition of phosphodiesterase. Because cGMP antagonizes the action of cAMP, agents that decrease cGMP inhibit mediator release. Anticholinergic drugs decrease cGMP levels and may have a role in the treatment of anaphylaxis.

Mediator release from mast cells and basophils is associated with an influx of calcium. Although calcium blocking agents theoretically may be useful in the treatment of anaphylaxis, clinical experience with use of these agents for this condition is lacking. Conversely, calcium administration may be harmful in anaphylaxis because of its association with enhanced mediator release. Other bivalent cations, such as magnesium and manganese, also enhance mediator release. Multiple tyrosine kinases are activated and regulate by exerting either stimulatory or inhibitory actions on the signal transduction cascade.53–55 Sphingosine-1-phosphate has been identified recently as one of the mediators that serves as a modulator in the mast cell. In addition, it is now labeled as a circulating mediator in anaphylaxis.⁵⁶

Pathophysiologic Effects of Mediators

The numerous mediators released during anaphylactic crisis have many physiologic effects that have been studied extensively in the laboratory. Although it is difficult to determine the specific actions of each mediator in anaphylaxis, the cumulative effects of mediator release have been described in the clinical setting. These effects include abnormalities secondary to increased vascular permeability; vascular resistance changes, primarily vasodilation; and bronchospasm. Autopsies of fatal cases of anaphylaxis reveal edema of the lungs, upper airway (including the larynx and epiglottis), skin, and viscera. Pulmonary congestion is typical in fatal anaphylaxis, and light microscopy often reveals fluid-filled pulmonary alveoli.⁵⁷ In another series of fatal cases of anaphylaxis, acute pulmonary emphysema was observed in almost half of cases.⁵⁸ This condition is characterized by hyperextended alveoli and thinning of the alveolar septum. Because of the association of acute pulmonary emphysema with laryngeal edema, these fatalities were thought to be caused by upper airway obstruction, with alveolar rupture resulting from forced exhalation against the obstruction.

Cardiac abnormalities, including arrhythmias, reduced contractility, and myocardial ischemia, have been described in anaphylaxis but seem to be uncommon.⁵⁹ These abnormalities may be secondary to the effects of histamine and other mediators on the myocardium. Other contributing factors include circulatory shock, hypotension, increased adrenergic tone, and drugs used to treat anaphylaxis.

Late-Phase or Biphasic Reactions

Both immune-mediated and non-immune-mediated anaphylactic reactions may be followed by late-phase reactions (also termed biphasic reactions). These reactions typically occur 6 to 12 hours after the initial reaction as a result of the migration of mast cells, basophils, and polymorphonuclear leukocytes into areas of antigen introduction. A secondary wave of mediator release and recurrence of symptoms may be observed.60–62

Clinical and Hemodynamic Features

The constellation of clinical signs and symptoms in anaphylaxis may vary widely for individuals; however, severe, rapidly progressive symptoms after exposure to antigen are characteristic. The portal of entry for the antigen, the rate of absorption, and the degree of hypersensitivity to the antigen also influence the clinical presentation. Current research is focusing on the role of genetic factors as well. Gastrointestinal symptoms, including nausea, vomiting, abdominal cramps, and diarrhea, may precede more generalized clinical manifestations after ingestion of an antigen. Inhalation of an antigen may be associated with nasal coryza, a sensation of tightness or a lump in the throat, hoarseness, stridor, wheezing, and dyspnea. Introduction of antigen through the skin may produce local pruritus, urticaria, and swelling before progression to systemic symptoms.

The most life-threatening reactions are usually explosive in nature, often occurring within minutes of exposure to the antigen. Victims of these reactions have been noted to describe a feeling of impending doom before more defined symptoms develop. Generalized cutaneous abnormalities include erythema, urticaria, and flushing. Swelling of the periorbital and perioral areas is characteristic. Upper and lower airway abnormalities are common and especially dangerous. Swelling of the posterior pharynx, uvula, tonsils, and vocal cords may develop rapidly. Auscultation of the chest may reveal generalized wheezing and prolongation of expiration. Auscultatory and radiographic signs of pulmonary edema are characteristic of severe episodes. Signs of circulatory shock include hypotension, oliguria, and lactic acidosis from intravascular volume depletion. In some instances, such as the intravenous injection of venom or a drug, circulatory shock may develop without preceding cutaneous and respiratory abnormalities. The clinical features of anaphylaxis may respond quickly to treatment or, in the most severe cases, may last for several hours to several days. An initial favorable response to treatment may be followed by a late-phase reaction—a recurrence of symptoms resulting from a second wave of mediator release approximately 6 to 12 hours after the initial reaction.60,62

