eMedicine - Anaphylaxis _ Article by Richard S Krause, MD

eMedicine - Anaphylaxis : Article by Richard S Krause, MD

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AnaphylaxisLast Updated: June 13, 2006

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Synonyms and related keywords: allergy, allergic reaction, severe allergic reaction,immunologic reaction, anaphylactoid reaction, urticaria, angioedema, anaphylactic shock,anaphylatoxin, aggregate anaphylaxis, antibodies, antibody, antigen, hypersensitivity,immunoglobulin E, IgE, bee sting, hives, hypotension, bronchospasm, penicillin allergy,cephalosporin allergy, IV contrast materials, Hymenoptera stings, erythema, pruritus, sensation oftightness in throat, conjunctival injection, dizziness, syncope, myocardial ischemia, cardiovascularcollapse, respiratory arrest, shock, stridor, complete airway obstruction, wheezing, edema oftongue, edema of lips, intravenous radiocontrast media, shellfish allergy, iodine allergy, foodallergy, peanut allergy, latex allergy, Foley catheter insertion

AUTHOR INFORMATION Section 1 of 10

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Author: Richard S Krause, MD, Clinical Assistant Professor, Residency ProgramDirector, Department of Emergency Medicine, State University of New York atBuffalo School of Medicine

Richard S Krause, MD, is a member of the following medical societies: AlphaOmega Alpha, American Academy of Emergency Medicine, American College ofEmergency Physicians, and Society for Academic Emergency Medicine

Editor(s): Roy Alson, MD, PhD, FACEP, FAAEM, Associate Medical Director,North Carolina Baptist AirCare; Associate Professor, Department of EmergencyMedicine, Wake Forest University School of Medicine; Francisco Talavera,PharmD, PhD, Senior Pharmacy Editor, eMedicine; Matthew M Rice, MD, JD,Vice President, Chief Medical Officer, Northwest Emergency Physicians,Assistant Clinical Professor of Medicine, University of Washington at Seattle;Assistant Clinical Professor, Uniformed Services University of Health Sciences;John Halamka, MD, Chief Information Officer, CareGroup Healthcare System,Assistant Professor of Medicine, Department of Emergency Medicine, Beth IsraelDeaconess Medical Center; Assistant Professor of Medicine, Harvard MedicalSchool; and Jonathan Adler, MD, Attending Physician, Department ofEmergency Medicine, Massachusetts General Hospital; Division of EmergencyMedicine, Harvard Medical School

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INTRODUCTION Section 2 of 10


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Background: Anaphylaxis refers to a severe allergic reaction in which prominentdermal and systemic signs and symptoms manifest. The full-blown syndromeincludes urticaria (hives) and/or angioedema with hypotension and bronchospasm.The classic form, described in 1902, involves prior sensitization to an allergen withlater re-exposure, producing symptoms via an immunologic mechanism. Ananaphylactoid reaction produces a very similar clinical syndrome but is notimmune-mediated. Treatment for both conditions is similar, and this article usesthe term anaphylaxis to refer to both conditions unless otherwise specified.

Pathophysiology: Rapid onset of increased secretion from mucous membranes,increased bronchial smooth muscle tone, decreased vascular smooth muscletone, and increased capillary permeability occur after exposure to an incitingsubstance. These effects are produced by the release of mediators, which includehistamine, leukotriene C4, prostaglandin D2, and tryptase.

In the classic form, mediator release occurs when the antigen (allergen) binds toantigen-specific immunoglobulin E (IgE) attached to previously sensitizedbasophils and mast cells. The mediators are released almost immediately whenthe antigen binds. In an anaphylactoid reaction, exposure to an inciting substancecauses direct release of mediators, a process that is not mediated by IgE.Increased mucous secretion and increased bronchial smooth muscle tone, as wellas airway edema, contribute to the respiratory symptoms observed in anaphylaxis.Cardiovascular effects result from decreased vascular tone and capillary leakage.Histamine release in skin causes urticarial skin lesions.

The most common inciting agents in anaphylaxis are parenteral antibiotics(especially penicillins), IV contrast materials, Hymenoptera stings, and certainfoods (most notably, peanuts). Oral medications and many other types ofexposures also have been implicated. Anaphylaxis also may be idiopathic.

Frequency:

In the US: The true incidence of anaphylaxis is unknown, partly because ofthe lack of a precise definition of the syndrome. Some clinicians reserve theterm for the full-blown syndrome, while others use it to describe mildercases. Fatal anaphylaxis is relatively rare; milder forms occur much morefrequently. Some authors consider up to 15% of the US population "at risk"for anaphylaxis. The frequency of anaphylaxis is increasing and this hasbeen attributed to the increased number of potential allergens to whichpeople are exposed. Up to 500-1,000 fatal cases of anaphylaxis per year areestimated to occur in the US.

Internationally: Reactions to insects and other venomous plants andanimals are more prevalent in tropical areas because of the greaterbiodiversity in these areas.

Mortality/Morbidity: Approximately 1 in 5000 exposures to a parenteral dose of apenicillin or cephalosporin antibiotic causes anaphylaxis. More than 100 deathsper year are reported in the United States. Fewer than 100 fatal reactions toHymenoptera stings are reported each year in the United States but this isconsidered to be an underestimate. One to 2% of people receiving IV radiocontrastexperience some sort of reaction. The majority of these reactions are minor, andfatalities are rare. Low molecular weight contrast causes fewer and less severereactions.

Race: Well-described racial differences in the incidence or severity of anaphylaxisdo not exist. Cultural and socioeconomic differences may influence exposurerates.

Embolism

Toxicity,Scombroid

Urticaria

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Patient Education

Allergy Center

Allergic Reactionand AnaphylacticShock Center

Severe AllergicReactionOverview

Severe AllergicReaction Causes

Severe AllergicReactionSymptoms

Severe AllergicReactionTreatment



Sex: No major differences have been reported in the incidence and prevalence ofanaphylactic reactions between men and women.

