Print|CloseWindow

Note: Large images and tables on this page may necessitate printing in landscape mode. |

Tintinalli's Emergency Medicine>Section 3. Resuscitation>

CHAPTER 27. ANAPHYLAXIS, ACUTE ALLERGIC REACTIONS, AND ANGIOEDEMA ANAPHYLAXIS AND ALLERGIC REACTIONS
Anaphylaxis is a medical emergency that requires immediate diagnosis and treatment. Definitions of anaphylaxis have conflicted over the years, but recent clarity has emerged based on consensus symposia. In simple terms, "anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death." 1,2 More detailed revisions of the definition2 for health professionals using clinical criteria suggest anaphylaxis is highly likely when any one of the three criteria listed in Table 27-1 occurs.1

Table 27-1 Clinical Criteria for Anaphylaxis 1. Acute onset of an illness (minutes to several hours) with involvement of the skin and/or mucosal tissue (e.g., hives/urticaria, pruritus, flushing, swollen lips, tongue, or uvula) associated with at least one of the following: Respiratory compromise (e.g., dyspnea, wheeze, stridor, etc.) or Reduced blood pressure or Associated symptoms of organ dysfunction (e.g., hypotonia, syncope, incontinence, etc.) 2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours): Involvement of the skin and/or mucosal tissue Respiratory compromise Reduced blood pressure or associated symptoms Persistent GI symptoms (e.g., cramps, vomiting) 3. Anaphylaxis should be suspected when patients are exposed to a known allergen and develop hypotension Reproduced with permission from Sampson HA, Munoz-Furlong A, Campbell RL, et al: Second symposium on the definition of anaphylaxis: a summary reportSecond National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin Immunol 117: 391, 2006.

The traditional nomenclature for anaphylaxis reserves the term anaphylactic for immunoglobulin E (IgE)-dependent reactions and the term anaphylactoid for IgE-independent events, which do not require a sensitizing exposure. As the final pathway in classic anaphylactic and anaphylactoid reactions is identical, anaphylaxis is the term now used to refer to both IgE and non-IgE reactions (e.g., IgE-independent, IgG- and immune complex complementmediated).3

Hypersensitivity is an inappropriate immune response to generally harmless antigens. Anaphylaxis represents the most dramatic and severe form of immediate hypersensitivity. Anaphylaxis occurs as part of a clinical continuum. It can begin with relatively minor symptoms and rapidly progress to a life-threatening respiratory and cardiovascular reaction.

Epidemiology
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. A significant number of anaphylaxis cases reported have no identified cause (idiopathic anaphylaxis). -Lactam antibiotics are estimated to cause 400 to 800 deaths in the U.S. annually, with a systemic allergic reaction occurring in 1 per 10,000 exposures.3 Hymenoptera stings constitute the next most common cause of anaphylaxis, with

fewer than 100 deaths in the U.S. annually. 3Table 27-2 contains a partial list of the more common causative agents, but the causes vary geographically and with age. 4 Pediatric surveillance studies have shown food allergy to be a very common cause of anaphylaxis in children.4,5 Latex hypersensitivity is also increasing in prevalence in the general population, with a resultant risk for anaphylaxis.
Table 27-2 Common Causes of Anaphylaxis and Allergic Reactions Drugs -Lactam antibiotics Acetylsalicylic acid Trimethoprim-sulfamethoxazole Vancomycin NSAIDs Virtually any drug Foods and additives Shellfish Soybeans Nuts (peanuts and tree nuts) Wheat Milk Eggs Salicylates Seeds Sulfites Others Hymenoptera stings Insect parts and molds Radiographic contrast material Vaccines Latex

Anaphylaxis caused by diagnostic and therapeutic interventions is almost unavoidable in medical practice and occurs in a variety of clinical scenarios. The lifetime individual risk of anaphylaxis is presumed to be 1% to 3%,6 with a mortality rate of 1%,6 and the prevalence of anaphylaxis may be increasing.7 Therefore, all physicians must be able to recognize anaphylaxis, treat it appropriately, and provide recommendations to prevent future episodes. 8

ED EPIDEMIOLOGY
Over 12 million visits for allergic reactions occurred in the U.S. over a period from 1993 to 2004, representing approximately 1% of all ED visits. 9 Anaphylaxis was reported in only 1% of all cases; however, other estimates range from as high as 5 per 1000 to as low as 2 per 10,000 ED visits. 6,10,11 ED research suggests that emergency physicians underuse the diagnosis of anaphylaxis, which leads to significant underestimation of the prevalence of anaphylaxis. For example, in one study of ED visits for food allergies, 51% were defined by the authors as meeting criteria for anaphylaxis;12 the same authors examined ED presentations of insect allergies and found 31% met thecriteria for anaphylaxis.13 In both cases this was much higher than the codes applied to the charts. The overall occurrence of less severe acute allergic reactions in the ED is obviously much higher than the reported prevalence of anaphylaxis, an incidence of 9.3 per 1000 ED visits.14