Hemodynamic descriptions of human anaphylaxis are limited to detailed studies of a few cases. The loss of circulating plasma volume is characteristic and is associated with hemoconcentration, hypotension, tachycardia, decreased cardiac filling pressures, and decreased cardiac output.63,64 Vasodilation, associated with a decrease in systemic vascular resistance, may contribute to the reduction in venous return and cardiac output. When oxygen delivery decreases to levels below systemic oxygen demands, anaerobic metabolic pathways are activated, and lactic acidosis emerges.⁶⁵ Decreases in myocardial contractility seem to be minimal in studies of human anaphylaxis using routine hemodynamic monitoring. This is supported by the observation that most patients with anaphylaxis respond favorably to fluid therapy and do not require inotropic support.^63–67 In a few case reports, reduced myocardial contractility has been observed in association with myocardial ischemia and infarction.^68–73 Some of these adverse cardiac effects have been associated with epinephrine administration, but in some cases they also have been noted before pharmacologic treatment.^68–73

Laboratory studies provide more detailed descriptions of the hemodynamic features of anaphylaxis. After antigenic challenge in primates, a transient increase in cardiac output is observed and is followed by decreases in arterial pressure, right and left ventricular filling pressures, and peripheral vascular resistance.⁷⁴ The transient increase in cardiac output has been attributed to vasodilation-induced left ventricular unloading or an increase in cardiac contractility or both. Elevated plasma levels of epinephrine, norepinephrine, and histamine have been shown in laboratory animals and humans and may contribute to this increase in contractility.^75,76 Cardiac output eventually decreases when hypotension and shock become established. In human and canine models of anaphylaxis, a reduction in venous return has been observed secondary to vasodilation and pooling of blood in the splanchnic circulation.^77–79 Loss of plasma volume from increased vascular permeability is probably a contributing factor.

When pulmonary edema fluid is sufficiently copious to be sampled from the airway of patients with anaphylaxis, albumin concentrations and oncotic pressures are nearly identical to plasma values. These findings and the association of pulmonary edema with low pulmonary artery wedge pressures suggest that the pulmonary edema in anaphylaxis is noncardiogenic and secondary to increased microvascular permeability.⁶³ Although transient pulmonary hypertension and increased pulmonary vascular resistance have been observed in primates immediately after antigen challenge,⁷⁴ it is unknown whether pulmonary hypertension characterizes human anaphylaxis.

Hemodynamic characteristics of human anaphylaxis are determined by generalized vasodilation and increased vascular permeability, which lead to venous pooling of blood and loss of circulating plasma volume. Permeability edema develops in the lung. Changes in cardiac contractility are not typical of human anaphylaxis; however, reduced contractility may characterize patients who exhibit signs of myocardial ischemia or infarction, especially in association with epinephrine therapy.

Management

Initial Management

The initial assessment of a patient with suspected anaphylaxis should be brief and specific because immediate therapeutic interventions are required. Because a variety of conditions may appear similar to anaphylaxis (Box 28.2), it is important to rule out these events quickly. Vasovagal episodes are among the most common conditions confused with anaphylaxis. Bradycardia, pale skin, and diaphoresis in an acutely ill patient are suggestive of a vasovagal attack, in contrast to the tachycardic, flushed appearance typical of anaphylaxis.

When it is strongly suspected that the patient is experiencing a severe or potentially severe anaphylactic episode, the following steps should proceed rapidly (Fig. 28.3): (1) assurance of a patent airway, (2) removal of toxin at the site of introduction or an attempt to delay the systemic absorption of toxin or both, (3) establishment of intravenous access for fluid therapy, and (4) initiation of pharmacologic support with epinephrine (Box 28.3). A team approach is essential in severe cases of anaphylaxis because assessment and interventions must proceed rapidly and, if possible, simultaneously.