Age: Anaphylaxis occurs in all age groups. While prior exposure is essential forthe development of true anaphylaxis, reactions occur even when no documentedprior exposure exists. Thus, patients may react to a first exposure to an antibioticor insect sting. Adults are exposed to more potential allergens than are pediatricpatients. The elderly have the greatest risk of mortality from anaphylaxis due to thepresence of preexisting disease.

CLINICAL Section 3 of 10


History:

Anaphylactic reactions almost always involve the skin or mucousmembranes. More than 90% of patients have some combination of urticaria,erythema, pruritus, or angioedema.

The upper respiratory tract commonly is involved, with complaints of nasalcongestion, sneezing, or coryza. Cough, hoarseness, or a sensation oftightness in the throat may presage significant airway obstruction.

Eyes may itch and tearing may be noted. Conjunctival injection may occur.

Dyspnea is present when patients have bronchospasm or upper airwayedema. Hypoxia and hypotension may cause weakness, dizziness, orsyncope. Chest pain may occur due to bronchospasm or myocardialischemia (secondary to hypotension and hypoxia).

GI symptoms of cramplike abdominal pain with nausea, vomiting, or diarrheaalso occur but are less common, except in the case of food allergy.

In a classic case of anaphylaxis, the patient or a bystander provides a historyof possible exposures that may have caused the rapid onset of skin andother manifestations. This history often is partial; exposure may not berecalled, or it may not be considered significant by the patient or physician.For example, when queried about medications, a patient may not mentionover-the-counter (OTC) products. The clinician may not realize that, whilereactions are usually rapid in onset, they also may be delayed.

Physical:

General

Physical examination of patients with anaphylaxis depends on affectedorgan systems and severity of attack. Vital signs may be normal orsignificantly disordered with tachypnea, tachycardia, and/orhypotension.

Place emphasis on determining the patient's respiratory andcardiovascular status.

Frank cardiovascular collapse or respiratory arrest may occur insevere cases. Anxiety is common unless hypotension or hypoxiacauses obtundation. Shock may occur without prominent skinmanifestations or history of exposure; therefore, anaphylaxis is part of



the differential diagnosis for patients who present with shock and noobvious cause.

General appearance and vital signs vary according to severity of attackand affected organ system(s). Patients commonly are restless due tosevere pruritus from urticaria. Anxiety, tremor, and a sensation of coldmay result from compensatory endogenous catecholamine release.Severe air hunger may occur when the respiratory tract is involved. Ifhypoperfusion or hypoxia occurs, the patient may exhibit a depressedlevel of consciousness or may be agitated and/or combative.Tachycardia usually is present, but bradycardia may occur in verysevere reactions.

Skin

The classic skin manifestation is urticaria (ie, hives). Lesions are redand raised, and they sometimes have central blanching. Intensepruritus occurs with the lesions. Lesion borders usually are irregularand sizes vary markedly. Only a few small or large lesions maybecome confluent, forming giant urticaria. At times, the entire dermis isinvolved with diffuse erythema and edema. Hives can occur anywhereon the skin.

In a local reaction, lesions occur near the site of a cutaneous exposure(eg, insect bite). The involved area is erythematous, edematous, andpruritic. If only local skin reaction (as opposed to generalized urticaria)is present, systemic manifestations (eg, respiratory distress) are lesslikely. Local reactions, even if severe, are not predictive of systemicanaphylaxis on re-exposure.

Lesions typical of angioedema also may manifest in anaphylaxis. Thelesions involve mucosal surfaces and deeper skin layers. Angioedemausually is nonpruritic and associated lesions are nonpitting. Lesionsmost often appear on the lips, palms, soles, and genitalia.

Pulmonary

Upper airway compromise may occur when the tongue or oropharynxis involved. When the upper airway is involved, stridor may be noted.The patient may have a hoarse or quiet voice and may lose speakingability as the edema progresses. Complete airway obstruction is themost common cause of death in anaphylaxis.

Wheezing is common when patients have lower airway compromisedue to bronchospasm or mucosal edema.

In angioedema, due to ACE inhibitors, marked edema of the tongueand lips may obstruct the airway.

Cardiovascular

Cardiovascular examination is normal in mild cases. In more severecases, compensatory tachycardia occurs due to loss of vascular tone.

Intravascular volume depletion may take place as a consequence ofcapillary leakage. These mechanisms also lead to development ofhypotension.



Relative bradycardia has been reported.

Causes:

A wide variety of substances can cause anaphylaxis. Anaphylaxis also maybe idiopathic.

In the classic form of anaphylaxis, a foreign protein is the inciting agent (eg,antigen). On initial exposure, the antigen elicits generation of an IgEantibody. The antibody residue binds to mast cells and basophils. On re-exposure, the antigen binds to the antibody, and the receptors are activated.Clinical manifestations result from release of immune response mediatorssuch as histamine, leukotrienes, tryptase, and prostaglandins. The samemechanism occurs when a nonimmunogenic foreign substance binds as aso-called hapten to a native carrier protein, creating an immunogenicmolecule. Factors influencing severity of a reaction include degree of hostsensitivity and dose, route, and rate of administration of the offending agent.

Parenteral exposures tend to result in faster and more severe reactions.Most severe reactions occur soon after exposure. The faster a reactiondevelops, the more severe it is likely to be. While most reactions occur withinhours, symptoms may not occur for as long as 3-4 days after exposure.