Pathophysiology
A better understanding of the pathophysiology of anaphylaxis is beginning to unfold. Studies have highlighted the role of regulation of mast cell activation in the progression to anaphylaxis. Understanding the mechanisms of anaphylaxis offers

potential therapeutic interventions for the prophylactic or emergency treatment of this life-threatening condition. Anaphylaxis, for the most part, is believed to arise from the activation of mast cells and basophils through a mechanism generally understood to involve crosslinking of IgE and aggregation of the high-affinity receptors for IgE. 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 A 2, followed by cyclooxygenases and lipoxygenases, produces arachidonic acid metabolites, including prostaglandins, leukotrienes, and platelet-activating factor. The inflammatory cytokine, tumor necrosis factor- is released as a preformed mediator, and also as a late-phase mediator with other cytokines and chemokines.

Many of these mediators are believed 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- activates neutrophils, recruits other effector cells, and enhances chemokine synthesis. These overlapping and synergistic physiologic effects contribute to the overall pathophysiology of anaphylaxis that variably presents with generalized urticaria and angioedema, bronchospasm, and other respiratory symptoms; hypotension, syncope, and other cardiovascular symptoms; and nausea, cramping, and other GI symptoms. 15

Clinical Features
Anaphylaxis is the most severe life-threatening form of a systemic allergic reaction, often involving respiratory or cardiovascular compromise. The clinical signs of systemic allergic reactions include diffuse urticaria and angioedema. At times, these major symptoms are accompanied by any of the following: abdominal pain or cramping, nausea, vomiting, diarrhea, bronchospasm, rhinorrhea, conjunctivitis, dysrhythmias, and/or hypotension. 6 Even mild, localized urticaria can progress to full anaphylaxis, and even to death.

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. As the cascade progresses, decreased level of consciousness, respiratory distress, and circulatory collapse may ensue. In its severest form, loss of consciousness and cardiorespiratory arrest may result. A complaint of a "lump in the throat" and hoarseness heralds life-threatening laryngeal edema in a patient with symptoms of anaphylaxis. In the vast majority of patients, signs and symptoms begin suddenly, often within 60 minutes of exposure. In general, the faster the onset of symptoms, the more severe the reaction, as evidenced by the fact that one half of anaphylactic fatalities occur within the first hour. After the initial signs and symptoms have abated, patients are at risk for a recurrence of symptoms. The exact incidence of this biphasic phenomenon is unclear, although it has been reported in

3% to 20% of patients.10 The effect is caused by a second phase of mediator release, peaking 4 to 8 hours after the initial exposure and exhibiting itself clinically 3 to 4 hours after the initial clinical manifestations have cleared. The latephase allergic reaction is primarily mediated by the release of newly generated cysteinyl leukotrienes, the former slowreacting substance of anaphylaxis.10

Diagnosis
The diagnosis of anaphylaxis is clinical. Anaphylaxis should be considered when involvement of any two or more body systems is observed, with or without hypotension or airway compromise (e.g., some combination of cutaneous,

respiratory, GI, or cardiovascular systems) (Table 27-3).1,2 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 mimic other presentations (e.g., syncope, gastroenteritis, and anxiety), or anaphylaxis may be a component of other diseases (e.g., asthma). Moreover, often, such as in food allergy, the inciting substance may not be known.
Table 27-3 Clinical Manifestations of Anaphylaxis System Respiratory Signs and Symptoms Rhinitis, pharyngeal edema, laryngeal edema, cough, bronchospasm, dyspnea

Cardiovascular Dysrhythmias, collapse, cardiac arrest Skin GI Eye GU Pruritus, urticaria, angioedema, flushing Nausea, emesis, cramps, diarrhea Pruritus, tearing, redness Urgency, cramps

The differential diagnosis of anaphylactic reactions is extensive, including vasovagal reactions, myocardial ischemia, arrhythmias, status asthmaticus, seizure, epiglottitis, hereditary angioedema, foreign body airway obstruction, carcinoid, mastocytosis, vocal cord dysfunction, and nonIgE-mediated drug reactions.6 The most common anaphylaxis imitator is a vasovagal reaction, which is characterized by hypotension, pallor, bradycardia, diaphoresis, and weakness, and sometimes by syncope.

Because the diagnosis of anaphylaxis is made clinically, laboratory investigations have a limited role to play. Histamine levels, elevated for 5 to 30 minutes postreaction, are unhelpful because they decline by presentation to the ED. 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,6 but these tests are rarely useful or collected in clinical emergency practice.

Treatment
EMERGENCY TREATMENT
Given the possible development of life-threatening complications, all acute allergic reactions require triage at the highest level of urgency. Anaphylaxis, as defined by airway compromise or hypotension, is obviously a true medical emergency and must be rapidly assessed and treated. With suspected anaphylaxis, the single most important step in treatment is the rapid administration of epinephrine. Moreover, with this rapid administration, many of the secondary measures discussed below may not be necessary.