Box 28.3 Pharmacologic Approach to the Acute Management of Anaphylaxis

Give epinephrine 0.3-0.5 mL of a 1 : 1000 solution intramuscularly with patient in a supine position. An additional dose may be repeated in 5- to 15-min intervals.

If patient remains in shock despite fluids and initial intramuscular epinephrine treatment, then intravenous epinephrine at the rate of 2-10 µg/min should be administered and titrated to effect.

Administer hydrocortisone 100-200 mg intravenously at 4- to 6-hour intervals (for severe cases). Taper rapidly as patient improves.

For Persistent Bronchospasm

Give aminophylline 5-6 mg/kg intravenously loading dose, then 0.4-0.9 mg/kg/min.

Give metaproterenol 0.2-0.3 mL (5% solution) in 2.5 mL normal saline solution administered by nebulization; repeat every 3-4 hours as needed.

Give ipratropium bromide aerosol (2 puffs) inhaled and repeated at 2-hour intervals.

Provide intravenous fluids according to degree of hemoconcentration or, in more severe cases, hemodynamic factors. Normal saline, Ringer’s lactate, 5% human serum albumin. Hydroxyethyl starch should be avoided.

For Hypotension and Shock

For continued hypotension and other signs of circulatory shock start with an epinephrine drip.

• Epinephrine drip at 2-10 µg/min

One of the following vasopressors may added for persistent hypertension:

• Norepinephrine drip 4-8 mg in 1 L normal saline at 4-8 µg/min

• Dopamine drip 200 mg in 0.5 L normal saline at 5-16 µg/kg/min

The following may be given if no contraindications:

• Diphenhydramine 25-50 mg orally or intravenously at 4-hour intervals

Figure 28.3 Overview of the clinical management of severe anaphylaxis.

Admission to the hospital is required for all patients experiencing severe anaphylaxis. Hospital personnel should have advanced airway skills and be capable of managing hemodynamic instability. Although symptom recurrence is uncommon in patients who respond favorably to treatment,⁷⁹ hospital admission and monitoring is recommended for all patients with severe anaphylaxis because of the potential for late-phase reactions, which may be severe and may occur 12 hours after the initial attack. While in the hospital, the patient should be monitored for signs of circulatory shock, respiratory failure, and upper airway obstruction. Blood pressure, urine output, and heart and respiratory rate require frequent evaluation.

The electrocardiogram should be monitored continuously during the acute period because anaphylaxis has been associated with serious arrhythmias and cardiac ischemia. In addition, drugs used to treat anaphylaxis and circulatory shock may precipitate cardiac problems. When signs of circulatory shock and impaired pulmonary gas exchange develop, advanced hemodynamic monitoring is required. As with other types of circulatory shock, fluid therapy, inotropic and vasopressor therapy, and optimization of ventilatory support require titration under hemodynamic guidance to maintain organ perfusion, pulmonary gas exchange, and systemic oxygen delivery.

Close attention to the airway is essential because laryngeal edema is an important cause of morbidity and death. Frequent assessment for hoarseness, stridor, and upper airway obstruction is required for patients whose airways are not protected with an endotracheal tube. The head and neck should be positioned to prevent airway obstruction by the tongue. If inspiratory stridor develops, endotracheal intubation should be attempted. Because intubation may be difficult in the presence of laryngeal edema, skilled personnel capable of performing difficult endotracheal intubations and emergency surgical airways should be available.

If intubated patients are unable to breathe spontaneously or have labored respirations, mechanical ventilation should be initiated. Positive end-expiratory pressure and other advanced ventilatory techniques are often necessary when hypoxemia, pulmonary edema, and decreased pulmonary compliance develop. In nonintubated patients, 6 to 8 L per minute of oxygen through a facemask is recommended.⁸⁰

The site of antigen introduction should be identified. If the patient is unconscious or unaware of the site of antigen introduction, a thorough search of skin surfaces should proceed. Retained stingers from Hymenoptera may be found and require complete and immediate removal. Delaying venomization from an extremity using a constricting band or local application of epinephrine or suctioning venom are controversial practices. However, immobilization is recommended. Thorough washing of the skin should follow exposure to antigen that has contacted the skin surface.