Drugs

Penicillin and cephalosporin antibiotics are the most commonlyreported medical agents in anaphylaxis. This prevalence is a functionof the immunogenicity and overuse of these agents. Because of theirmolecular and immunologic similarity, cross-sensitivity may exist.Reports often assert that 10% of patients allergic to a penicillinantibiotic are allergic to cephalosporins. A recent report suggests thatactual incidence of cross-reactivity is lower (perhaps 1%), with mostreactions considered mild. A more recent review indicated that patientswith a history of allergy to penicillin seem to have a higher risk (by afactor of about 3) of subsequent reaction to any drug and that the riskof an allergic reaction to cephalosporins in patients with a history ofpenicillin allergy may be up to 8 times as high as the risk in those withno history of penicillin allergy (ie, at least part of the observed "crossreactivity" may represent a general state of immunehyperresponsiveness, rather than true cross-reactivity).

Reactions tend to be more severe and rapid in onset when theantibiotic is administered parenterally.

Anaphylaxis may occur in a patient with no prior history of drugexposure.

History of penicillin or cephalosporin allergy often is unreliable and isnot predictive of future reactions. Up to 85% of patients reporting anallergic reaction to penicillin do not react on subsequent exposure.When a drug in either class is the drug of choice for a patient with a life-threatening emergency, a number of options exist. When the history isindefinite, the drug may be administered under close observation;however, when possible, obtain the patient's informed consent.Immediate treatment measures for anaphylaxis should be available.Alternatively, when the history is more convincing, a desensitization orprophylactic pretreatment protocol may be instituted or another agentselected.



Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) commonlyare implicated in allergic reactions and anaphylaxis. Bronchospasm iscommon in patients with reactive airway disease and nasal polyps.Cross-reactivity may occur between the various NSAIDs.

Intravenous radiocontrast media

IV administered radiocontrast media causes an anaphylactoid reactionthat is clinically identical to true anaphylaxis and is treated in the sameway. The reaction is not related to prior exposure. Shellfish or "iodineallergy" is not a contraindication to use of IV contrast and does notmandate a pretreatment regimen. As with any "allergic" patient, giveconsideration to use of low molecular weight (LMW) contrast.

The term iodine allergy is a misnomer. Iodine is an essential traceelement present throughout the body. No one is allergic to iodine.Patients who report iodine allergy usually have had either a priorcontrast reaction or a shellfish allergy. Manage these patients asindicated earlier.

Approximately 1-3% of patients who receive hyperosmolar IV contrastexperience a reaction. Use of LMW contrast decreases incidence ofreactions to approximately 0.5%. Personnel, medications, andequipment needed for treatment of allergic reactions always should beavailable when these agents are administered. Obtain consent beforeadministration.

Reactions to radiocontrast usually are mild (most commonly urticarial),with only rare fatalities reported. Risk of a fatal reaction has beenestimated at 0.9 cases per 100,000 exposures.

Mucosal exposure (eg, GI, genitourinary [GU]) to radiocontrast agentshas not been reported to cause anaphylaxis; therefore, a history ofprior reaction is not a contraindication to GI or GU use of these agents.

Pretreatment with antihistamines or corticosteroids and use of LMWagents lead to lower rates of anaphylactoid reactions to IV contrast.Consider these measures for patients who have prior history ofreaction, since rate of recurrence is estimated at 17-60%. Patients whoare atopic and/or asthmatic also are at increased risk of reaction. Inaddition, allergic reaction is more difficult to treat in those taking beta-blockers.

Hymenoptera stings

Hymenoptera stings are a common cause of allergic reaction andanaphylaxis. An uncertain but enormous number of exposures occur;accurate reaction rates are difficult to estimate. In the United States,Hymenoptera envenomations result in fewer than 100 reported deathsper year.

Local reaction and urticaria without other manifestations of anaphylaxisare much more common than full-blown anaphylaxis. Generalizedurticaria is a risk factor for subsequent anaphylaxis; but a localreaction, even if severe, is not a risk factor for anaphylaxis.

Caution patients treated and released from the ED after an episode ofanaphylaxis or generalized urticaria from Hymenoptera envenomationto avoid future exposure when possible. Consider referral to an



allergist for desensitization, particularly when further exposure is likely.Additionally, consider prescribing a treatment kit with an epinephrineauto-injector and oral antihistamine. Both are effective measures inpreventing or ameliorating future reactions.

Allergies

Food allergy is common. Symptoms usually are mild and limited to theGI tract, but full-blown anaphylaxis can occur. Fatalities are rarecompared to number of exposures; however, the number of exposuresis so high that foods may be the commonest cause of anaphylaxis.Anaphylaxis due to foods may be an underrecognized cause of suddendeath and an unappreciated cause of diagnosed anaphylaxis.Commonly implicated foods include nuts (especially peanuts),legumes, fish and shellfish, milk, and eggs.

Latex allergy is an increasingly recognized problem in medical settings,where use of gloves and other latex products is ubiquitous. Mostreactions are cutaneous or involve the mucous membranes.Anaphylactic reactions occur and have been reported with seeminglybenign procedures (eg, Foley catheter insertion, intraperitonealexposure to gloves during surgery).

DIFFERENTIALS Section 4 of 10


AngioedemaAnxietyAsthmaConversion DisorderEpiglottitis, AdultForeign Bodies, TracheaMyocardial InfarctionPulmonary EmbolismToxicity, ScombroidUrticaria

Other Problems to be Considered:

Globus hystericusHereditary angioedemaMonosodium glutamate poisoning (ie, Chinese restaurant syndrome)

WORKUP Section 5 of 10


Lab Studies:

The diagnosis of anaphylaxis is clinical and does not rely on laboratory testing. When typicalsymptoms are noted in association with a likely exposure, diagnosis is virtually certain. Ancillarytesting may help assess severity of reaction, although this is primarily a clinical judgment. Whenunclear, ancillary testing may help establish the diagnosis.

The only potentially useful test at the time of reaction is measurement of serum mast celltryptase. Tryptase is released from mast cells in both anaphylactic and anaphylactoid reactions.