FIRST-LINE THERAPY
Most treatment guidelines derive from expert panels and consensus statements. Emergency management starts with the ABCs (airway, breathing, circulation) of resuscitation. The first-line therapies for anaphylaxis (e.g., epinephrine, IV fluids, and oxygen) have immediate effect during the acute stage of anaphylaxis. Vital signs, IV access, oxygen administration, cardiac monitoring, and pulse oximetry measurements should be initiated immediately.

Airway and Oxygenation

Securing the airway is the first priority. The airway should be examined for signs and symptoms of angioedema (e.g., uvula edema or hydrops, audible stridor, respiratory distress, hypoxia). If angioedema is producing respiratory distress, intubation should be completed early, as delay may result in complete airway obstruction secondary to progression of angioedema. The patient should be given sufficient oxygen to maintain arterial oxygen saturation >90%.

Decontamination
Terminate exposure to the causative agent if it can be identified. However, gastric lavage is not recommended for foodborne allergens. In insect stings, as the stinger continues to inject venom even if it is detached from the insect, remove any stinging remnants (see Chapter 205, Bites and Stings). 16

Epinephrine
Epinephrine is a mixed 1- and 2-receptor agent. The 1-receptor activation reduces mucosal edema and membrane leakage and treats hypotension, whereas the 2-receptor activation provides bronchodilation and controls mediator

release.17 Most consensus guidelines for the past 30 years agree that epinephrine is the drug of choice and the first drug that should be administered in acute anaphylaxis, but research indicates that it is underused in anaphylaxis.9,12,13,17,18 ED studies suggest that for food allergies,12 insect stings,13 and all allergic reactions9 the use of epinephrine is lower than second-line therapies such as corticosteroids and antihistamines. Moreover, the 12-year trend in the U.S. shows a statistically significant decline in epinephrine use and use in only 50% of the cases defined as

anaphylaxis.9 Finally, epinephrine is often dosed suboptimally to treat anaphylaxis and is underprescribed for potential future self-administration. Experts believe that most of the reasons proposed to withhold its clinical use are flawed and that the therapeutic benefits of epinephrine exceed the risk when given in appropriate (e.g., IM) doses. 8 These results are concerning and suggest that the controversy surrounding its use must be clarified.

In patients without signs of cardiovascular compromise or collapse, IM epinephrine can be administered. 19 The dose is epinephrine, 0.3 to 0.5 milligram (0.3 to 0.5 mL of the 1:1000 dilution) IM repeated every 5 to 10 minutes according to response or relapse. For convenience, patient safety, 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., Napa, CA). The most recent United Kingdom guideline

recommends a higher starting dose than others, 20 but the evidence for this decision is unclear. Most patients do not need more than a single dose. IM dosing provides higher, more consistent, and more rapid peak blood epinephrine levels than SC administration, and should now be the treatment of choice for adults and children. 2,19,21 Injections into the thigh are more effective at achieving peak blood levels than are injections into the deltoid area. 19 Caution is warranted in patients taking -blockers, because epinephrine use may result in severe hypertension secondary to unopposed adrenergic stimulation.

If the patient is refractory to treatment despite repeated IM epinephrine, or with signs of cardiovascular compromise or collapse, then institute an IV infusion of epinephrine. Initially, epinephrine, 100 micrograms (0.1 milligram) IV, should be given as a 1:100,000 dilution. This can be done by placing epinephrine, 0.1 milligram (0.1 mL of the 1:1000 dilution), in 10 mL of normal saline (NS) solution and infusing it over 5 to 10 minutes (a rate of

1 to 2 mL/min).3 If the patient is refractory to the initial bolus, then an epinephrine infusion can be started by placing epinephrine, 1 milligram (1.0 mL of the 1:1000 dilution), in 500 mL of 5% dextrose in water or NS and administering at a rate of 1 to 4 micrograms/min (0.5 to 2 mL/min), titrating to effect. Physicians are often hesitant to give IV epinephrine because of its side effects (e.g., tachycardia, arrhythmia, tremor). 22 It should be stressed that the initial adult dose is very dilute, is given over 5 to 10 minutes, and can be stopped immediately if arrhythmias or chest pain occur.

Crystalloids
If hypotension is present, it is generally the result of distributive shock and responds to fluid resuscitation. Patients should receive an NS bolus of 1 to 2 L (10 to 20 mL/kg in children) concurrently with the epinephrine infusion. There is no evidence that albumin or hypertonic saline should replace NS at this time.

SECOND-LINE THERAPY
The second-line anaphylaxis treatments include corticosteroids, antihistamines, asthma medications, and glucagon. 6 These drugs are used to treat anaphylaxis refractory to the first-line treatments or associated with complications, and also to prevent recurrences.