The mainstay of pharmacologic therapy for anaphylaxis is epinephrine. Epinephrine is of proven efficacy in reversing the bronchoconstriction and hypotension associated with anaphylaxis. The β-adrenergic effects of epinephrine inhibit mediator release by increasing intracellular levels of cAMP. In addition, β-adrenergic stimulation reverses bronchospasm, increases myocardial contractility, and increases heart rate. The α-adrenergic vasoconstrictive properties of epinephrine may increase diastolic pressure and enhance coronary flow.

All medical personnel should be aware that two dilutions of epinephrine are commonly available: 1 mg/mL or 1 : 1000 dilution and 0.1 mg/mL or 1 : 10,000 dilution. For the initial treatment of anaphylaxis, most authorities recommend that 0.3 to 0.5 mg of the 1 : 1000 solution (0.3 to 0.5 mL) be given intramuscularly. This dose may be repeated at 5- to 15-minute intervals if symptoms do not improve. In children, the recommended dose is 0.01 mg/kg not to exceed 0.5 mg.

Fluid therapy is an essential component of anaphylaxis treatment. Adults should receive 1 to 2 L of normal saline as soon as possible for severe anaphylaxis. Fluids reverse the intravascular volume deficits typical of anaphylaxis. Both crystalloidal and colloidal fluids are effective. Clinicians should be aware that two to three times as much crystalloid is required compared with colloid to achieve comparable intravascular volume repletion. However, colloid may trigger another anaphylaxis reaction by itself. Reversal of hemoconcentration is a reasonable resuscitative goal for patients who are stable and responding favorably to treatment. In unstable patients with wide fluctuations in vital signs and worsening pulmonary function, fluid therapy should be administered in the ICU with advanced hemodynamic monitoring capability.

If hypotension and other signs of circulatory shock persist after the initial administration of epinephrine and fluids, then intravenous epinephrine is recommended. Bolus doses are no longer recommended because of dosing errors and side effects.⁸¹ The initial dose for intravenous epinephrine infusion is 2 to 10 µg per minute, titrated to effect on blood pressure.⁸² Sometimes patients may need an additional vasopressor along with epinephrine.

Additional Therapeutic Options

Although the role of epinephrine in anaphylaxis is established, the role of antihistamines and corticosteroids continues to be debated.⁸⁰ Nonetheless, corticosteroids should be administered in severe cases of anaphylaxis because there is evidence that they prevent or attenuate late-phase reactions, increase tissue responsiveness to β-agonists, and inhibit the synthesis of histamine. Methylprednisolone or hydrocortisone may be given for 72 hours and can then be rapidly tapered off because almost all the biphasic reactions occur within 72 hours.^83,84

Inhalational drugs may be useful in patients with persistent bronchospasm. Inhalational β-agonists include metaproterenol and albuterol. Ipratropium bromide is an inhalational bronchodilator with anticholinergic properties and may have a favorable effect on mediator release by decreasing cGMP levels. This agent may be used in combination with inhalational β-agonists.

Laryngeal edema, if mild, may respond to nebulized racemic epinephrine. Localized vasoconstriction from the α-adrenergic properties of these drugs minimizes edema formation in the larynx and adjacent areas. Racemic epinephrine may be administered by nebulization (0.5 mL of a 2.25% solution diluted in 3.5 mL distilled water). Intravenous corticosteroid therapy also may be useful in this condition. Severe laryngeal edema associated with respiratory distress or stridor should always be treated with intubation of the trachea.

Several other agents have been used in cases of human anaphylaxis or in laboratory models of anaphylaxis with apparent success. Glucagon, a pancreatic hormone that increases intracellular cAMP levels by activating adenylate cyclase, was effective in a case report of a patient with anaphylaxis who was receiving beta-blocker therapy.85,86 Current research focuses on understanding mast cell and basophil biology, targeting tyrosine kinases, and developing antibodies to IgE.^87,88

Arrangements must be made for patients who have experienced anaphylaxis to receive follow-up care by a physician experienced in the management of acute allergic events. Skin testing may be required to identify the inciting agent. Instructions in self-treatment after antigen exposure are necessary. Autoinjectors of epinephrine 0.15 mg and 0.30 mg (1 : 1000) and oral antihistamines for patients to self-administer are available.