Levels are usually raised in severe reactions. Mast cell tryptase is raised transiently with bloodlevels reaching a peak approximately an hour after reaction onset.

Tryptase levels may aid in later diagnosis and treatment.

Consider the test in cases for which diagnosis of anaphylaxis is uncertain.

The utility of this test awaits full evaluation.

Cardiac monitoring in patients with severe reactions and in those with underlying cardiovasculardisease is important, particularly when adrenergic agonists are used in treatment. Pulseoximetry also is useful.

Imaging Studies:

Imaging studies are not generally useful in the diagnosis and management of anaphylaxis,although they may be used as diagnostic aids when diagnosis is unclear.

Other Tests:

Sensitivity testing

Testing for sensitivity to penicillin antibiotics may be useful when a penicillin orcephalosporin antibiotic is the drug of choice for a serious infection in a patient who has ahistory of severe allergic reaction. Obtain informed consent, and ensure that resuscitativeequipment is immediately available. Protocols for acute testing for allergy to penicillin orcephalosporin antibiotics involve administration of increasing IV doses of the chosenantibiotic, while observing the patient for pruritus, flushing, urticaria, dyspnea,hypotension, or other manifestations of anaphylaxis. If no manifestations are observed, afull dose of the antibiotic may be administered safely.

A suggested protocol for IV testing begins with 0.001 mg of the chosen drug. At 10-minintervals, incrementally increase the dose (eg, 0.001 mg, 0.005 mg, 0.01 mg, 0.05 mg, 0.1g, 0.5 mg, 1 mg, 10 mg, 50 mg, 100 mg, full dose), while observing the patient. Many otherprotocols exist. In most circumstances, perform desensitization on an inpatient basis. Ifthe necessary resources are available, desensitization may be performed in the ED.

Procedures:

Intravenous contrast reaction prevention

Patients with a history of severe reactions to IV contrast material may require use ofcontrast in an urgent or emergency situation. Alternatives (eg, spiral CT scan for ureteralstone, Doppler ultrasound for deep venous thrombosis [DVT]) should be considered butare not always feasible. In these circumstances, a prophylactic regimen of corticosteroidsand antihistamines may be used. The precise efficacy of these regimens is difficult toevaluate, but they generally are considered effective. One author states that therecurrence rate for patients with a previous reaction was reduced from 17-60% to 9%when conventional contrast material was used; the rate was reduced to less than 1%when low osmolality material was employed after a pretreatment regimen.

The use of H2 blockers has not been shown to decrease the risk of reaction to IVcontrast. One study suggests H2 blockers actually appear to increase the risk.

A widely quoted protocol for prevention of reactions to IV contrast suggests the following:

Use low osmolality contrast.

Administer hydrocortisone (200 mg IV); wait 2 hours if clinically appropriate.



Administer diphenhydramine (50 mg IM) immediately before the procedure.

Desensitization regimens

Desensitization regimens for penicillin and cephalosporin antibiotic allergy have beenshown effective. Because these regimens are lengthy (approximately 6 h), they havelimited applicability to the ED. When patients wait for long periods in the ED or in anobservation unit, consider desensitization regimens.

A typical desensitization regimen involves administering the antibiotic of choice in aninitial dose of 0.01 mg. While observing the patient, double the dose every 10-15 minutesuntil a full dose has been administered.

Desensitization regimens do not protect against non–IgE-mediated reactions that may besevere or even life threatening (eg, Stevens-Johnson syndrome).

While theoretically attractive, premedication regimens have not been clinically shown todecrease incidence or severity of IgE-mediated allergic reactions to antibiotics.

TREATMENT Section 6 of 10


Prehospital Care:

Prehospital patients with symptoms of severe anaphylaxis should first receive standardinterventions. Interventions include high-flow oxygen, cardiac monitoring, and IV access. Thesemeasures are appropriate for an asymptomatic patient who has a history of serious reactionand has been re-exposed to the inciting agent. Additional treatment depends upon the conditionof the patient and the severity of the reaction. Measures beyond basic life support (BLS) are notnecessary for patients with purely local reactions.

Immediately assess airway patency due to the potential for compromise secondary to edema orbronchospasm. Active airway intervention may be difficult due to laryngeal or oropharyngealedema. In this circumstance, it may be preferable to defer intubation attempts, and insteadventilate with a bag/valve/mask apparatus while awaiting medications to take effect. In extremecircumstances, cricothyrotomy or catheter jet ventilation may be lifesaving. Inhaled beta-agonists are used to counteract bronchospasm and should be administered to patients who arewheezing.

The IV line should be of large caliber due to the potential requirement for large-volume IV fluidresuscitation. Isotonic crystalloid solutions (ie, normal saline, Ringer lactate) are preferred. Akeep vein open (KVO) rate is appropriate for patients with stable vital signs and only cutaneousmanifestations. If hypotension or tachycardia is present, administer a fluid bolus of 20 mg/kg forchildren and 1 L for adults. Further fluid therapy depends on patient response. Large volumesmay be required in the profoundly hypotensive patient.

Administer epinephrine to patients with systemic manifestations of anaphylaxis. With mildcutaneous reactions, an antihistamine alone may be sufficient, thus the potential adverseeffects of epinephrine can be avoided. Patients on beta-blocker medications may not respondto epinephrine. In these cases, glucagon may be useful. The Medication section describesdosage, routes of administration, and contraindications for medications discussed in thissection. Antihistamines (eg, H1 blockers), such as diphenhydramine (Benadryl) are importantand should be administered for all patients with anaphylaxis or generalized urticaria.

Corticosteroids are used in anaphylaxis primarily to decrease the incidence and severity ofdelayed or biphasic reactions. Corticosteroids may not influence the acute course of thedisease; therefore, they have a lower priority than epinephrine and antihistamines.