Corticosteroids
All patients with anaphylaxis should receive corticosteroids. Methylprednisolone, 80 to 125 milligrams IV (2 milligrams/kg in children; up to 125 milligrams), or hydrocortisone, 250 to 500 milligrams IV (5 to 10 milligrams/kg in children; up to 500 milligrams), are equally appropriate. Methylprednisolone produces less fluid retention than hydrocortisone and is preferred for elderly patients and for those patients in whom fluid retention would be problematic (e.g., renal and cardiac impairment).

Antihistamines
All patients with anaphylaxis should receive a histamine-1 blocker, such as diphenhydramine, 25 to 50 milligrams IV. 3,23 Because the histamine-2 blockers are effective in shock refractory to epinephrine, fluids, steroids, and histamine-1 blockers, it is recommended that histamine-2 blockers, such as ranitidine or cimetidine, be given as well. 3,23 Cimetidine should not be used for patients who are elderly (side effects), have multiple comorbidities (interference with metabolism of many drugs), have renal or hepatic impairment, or whose anaphylaxis is complicated by -blocker use (prolongs metabolism of -blockers and may prolong anaphylactic state). After the initial IV dose of steroids and antihistamines, the patient may be switched to oral medication (Table 27-4).
Table 27-4 Drug Treatment of Anaphylaxis and Allergic Reactions

Drug

Adult Dose

Pediatric Dose

First-Line Therapy Epinephrine IM: 0.30.5 milligram (0.30.5 mL of 1:1000

IM: 0.01 milligram/kg (0.01 mL/kg of 1:1000 dilution)

dilution); or EpiPen 0.3 milligram epinephrine (or or EpiPen Junior 0.15 milligram of epinephrine (or equivalent preformulated product) equivalent preformulated product) IV single dose: 10 micrograms over 510 min; 1:100,000 dilution given as 0.1 milligram in 10 mL at 1 mL/min IV infusion: 14 micrograms/min Titrate to SaO2 90% 12 L bolus IV infusion: 0.10.3 microgram/kg/min; maximum, 1.5 micrograms/kg/min Titrate to SaO2 90% 1015 mL/kg bolus

Oxygen IV fluids: NS or LR

Second-Line Therapy H1 Blockers Diphenhydramine H2 Blockers Ranitidine Cimetidine Corticosteroids Hydrocortisone 250500 milligrams IV 510 milligrams/kg IV (maximum, 500 milligrams) 12 milligrams/kg IV (maximum, 125 milligrams) 12 milligrams/d PO divided twice a day or daily 50 milligrams IV over 5 min 300 milligrams IV 0.5 milligram/kg IV over 5 min 48 milligrams/kg IV 2550 milligrams every 6 h IV, IM, or PO 1 milligram/kg every 6 h IV, IM, or PO

Methylprednisolone 80125 milligrams IV Prednisone 4060 milligrams/day PO divided twice a day or daily

To be used after initial IV dose (for outpatients: 3 To be used after initial IV dose (for outpatients: 35 d; 5 d; tapering not required) tapering not required)

Treatment of Bronchospasm, Add: Albuterol Ipratropium bromide Magnesium sulfate Single treatment: 2.55.0 milligrams nebulized (0.51.0 mL of 0.5% solution) 46 puffs with holding chamber Both repeated every 20 min as needed Continuous nebulization: 510 milligrams/h Single treatment: 250500 micrograms nebulized 46 puffs with holding chamber Both repeated every 20 min as needed 2 grams IV over 20 min Single treatment: 1.252.5 milligrams nebulized (0.25 0.5 mL of 0.5% solution) 46 puffs with holding chamber repeated every 20 min Both repeated every 20 min as needed Continuous nebulization: 35 milligrams/h Single treatment: 125250 micrograms nebulized 46 puffs with holding chamber Both repeated every 20 min as needed 2550 milligrams/kg IV over 20 min

Treatment for Patients on Glucagon

-Blockers with Refractory Hypotension, Add: 50 micrograms/kg IV every 5 min

1 milligram IV every 5 min until hypotension resolves, followed by 515 micrograms/min infusion

Abbreviations: H1 = histamine-1; H2 = histamine-2; LR = lactated Ringer's; NS = normal saline; SaO2 = arterial oxygen saturation.

Agents for Allergic Bronchospasm

If wheezing is present, a selective bronchodilator, such as intermittent or continuous nebulized albuterol/salbutamol, should be instituted. As might be expected, asthmatics are often more refractory to the treatment of allergic

bronchospasm. For severe bronchospasm refractory to the above-mentioned treatments, other treatments, such as

anticholinergics24 and magnesium sulfate, can be added.25 Anticholinergic agents should be added to the nebulized albuterol (ipratropium bromide, 250 to 500 micrograms/dose) in severe acute bronchospasm. Magnesium sulfate

improves pulmonary function and reduces admissions when administered in severe acute asthma. 25 It is inexpensive and free of major side effects when used in single doses of magnesium sulfate, 2 grams IV over 20 to 30 minutes in adults and 25 to 50 milligrams/kg in children. Bronchodilator and stimulant agents should be used with caution (lower dose and slower rate) in elderly patients. IV aminophylline and -agonists are not recommended for the early management of acute bronchospasm because their benefits are marginal, as compared to other agents, and their sideeffect profiles are impressive. There are no data yet to recommend the administration of leukotriene receptor antagonists in the treatment of anaphylaxis.