Emergency Department Care:

ED care begins with standard monitoring and treatment, including oxygen, cardiac monitoring,and a large-bore IV with isotonic crystalloid solution. Further intervention depends on severity ofreaction and affected organ system(s).

Rapidly assess airway patency in patients with systemic signs or symptoms. If required,intubation may be difficult to achieve because of upper airway or facial edema. Standard rapidsequence induction (RSI) techniques can be used but may cause loss of the airway in a patientwhose airway anatomy is altered by edema. Epinephrine may rapidly reverse airwaycompromise, and bag/valve/mask ventilation may be effective in the interim when intubation isnot possible. Surgical airway intervention using standard cricothyrotomy is an option whenorotracheal intubation or bag/valve/mask ventilation is not effective.

Wheezing or stridor indicates bronchospasm or mucosal edema. Treatment withepinephrine and inhaled beta-agonists is effective for these indications.

Recommendations to treat refractory bronchospasm with corticosteroids have been madebecause of their effectiveness in reactive airway disease. As in asthma therapy, onset ofaction is delayed for several hours. Aminophylline also has been recommended forbronchospasm in anaphylaxis and may be more rapidly effective than corticosteroids.

Hypotension in anaphylaxis usually is due to vasodilatation and capillary fluid leakage.Epinephrine is the primary pharmacologic treatment for these findings. H1-blockingantihistamines also may have a role in reversing hypotension. Some authors also recommendH2-blocking agents. Large volume fluid resuscitation with isotonic crystalloid often is needed tosupport the circulation in patients with cardiovascular manifestations of anaphylaxis.

Refractory hypotension first should be treated with large volumes of crystalloid andrepeated doses of epinephrine or a continuous epinephrine infusion. If this is not effective,other pressors with alpha-adrenergic activity, such as levarterenol (Levophed) ordopamine, may be considered. Cases of effective use of military antishock trousers(MAST) for refractory hypotension have been reported.

Mediators of anaphylaxis are not considered to have direct myocardial toxicity. In patientswith preexisting heart disease, ischemic myocardial dysfunction may occur due tohypotension and hypoxia. Epinephrine still may be necessary in patients with severeanaphylaxis, but remember the potential for exacerbating ischemia. If pulmonarycongestion or evidence of cardiac ischemia is present, fluid resuscitation should beapproached more cautiously.

Patients taking beta-blockers may be resistant to the effects of epinephrine. Larger thanusual doses may be needed. Glucagon may be effective in this circumstance, because itincreases intracellular cyclic adenosine monophosphate (cAMP) levels by a mechanismthat does not depend upon beta-receptors.

Cutaneous effects of anaphylaxis are uncomfortable but not life threatening. Patients oftenrespond promptly to epinephrine and H1 antihistamines. Some authors state thatcorticosteroids help prevent recurrence of symptoms (both cutaneous and systemic) that mayoccur 6-8 hours after successful treatment (so-called biphasic reaction). H2 blockers may havean added effect.

GI symptoms in anaphylaxis respond to H1 antihistamines and epinephrine.

Consultations:

Acute manifestations of anaphylaxis usually respond to ED treatment. In refractory cases,consult with an allergist, cardiologist, pulmonologist, or other intensivist.



Consultation with an allergist (when available) is appropriate when desensitization to anantibiotic is contemplated.

When a patient at high risk for contrast reaction is under consideration for a contrast study,consultation with the radiologist regarding pretreatment and choice of contrast agent isappropriate.

Refer patients who are treated and released from the ED after an episode of anaphylaxis orgeneralized urticaria to their primary care physician or to an allergist for follow-up. At that time,consideration can be given to skin testing and possible desensitization.

MEDICATION Section 7 of 10


Primary drug treatments for acute anaphylactic reactions are epinephrine and H1 antihistamines.These agents clearly are effective; do not delay or defer their use in favor of other treatments. Inhaledbeta-agonists lack some of the adverse effects of epinephrine. Inhaled beta-agonists are useful forcases of bronchospasm, but they may not have additional effects when optimal doses of parenteralepinephrine are used. Corticosteroids mainly are effective in preventing biphasic (ie, delayed)reactions. Due to this delayed effect, corticosteroids are not first-line treatments. H2-blockingantihistamines theoretically are attractive agents, but evidence supporting their clinical effectivenessis less than for H1-blocking agents. Glucagon may be useful in treating refractory cardiovasculareffects in patients taking beta-blockers.

Drug Category: Parenteral adrenergic agents -- Reverse cardiovascular, cutaneous, GI, andpulmonary manifestations of anaphylaxis.

Drug Name

Epinephrine (EpiPen, Adrenalin) -- DOC for shock, angioedema,airway obstruction, bronchospasm, and urticaria in severeanaphylactic reactions. Administered SC or IM, except for patientsin extremis for whom it is administered IV. May be administeredSL or via ET when no IV access available. Continuous infusionmay be administered in cases of refractory shock.0.3-0.5 mL 1:1000 soln SC or IM q15min1 mL 1:10,000 soln (diluted in 10 mL NS) IV; slow administration;repeat prn



0.3-0.5 mL 1:1000 soln SL q15min1.0 mL 1:1000 soln ET in approximately 10 mL NSIV infusion: 0.1-1 mcg/kg/min

Pediatric Dose

0.01 mL/kg (minimum 0.1 mL) 1:1000 soln SC or IM q15min0.01 mL/kg (minimum 0.1 mL) 1:10,000 soln IV prn0.01 mL/kg (minimum 0.1 mL) 1:1000 soln SL q15min0.01 mL/kg (minimum 0.1 mL) 1:1000 soln ET in approximately 1-3 mL NSIV infusion: 0.1-1.0 mcg/kg/min

Contraindications

May be administered in life-threatening anaphylactic reactions,even when the following relative contraindications are present: (1)coronary artery disease, (2) uncontrolled hypertension, (3) seriousventricular arrhythmias, and (4) second stage of labor

Interactions

Sympathomimetics cause additive effects; beta-blockersantagonize therapeutic effects of epinephrine; digitalis potentiatesproarrhythmic effect of epinephrine; TCAs and MAOIs potentiatecardiovascular effects of epinephrine; phenothiazine causes aparadoxical decrease in BP

Pregnancy B - Usually safe but benefits must outweigh the risks.

Precautions

Adverse effects include cardiac ischemia or arrhythmias, fear,anxiety, tremor, and hypertension with subarachnoid hemorrhage;use with caution in elderly and in patients that have diabetesmellitus, hyperthyroidism, prostatic hypertrophy, hypertension,cardiovascular disease, and cerebrovascular insufficiency; rapidIV infusions also may cause death from cerebrovascularhemorrhage or cardiac arrhythmias

Drug Category: Inhaled beta-agonists -- Used to treat bronchospasm. Doses are identical tothose used in the treatment of asthma.

Drug NameAlbuterol (Proventil, Ventolin) -- Numerous inhaled beta-agonistsare used for treatment of bronchospasm; albuterol is the mostcommonly used preparation.

Adult Dose 0.5 mL 0.5% soln in 2.5 cc NS nebulized q15minPediatric Dose 0.03-0.05 mL/kg 0.5% soln in 2.5 cc of NS via nebulizer q15min

Contraindications

In a life-threatening anaphylactic reaction, albuterol may beadministered even in the presence of (1) severe coronaryinsufficiency or (2) uncontrolled, severe hypertensionSignificant effects are much less likely than with parenteralsympathomimetics

Interactions

Sympathomimetics cause additive effects; beta-blockersantagonize therapeutic effects; digitalis potentiates proarrhythmiceffects; TCAs and MAOIs potentiate cardiovascular effects;phenothiazine causes a paradoxical decrease in BP

Pregnancy B - Usually safe but benefits must outweigh the risks.

Precautions

Inhaled beta-agonists are relatively well-tolerated; beta 2-agonists, such as albuterol, have relatively few cardiovascularadverse effects when compared with agents that also have beta1-agonist activity or with parenteral sympathomimetics

Drug Category: H1-receptor blockers (Antihistamines) -- Primarily effective against cutaneouseffects of anaphylaxis. Also may help antagonize cardiac and respiratory effects; should be usedroutinely in most cases of anaphylaxis. IV administration is preferable when a rapid effect is desired.IM dosing also is effective but has a slower onset than IV and may cause local tissue irritation. POdoses must be larger than parenteral doses because of 50% first-pass metabolism in the liver. Most



recommendations for use of antihistamines state that they should be continued for 2-3 days aftertreatment of the acute anaphylactic event.

Drug Name Diphenhydramine (Benadryl) -- Many effective H1 blockers exist;diphenhydramine is effective and widely available.

Adult Dose 25-50 mg IV/IM q4-6h50 mg PO q4-6h

Pediatric Dose 1-2 mg/kg IV/IM q4-6h2 mg/kg PO q4-6h

Contraindications Documented hypersensitivity, MAOIs

InteractionsPotentiates effect of CNS depressants; due to alcohol content, donot give syrup dosage form to patient taking medications that cancause disulfiramlike reactions

Pregnancy C - Safety for use during pregnancy has not been established.

Precautions May exacerbate angle closure glaucoma, hyperthyroidism, pepticulcer, and urinary tract obstruction

Drug Category: H2-receptor blockers (Antihistamines) -- H2 blockers are used commonly byclinicians in treatment of allergic reactions and urticaria. Evidence of additive effect with H1-blockeranaphylaxis exists, but they should not be considered first-line therapy.

Drug NameCimetidine (Tagamet) -- Many H2 blockers are available.Cimetidine is the prototype drug; other agents have much lessevidence of effectiveness in anaphylaxis.

Adult Dose 300 mg PO/IV/IM q6hPediatric Dose 5-10 mg/kg PO/IV/IM q6h

Contraindications Documented hypersensitivity

Interactions

Multiple drug interactions are related to inhibition of hepaticmicrosomal enzymes; cimetidine is known to increase bloodconcentration of (1) warfarin, (2) benzodiazepines, (3) lidocaine,(4) TCAs, (5) terfenadine, (6) phenytoin, and (7) theophylline


Precautions

Cimetidine carries relatively few serious adverse effects,particularly when only short-term acute use is considered; in theacute setting consider important adverse effects to include (1)headache and confusion and (2) cardiac arrhythmias andhypotension from rapid IV administration

Drug Category: Corticosteroids -- These agents have a role in reversing bronchospasm andcutaneous effects of anaphylaxis. Corticosteroids have a delayed onset of action and do not reversethe cardiovascular effects of anaphylaxis. These agents should be used in severe reactions, but theuse of epinephrine and H1 antihistamines has a higher priority. Some authors state thatcorticosteroids help prevent or ameliorate recurrent (biphasic) anaphylaxis, but the true incidence ofthis condition has not been determined, and recurrences are usually less severe than the initialattack.

While corticosteroids usually are administered IV in patients with anaphylaxis for presumed rapidity ofeffect, PO and IV corticosteroids are equally efficacious in asthma therapy. When administeredacutely, corticosteroids commonly are continued for 2-3 days. In asthma treatment, large parenteraldoses customarily are administered acutely, followed by lower PO dosing for varying periods. Long-acting parenteral preparations may be administered as an alternative and have been shown effectivein asthma therapy. Optimal dosage range for corticosteroids has not been established; thus, a rangeof dosages is provided based on published recommendations.

Methylprednisolone (Solu-Medrol, Adlone, Medrol, Depo-Medrol) -- A multitude of corticosteroid preparations are available.Methylprednisolone is widely available in the ED because of other



uses (ie, acute asthma, spinal cord injury). Supplied in bothparenteral and oral formulations. Discussed here as typical drugof this class.