Glucagon
Concurrent use of -blocking drugs by the patient is a risk factor for severe prolonged anaphylaxis. In one study, three of five patients who had severe protracted reactions were being treated with -blocking drugs.3 For patients taking blockers with hypotension refractory to fluids and epinephrine, glucagon should be used in a dose of 1 milligram IV every 5 minutes until hypotension resolves, followed by an infusion of 5 to 15 micrograms/min. The side effects of glucagon include nausea, vomiting, hypokalemia, dizziness, and hyperglycemia.

Disposition and Follow-Up

ADMISSION/DISCHARGE
Admission to hospital is rare and in the largest study of allergic reactions treated in the ED, admission occurred in only 4% of cases.9 All unstable patients with anaphylaxis refractory to treatment or where airway interventions were required should be admitted to the intensive care unit. Patients who receive epinephrine should be observed in the ED, but the duration of observation is based on experience rather than clear evidence. Observation for at least several hours after the end of treatment appears routine. If patients remain symptom free after appropriate treatment following 4 hours of

observation, the patient can be safely discharged home. 10 Estimates on the occurrence of late recurrence reactions vary, yet they are thought to be rare. However, prolonged observation periods should be considered in patients with a past history of severe reaction and those using -blockers. Other factors to consider in discharge planning include distance from medical care, whether the patient lives alone, significant comorbidity (including but not limited to asthma), and age.3

OUTPATIENT CARE AND PREVENTION

Emergency physicians should provide discharge plans for patients that reduce the chance of recurrence and reduce the frequency and severity of future episodes (Table 27-5). For all allergic reactions, the patient should be instructed on how to avoid future exposure to the causative agent if known and possible; however, in one ED-based study of food allergies this was completed only 49% of the time. 12 A prescription and clear instructions on the use of an epinephrine autoinjector should be provided to patients with serious allergic reactions or anaphylaxis when the risk of another reaction is judged to be substantial. If delay in filling a prescription is anticipated, patients can be discharged from the ED with an epinephrine autoinjector (EpiPen ). In ED-based studies of food12 and insect13 allergies, autoinjector prescriptions were infrequently documented (16% and 27%, respectively). Given the unpredictability of allergic occurrences, prescriptions should include sufficient samples for multiple locations (e.g., home, vehicle, work), and patients should be advised to carry epinephrine with them at all times.
Table 27-5 Discharge Planning for Patients with Anaphylaxis Education Identification of inciting allergen, if possible Instructions on avoiding future exposure Instructions on use of medications and epinephrine autoinjector Advise about personal identification/allergy alert tag Medications Diphenhydramine, 2550 milligrams PO for several days

Prednisone, 4060 milligrams PO for several days Epinephrine autoinjector for future reactions Referral to allergist

All patients with severe or frequent allergic reactions warrant referral to an allergist for in-depth preventive management and attempts at allergen identification. However, ED-based studies of food12 and insect13 allergies indicate that allergist referral is uncommon (12% and 20%, respectively). Patients with anaphylactic reactions should be offered educational options [e.g., Web sites (see useful Web links summary on the DVD)], advice on advocacy groups, and education regarding food contamination for food allergies, and encouraged to wear personal identification of this condition (e.g., MedicAlert bracelets). Any anaphylactic patient taking a -blocker should be switched to another antihypertensive drug.

Treatment in the outpatient setting should include antihistamines and a short course of corticosteroids, although the evidence for this is weak. Prolonged corticosteroid treatment should not be required for most patients, but an aggressive longer-term approach does reduce the frequency of relapses in patients with idiopathic anaphylaxis.26 The evidence to treat less-severe allergic reactions with corticosteroids is lacking. All patients should be provided with a patient information sheet detailing signs and symptoms to watch for and clear instructions for follow-up and immediate return if there is any recurrence of symptoms. Finally, a written action plan on steps to take in the event of future allergen exposure or symptom development may reduce the severity of future attacks.

URTICARIA AND ANGIOEDEMA

Urticaria, or hives, is a cutaneous reaction marked by the development of pruritic, erythremic wheals of varying size that generally are described as "fleeting." Erythema multiforme is a more pronounced variation of urticaria, characterized by typical target skin lesions. Angioedema is believed to be a similar but deeper reaction characterized by edema formation in the dermis, most generally involving the face and neck, and distal extremities. These manifestations may accompany many allergic reactions, but also may be nonallergic in nature. As with all allergic manifestations, obtain a detailed history. If an etiologic agent can be identified, future reactions may be avoided, although many acute urticarial reactions are viral in nature. This is especially true in children, or with any hives persisting or recurring for more than 24 hours.