Adult Dose 40-250 mg IV/IM q6h2-60 mg PO qd

Pediatric Dose 1-2 mg/kg IV/IM q6h1 mg/kg PO qd

ContraindicationsOther than a previous severe reaction to the drug, there are noabsolute contraindications to the use of corticosteroids fortreatment of severe anaphylaxis

Interactions

The most important interactions in the acute setting are (1)ulcerogenesis with NSAIDs, (2) increased weakness in patientswho have MyG with anticholinesterases, and (3) possible viraldissemination with live virus vaccines


Precautions

Short-term use of corticosteroids, even in large doses, hasminimal harmful effects; multiple adverse effects from chronicusage; benefits and risks should be considered in pregnantfemales; patients who are immunosuppressed and are receivingcorticosteroids are at risk for dissemination or activation of certaininfections

Drug Category: Antidote, Hypoglycemia -- Glucagon appears to benefit by stimulating therelease of endogenous catecholamines.

Drug Name

Glucagon -- Has inotropic, chronotropic, and vasoactive effectsthat are independent of beta-receptors. Glucagon also causesendogenous catecholamine release. Patients taking beta-blockingagents may be resistant to effects of epinephrine or otheradrenergic agents used to treat the cardiovascular effects ofanaphylaxis. Glucagon may be effective in these patients. Shouldbe used in addition to epinephrine, not as a substitute. Reports ofeffectiveness of glucagon in anaphylaxis are anecdotal; therefore,it is difficult to specify a dose. Smaller doses are effective inelevating blood sugar in patients with hypoglycemia, but largerdoses have been recommended in beta-blocker overdose.Given parenterally. IV route is preferable, if available.

Adult Dose 1-10 mg IV/IM/SC; typically 1-2 mg q5min to effect

Pediatric Dose Not established; adult dose is approximately equivalent to 0.02mg/kg

Contraindications Documented hypersensitivity

Interactions

Effects of anticoagulants may be enhanced by glucagon (althoughonset may be delayed); monitor PT activity and for signs ofbleeding in patients receiving anticoagulants; adjust doseaccordingly


Precautions

Monitor blood glucose levels in hypoglycemic patients until theyare asymptomatic; glucagon is effective in treating hypoglycemiaonly if sufficient liver glycogen is present; since liver glycogenavailability is necessary to treat hypoglycemic patients, glucagonhas virtually no effects on patients in states of starvation, adrenalinsufficiency, or chronic hypoglycemia



FOLLOW-UP Section 8 of 10


Further Inpatient Care:

Most patients with anaphylaxis may be treated successfully in the ED and then discharged.Treatment success operationally may be defined as complete resolution of symptoms followedby a short period of observation. The purpose of observation is to monitor for recurrence ofsymptoms (ie, biphasic anaphylaxis).

Hospital admission is required for patients who (1) fail to respond fully, (2) have a recurrentreaction or a secondary complication (eg, myocardial ischemia), (3) experience a significantinjury from syncope, or (4) need intubation. As with many other conditions, consider a loweradmission threshold when patients are at age extremes or when they have significant comorbidillness.

The presenting manifestation(s) of anaphylaxis dictate inpatient care. Essentially, this careconsists of continuing the care initiated in the ED.

Consider ICU admission for patients with persistent hypotension. The primary means of supportare adrenergic agents (eg, epinephrine, dopamine) and fluid resuscitation. Persistenthypotension in the face of pressors and fluid resuscitation is an indication for invasivehemodynamic monitoring with evaluation of cardiac function and peripheral vascularresistance. Use of these parameters provides the basis for objective decisions regarding theuse of fluids and pressors.

Inpatient management of airway compromise consists of continuation of parenteral and inhaledadrenergic agents and corticosteroids that were initiated in the ED.

Cutaneous manifestations of anaphylaxis are treated with repeated doses of antihistamines.

Further Outpatient Care:

Discharged patients who have been successfully treated for anaphylaxis usually shouldcontinue antihistamines for 2-5 days to prevent recurrence. When corticosteroids have beenused as part of the initial treatment, common practice continues that treatment for a shortperiod.

In/Out Patient Meds:

Inpatient medications are identical to those listed for ED care (see Medication).

Outpatient medications

Outpatient medications primarily consist of oral forms of the medications used in EDtreatment. Adrenergic medications are not listed in this chapter, as it is assumed thatpatients who require these on an on-going basis will be admitted.

Consider patients who experience severe reactions to bites, stings, food, or other possiblyunavoidable causes, as candidates for an epinephrine auto-injector prescription. Theseinjectors may be packaged as kits that also contain an oral antihistamine.

The following regimens are used commonly by clinicians, though very little hard dataconcerning the natural history of anaphylaxis treated in the ED exists. In light of this, donot construe the following as an unqualified recommendation or as a standard of care.Evidence for efficacy of H2-blocker antihistamines is particularly sparse. The newernonsedating antihistamines have not been studied in the context of treatment foranaphylaxis.



H1-blocker antihistamines

Diphenhydramine (Benadryl) - Adults: 25 mg PO q6h for 2-5 d; Children: 1 mg/kg POq6h for 2-5 d

Hydroxyzine (Atarax) - Adults: 25 mg PO q8h for 2-5 d; Children: 1 mg/kg PO q8h for2-5 d

Corticosteroids

Prednisone - Adults: 20-80 mg PO qd for 2-5 d; Children: 1-2 mg/kg PO qd for 2-5 d

Many other glucocorticoid preparations may be used.

H2-blocker antihistamines

Cimetidine - 300 mg PO qid for 2-5 d; Children: Not recommended

Epinephrine auto-injectors prefilled syringes: A number of forms are available.Instructions for self-administration are included.

Ana-Kit (Bayer): This product is a syringe with 0.3 cc 1:1000 epinephrine solutionpackaged with four 2-mg chewable chlorpheniramine tablets. The syringe has 0.1 ccgradations, allowing the injection of smaller doses for pediatric patients.

EpiPen and EpiPen Jr. Auto-Injector (Center): This product is an auto-injectingsyringe containing 0.3 cc 1:1000 epinephrine solution (EpiPen) or 0.3 cc 1:2000solution (EpiPen Jr).

Transfer:

Requirements for treating a patient with anaphylaxis are likely to exist in most hospitals withinthe United States and Canada; therefore, transfer of patients with anaphylaxis would be a veryunusual occurrence in these locations.

Deterrence/Prevention:

Preventive therapy for anaphylaxis depends on identification of the inciting agent. When theagent has been identified, the key to prevention is avoidance. Certain prophylactic orpreventative therapies may be employed when re-exposure cannot be avoided. When theinciting agent is not obviously known from the history, allergy testing may help identify it. Whenthe allergen is a therapeutic agent for which subsequent usage is medically necessary,desensitization or pretreatment protocols may be employed.

Desensitization therapy for reactions to Hymenoptera venom is partially effective inpreventing or ameliorating subsequent severe reactions.

At minimum, patients discharged from the ED after a severe reaction to Hymenopteravenom should be informed of the availability of this treatment. Referral to the patient'sprimary care source or directly to an allergist also may be appropriate.

Complications:

Complications from anaphylaxis are rare, and most patients completely recover. Myocardialischemia may result from hypotension and hypoxia, particularly when underlying coronaryartery disease exists. Ischemia or arrhythmias may result from treatment with pressors.Prolonged hypoxia also may cause brain injury. At times, a fall or other injury may occur whenanaphylaxis leads to syncope.



Prognosis:

Anaphylaxis may occur following re-exposure to the inciting agent. Rates of recurrence varywith the nature of the inciting agent and host factors. Other than the possibility of recurrence orthe occurrence of complications, anaphylaxis carries no long-term effects.

Patient Education:

As described above, caution patients who are discharged after an episode of anaphylaxis toavoid exposure to an inciting agent. When no inciting agent has been identified, considerreferral to an allergist to identify the cause of anaphylaxis.

Inform patients who react to Hymenoptera venom of the availability of desensitization therapy,and consider a self-administered epinephrine prescription.

Sting avoidance is important for hypersensitive persons. Patients must be educated concerningsteps they can take to reduce the risk of insect stings.

Caution patients to avoid use of perfumes or hygiene products that include perfumes,particularly floral scents, as these attract flying Hymenoptera.

Brightly colored clothing attracts bees and other pollinating insects.

Avoid locations of known hives or nests, and avoid using equipment that disturbs the hive.

Persons who are sensitive to Hymenoptera and who must be outdoors should carry asting kit.

On discharge, warn patients of the possibility of recurrent symptoms, and instruct them to seekfurther care if this occurs.

For excellent patient education resources, visit eMedicine's Allergy Center and AllergicReaction and Anaphylactic Shock Center. Also, see eMedicine's patient education articleSevere Allergic Reaction (Anaphylactic Shock).

MISCELLANEOUS Section 9 of 10


Medical/Legal Pitfalls:

Claims of medical negligence related to the emergency treatment of anaphylaxis are notcommon. Potential pitfalls are as follows:

Failure to consider the diagnosis in patients with unexplained syncope or shock

Failure to warn the patient of avoidance or preventive measures

Prescription or administration of a drug to which the patient is known allergic

Failure to appreciate the potentially serious nature of symptoms, such as syncope orthroat tightness, in a patient with an allergic reaction

Complications of epinephrine administration in patients without clear indication

BIBLIOGRAPHY Section 10 of 10


Anne S, Reisman RE: Risk of administering cephalosporin antibiotics to patients with historiesof penicillin allergy. Ann Allergy Asthma Immunol 1995 Feb; 74(2): 167-70[Medline].



Atkinson TP, Kaliner MA: Anaphylaxis. Med Clin North Am 1992 Jul; 76(4): 841-55[Medline].Barach EM, Nowak RM, Lee TG, et al: Epinephrine for treatment of anaphylactic shock. JAMA1984 Apr 27; 251(16): 2118-22[Medline].Bochner BS, Lichtenstein LM: Anaphylaxis. N Engl J Med 1991 Jun 20; 324(25): 1785-90[Medline].Caplan EL, Ford JL, Young PF, Ownby DR: Fire ants represent an important risk foranaphylaxis among residents of an endemic region. J Allergy Clin Immunol 2003 Jun; 111(6):1274-7[Medline].Greenberger PA: Contrast media reactions. J Allergy Clin Immunol 1984 Oct; 74(4 Pt 2): 600-5[Medline].Kelkar PS, Li JT: Cephalosporin allergy. N Engl J Med 2001 Sep 13; 345(11): 804-9[Medline].Reisman RE: Insect stings. N Engl J Med 1994 Aug 25; 331(8): 523-7[Medline].Sheffer AL: Anaphylaxis. J Allergy Clin Immunol 1988 May; 81(5 Pt 2): 1048-50[Medline].Sheffer AL: Anaphylaxis. J Allergy Clin Immunol 1985 Feb; 75(2): 227-33[Medline].Stark BJ, Sullivan TJ: Biphasic and protracted anaphylaxis. J Allergy Clin Immunol 1986 Jul; 78(1 Pt 1): 76-83[Medline].Terr AI: Anaphylaxis. Clin Rev Allergy 1985 Feb; 3(1): 3-23[Medline].

NOTE:

Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. Theauthors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally acceptedwithin medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors,editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, norare they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this articlefrom other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULLDISCLAIMER

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eMedicine - Anaphylaxis _ Article by Richard S Krause, MD

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