Urticaria
Treatment of urticarial reactions is generally supportive and symptomatic, with attempts to identify and remove the offending agent. Antihistamines, with or without corticosteroids, are usually sufficient, although epinephrine can be considered in severe or refractory cases. The addition of a histamine-2 receptor blocker, such as ranitidine, may also be useful in more severe, chronic, or unresponsive cases. Cold compresses may be soothing to affected areas. Referral to an allergy specialist is again indicated in severe, recurrent, or refractory cases.

Angioedema
Angioedema of the tongue, lips, and face has the potential for airway obstruction. Angioedema is caused by a variety of agents, but use of an angiotensin-converting enzyme (ACE) inhibitor is a common trigger, with angioedema occurring in 0.1% to 0.7% of patients taking ACE inhibitors. Fortunately, most cases are mild and transient. Management is

supportive, with special attention to the airway, which can become occluded rapidly and unpredictably. 27 Typical allergic reaction drugs, such as antihistamines and corticosteroids, are not beneficial because ACE-inhibitor angioedema is not associated with an increase in IgE. Epinephrine, antihistamines, and steroids are often still used, but benefits have not been clearly demonstrated. Immediate withdrawal from the ACE inhibitor is indicated, and another antihypertensive should be prescribed with the important exception that angiotensin II receptorblocking agents should not be used. Patients with mild swelling and no evidence of airway obstruction can be observed in the ED and discharged if swelling diminishes. Rebound or recurrent swelling will not occur unless the patient takes an ACE inhibitor again. Patients with moderate to severe swelling, dysphagia, or respiratory distress are best admitted for close observation. Hereditary angioedema is an autosomal dominant disorder with a characteristic complement pathway defect: low levels of C1 esterase inhibitor or elevated levels of dysfunctional C1 esterase inhibitor with low levels of C4 between acute attacks.28 Reactions often involve the upper respiratory tract and GI tract. Attacks can last from a few hours to 1 to 2

days. Minor trauma often precipitates a reaction. Many of the typical treatments for allergic reactions, such as epinephrine, steroids, and antihistamines, are ineffective. Prophylaxis of acute attacks may be possible with attenuated androgens, such as stanozolol, 2 milligrams/d, or danazol, 200 milligrams/d. Acute attacks can be shortened by C1 esterase inhibitor replacement by a concentrate. Successful treatment with fresh frozen plasma has also been reported and may be tried if C1 esterase inhibitor is not available. 29 Treatment of patients is complex and best done in coordination with the appropriate specialist.

OTHER COMMON ALLERGIC PROBLEMS Food Allergy Reactions

Hypersensitivity reactions to ingested foods are generally caused by IgE-mediated reactions to food proteins and, rarely, by additives. Their frequency is rising for unknown reasons. 30 IgE-coated mast cells lining the GI tract react to allergens in ingested foods and produce clinical findings associated with the release of biologic mediators. NonIgE-mediated food allergy reactions have also been described. Dairy products, eggs, nuts, and shellfish are some of the most commonly implicated foods. A detailed dietary history within the 24 hours of allergic symptoms may provide the best clues to food allergy, with particular attention to other allergic history and prior reactions. Diagnosis is often difficult, however, and it may require multiple episodes before an offending agent is identified. Symptoms of food allergy include swelling and itching of the lips, mouth, and pharynx; nausea; abdominal cramps; vomiting; and diarrhea. Cutaneous manifestations, such as angioedema and urticaria, as well as anaphylaxis, can occur. Treatment for mild reactions is supportive, with the administration of antihistamines to lessen symptoms. More severe reactions or anaphylaxis are managed as described above in Treatment.

Insect Sting Allergic Reactions

Insect stings can produce significant, and sometimes fatal, reactions, particularly in sensitized patients. True stinging insects belong to the order Hymenoptera, which includes three families: Apidae (honeybees), Formicidae (fire ants), and Vespidae (wasps, yellow jackets, and hornets) (see Chapter 205, Bites and Stings). The venoms of each family are unique, although all have similar types of components, mostly proteins. This difference accounts for the limited crossreactivity seen between the insect families, although cross-reactivity among the vespids is common. The normal, toxinmediated reaction to these stings includes localized pain, pruritus, swelling, and redness. Often this is confused with cellulitis. Sensitized individuals may have exaggerated local reactions with or without systemic manifestations. Systemic reactions run from mild to angioedema or anaphylaxis. Diagnosis depends on clinical history, with particular attention to past reactions, and an examination to locate the site of the sting. Treatment is symptomatic and supportive. Mild local reactions can be managed with application of ice and oral antihistamines. More generalized reactions or local reactions of the head and neck may benefit from a short course of corticosteroids. Severe reactions are managed as previously described. Patients with severe reactions should be advised to carry self-administered epinephrine and antihistamines.

Allergic Drug Reactions

Although adverse reactions to drugs are a common clinical problem, true hypersensitivity reactions probably account for less than 10% of these problems.31 Because most drugs are small organic molecules, they are generally unable to stimulate an immune response alone. However, when a drug or metabolite becomes protein-bound, either in serum or on cell surfaces, the drugprotein complex can become an allergen and stimulate immune system responses. Thus, the ability of a drug or its metabolites to sensitize the immune system depends on the ability to bind to tissue proteins.

Penicillin is the drug most commonly implicated in eliciting true allergic reactions and accounts for approximately 90% of all allergic drug reactions. Of those patients with fatal anaphylactic drug reactions, approximately 75% reacted to penicillin.32 Overall, fewer than 25% of patients who die of penicillin anaphylaxis exhibited allergic reactions during previous treatment with the drug. Parenteral penicillin administration is more than twice as likely to produce fatal allergic reactions as is oral administration. The cross-reactivity of penicillin allergy with cephalosporins is about 7%. Patients with a previous life-threatening or anaphylactic reaction to penicillin should not be given cephalosporins.33

The clinical manifestations of drug allergy vary widely. A generalized reaction similar to immune-complex or serum sickness reactions is very common, especially with common agents like trimethoprim-sulfamethoxazole and certain cephalosporins (cefaclor being the most frequent). Although data are conflicting on the cross-reactivity of sulfonamide antibiotics with other sulfa-containing compounds, it is best to avoid the latter in patients with allergy to sulfonamide antibiotics (Table 27-6).34 Serum sickness usually begins in the first or second week after the administration of the drug and can take many weeks to subside after drug withdrawal. Generalized malaise, arthralgias, arthritis, pruritus, urticarial eruptions, fever, adenopathy, and hepatosplenomegaly are common signs and symptoms. Drug fever may occur without other associated clinical findings and may also occur without an immunologic basis. Circulating immune complexes are probably responsible for the lupus-like reactions caused by some drugs. Cytotoxic reactions, such as penicillin-induced hemolytic anemia, can occur. Skin eruptions include erythema, pruritus, urticaria, angioedema, erythema multiforme, and photosensitivity. Severe reactions, such as those seen in Stevens-Johnson syndrome and toxic epidermal necrolysis, may also occur. Pulmonary complications, including bronchospasm and airway obstruction, can occur.
Table 27-6 Some Products Containing Sulfonamides Trimethoprim-sulfamethoxazole Furosemide Glipizide Thiazides Diazoxide Silver sulfadiazine Mafenide acetate Bumetanide Celecoxib

Delayed hypersensitivity reactions may be manifested as a contact dermatitis from drugs applied topically. Diagnosis is best determined by a careful and thorough history. Treatment is supportive, with oral or parenteral antihistamines and corticosteroids, as discussed above. Immediate drug withdrawal is important, but reactions can continue or recur after a period of abstinence. Referral to an allergy specialist is indicated.

PRACTICE GUIDELINES
There are currently a variety of clinical practice guidelines for the diagnosis and treatment of anaphylaxis and allergic reactions in the ED. These have been reviewed and found to vary with respect to recommendations and adherence to standard criteria for guideline development. 18 The most recent and comprehensive guideline is the revised UK guideline.20

ACKNOWLEDGMENT
The authors gratefully acknowledge the contributions of Stuart Carr, the coauthor of this chapter in the previous edition.

REFERENCES
1. Sampson HA, Munoz-Furlong A, Campbell RL, et al: Second symposium on the definition of anaphylaxis: a summary reportSecond National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin Immunol 117: 391, 2006.[PMID: 16461139] 2. Sampson HA, Munoz-Furlong A, Bock SA, et al: Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol 110: 584, 2005. 3. Johansson SGO, Bieber T, Dahl R, et al: Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the WAO, October 2003. J Allergy Clin Immunol 113: 832, 2004.[PMID: 15131563] 4. Alves B, Sheikh A: Age specific aetiology of anaphylaxis. Arch Dis Child 85: 348, 2001.[PMID: 11572233] 5. Simons FE, Chad ZH, Gold M: Real-time reporting of anaphylaxis in infants, children and adolescents by physicians involved in the Canadian Pediatric Surveillance Program. J Allergy Clin Immunol 109: s181, 2002.

6. Kemp SF, Lockey RF: Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 110:341, 2002. [PMID: 12209078] 7. Gupta R, Sheikh A, Strachan DP, Anderson HR: Time trends in allergic disorders in the UK. Thorax 62: 91, 2007. [PMID: 16950836] 8. Kemp SF, Lockey RF, Simmons FER, on behalf of the World Allergy Organization Ad Hoc Committee on Epinephrine in Anaphylaxis: Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization. Allergy 63: 1061, 2008.[PMID: 18691308] 9. Gaeta TJ, Clark S, Pelletier AJ, Camargo CA Jr.: National study of US emergency department visits for acute allergic reactions, 1993 to 2004. Ann Allergy Asthma Immunol 98: 360, 2007.[PMID: 17458433] 10. Brady WJ, Luber S, Carter T, et al: Multiphasic anaphylaxis: an uncommon event in the emergency department. Acad Emerg Med 4: 193, 1997.[PMID: 9063545] 11. Stewart AG, Ewan PW: The incidence, aetiology and management of anaphylaxis presenting to an accident and emergency department. QJM 89: 859, 1996.[PMID: 8977966] 12. Clark S, Bock SA, Gaeta TJ, et al: Multicenter study of emergency department visits for food allergies. J Allergy Clin Immunol 113: 347, 2004.[PMID: 14767453] 13. Clark S, Long AA, Gaeta TJ, Camargo CA Jr.: Multicenter study of emergency department visits for insect sting allergies. J Allergy Clin Immunol 116: 643, 2005.[PMID: 16159637] 14. Braganza SC, Acworth JP, McKinnon DRL, et al: Paediatric emergency department anaphylaxis: different patterns from adults. Arch Dis Child 91: 159, 2006.[PMID: 16308410] 15. Peavy RD, Metcalfe DD: Understanding the mechanism of anaphylaxis. Curr Opin Allergy Clin Immunol 8: 310, 2008. [PMID: 18596587] 16. Laskowski-Jones L: First aid for bee, wasp, and hornet stings. Nursing 37: 58, 2006. 17. Simons FER: Emergency treatment of anaphylaxis. BMJ 336: 1141, 2008.[PMID: 18497373] 18. Alrasbi M, Sheikh A: Comparison of international guidelines for the emergency medical management of anaphylaxis. Allergy 62:838, 2007.[PMID: 17620061] 19. Simons FER, Gu X, Simons KJ: Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol 108: 871, 2001.[PMID: 11692118] 20. Emergency treatment of anaphylactic reactions. Guidelines for healthcare providers. Working Group of the Resuscitation Council (UK), 2008. Available at: http://www.resus.org.uk/pages/reaction.pdf. Accessed April 20, 2009. 21. Simons FE, Roberts JR, Gu X, Simons KJ: Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 110: 33, 1998. 22. Putland M, Kerr D, Kelly AM: Adverse events associated with the use of intravenous epinephrine in emergency department patients presenting with severe asthma. Ann Emerg Med 47:559, 2006.[PMID: 16713785] 23. Winbery SL, Lieberman PL: Histamine and antihistamines in anaphylaxis. Clin Allergy Immunol 17: 287, 2002. [PMID: 12113221] 24. Plotnick LH, Ducharme FM: Should inhaled anticholinergics be added to beta2 agonists for treating acute childhood and adolescent asthma? A systematic review. BMJ 317: 971, 1998.[PMID: 9765164] 25. Rowe BH, Bretzlaff JA, Bourdon C, et al: Intravenous magnesium sulfate treatment for acute asthma in the emergency department: a systematic review of the literature. Ann Emerg Med 36: 181, 2000.[PMID: 10969218] 26. Ring J, Darsow U: Idiopathic anaphylaxis. Curr Allergy Asthma Rep 2: 40, 2002.[PMID: 11895624] 27. Chiu AG, Newkirk KA, Davidson BJ, et al: Angiotensin-converting enzyme inhibitor-induced angioedema: a multicenter review and an algorithm for airway management. Ann Otol Rhinol Laryngol 110: 834, 2001.[PMID: 11558759] 28. Ebo DG, Stevens WJ: Hereditary angioneurotic edema: a review of the literature. Acta Clin Belg 55: 22, 2000.[PMID:

10783504] 29. Pekdemir M, Ersel M, Aksay E, et al: Effective treatment of hereditary angioedema with fresh frozen plasma in an emergency department. J Emerg Med 33: 137, 2007.[PMID: 17692764] 30. O'Leary PF, Shanahan F: Food allergies. Curr Gastroenterol Rep 4: 373, 2002.[PMID: 12228039] 31. Babu KS, Belgi G: Management of cutaneous drug reactions. Curr Allergy Asthma Rep 2: 26, 2002.[PMID: 11895622] 32. Lieberman P, Camargo CA, Jr., Bohlke K, et al: Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol 97:596, 2006.[PMID: 17165265] 33. Kelkar PS, Li JT: Cephalosporin allergy. N Engl J Med 345: 808, 2001. 34. Wilholm BE: Identification of sulfonamide-like adverse drug reactions to celecoxib in the World Health Organization database. Curr Med Res Opin 17: 210, 2001.

Useful Web Resources

The Food Allergy & Anaphylaxis Network (FAAN)http://www.foodallergy.org Anaphylaxis Canadahttp://www.anaphylaxis.org/ EMNet: Anaphylaxishttp://www.emnet-usa.org/search_main.cfm?terms=anaphylaxis&submit=&x=19&y=9 MedicAlert U.S.www.medicalert.org
Copyright The McGraw-Hill Companies. All rights reserved. Privacy Notice. Any use is subject to the Terms of Use and Notice.