Anaphylaxis

Otolaryngol Clin N Am

36 (2003) 1009–1020

Anaphylaxis

Michael C. Noone, MD*, J. David Osguthorpe, MDDepartment of Otolaryngology-Head and Neck Surgery,

Medical University of South Carolina, 135 Rutledge Avenue,

Suite 1130, Charleston, SC 29425, USA

Anaphylaxis is an amplified, harmful immunologic reaction that occursafter re-exposure to an antigen to which an organism has become sensitive.True anaphylaxis is a systemic reaction caused by antigen-specific cross-linking of IgE molecules or complement proteins on the surface of tissuemast cells and peripheral blood basophils, resulting in the immediate releaseof potent mediators. Immediate systemic reactions that resemble anaphy-laxis but are not caused by an IgE-mediated immune response are referredto as anaphylactoid reactions [1]. It is important for physicians, especiallythose who treat allergies, to understand the pathophysiology, know thetreatment for, and recognize the clinical signs of anaphylaxis.

The word anaphylaxis comes from the Greek terms ‘‘ana’’ meaningbackward and ‘‘phylaxis’’ meaning protection [2]. Portier and Richet [3]introduced the term in 1902 to describe a paradoxical clinical observationwhich occurred in an experiment immunizing dogs against a toxin derivedfrom the sea anemone. The dogs had a ‘‘backward protection’’ from thisimmunization that caused increased sensitivity and even death. The earliestcase of anaphylaxis was recorded in 2640 bc in which the Egyptian pharaoh,Menes, was depicted in hieroglyphics as having died from a wasp sting [4].

Classification and pathophysiology

Anaphylaxis can be classified into five different types: allergen-inducedanaphylaxis, anaphylactoid reactions, exercise-induced anaphylaxis, food-and-exercise-induced anaphylaxis, and idiopathic anaphylaxis [5]. Allergen-induced anaphylaxis is an IgE- or complement-mediated type of reaction inwhich susceptible individuals form IgE or complement proteins (C3a, C5a)

* Corresponding author.

E-mail address: [email protected] (M.C. Noone).

0030-6665/03/$ - see front matter � 2003 Elsevier Inc. All rights reserved.

doi:10.1016/S0030-6665(03)00062-8

mailto:[email protected]

1010 M.C. Noone, J.D. Osguthorpe / Otolaryngol Clin N Am 36 (2003) 1009–1020

to certain antigens after at least one exposure to such antigens. Theseproteins bind respectively to either high-affinity IgE receptors or complementreceptors on the surface of mast cells. Subsequent exposure to the antigencauses cross-linking of the IgEs or complement proteins on the mast cellsurface and release of the many potent chemical mediators of anaphylaxis(Fig. 1). Preformed mast cell mediators include histamine, tryptase, chymase,heparin, and chondroitin sulfate and cause the acute symptoms ofanaphylaxis [2,6]. Prostaglandins, leukotrienes, and platelet-activating factorare generated through metabolism of arachidonic acid from the mast cellmembrane and cause the late-phase reaction which occurs hours after theantigen exposure (Table 1) [1,2]. Common allergens for the IgE-mediatedanaphylaxis include foods, medications, insect stings, and latex. Causes ofcomplement protein activation include dialysis membranes, human proteins(eg, transfusion or other blood product) and some immune complexes.Anaphylactoid reactions, on the other hand, involve a direct activation ofmast cells that is independent of IgE antibodies or the complement cascade.Hyperosmolar solutions such as radiology contrast material and vancomycinare examples. Exercise, alone or in combination with certain foods, also cancause an anaphylactic-type reaction. Idiopathic anaphylaxis is characterizedby the severity and frequency of symptoms [5].

Epidemiology

Anaphylaxis and anaphylactoid reactions have many potential causes. Ina Mayo Clinic study of the inciting factors for anaphylaxis, records from179 patients were reviewed [7]. Foods were found to be the causative agent

Fig. 1. Mast cell degranulation caused by crosslinking IgE molecules by antigen.

1011M.C. Noone, J.D. Osguthorpe / Otolaryngol Clin N Am 36 (2003) 1009–1020

in 33% of the patients, insect stings in 14%, and medications in 13%.Exercise was the inciting event in 7%, and no trigger was found in 19%.Approximately 1 in every 3000 patients in United States hospitals suffers ananaphylactic reaction. The risk of death among those who suffer sucha reaction is about 1%, causing about 1000 deaths annually [8].

Allergies to specific foods occur in up to 8% of children younger than3 years of age and in approximately 2% of adults [9]. Most reactions arecaused by peanuts, tree nuts, shellfish, milk, eggs, and the bisulfite additivesto many foods. The onset of symptoms is generally within 30 minutes ofingestion. Many persons can lose their reactivity to a food allergen if thefood is identified and eliminated from the diet for approximately 2 years.(Such sensitivity, known as cyclic food allergy, is discussed elsewhere in thisissue.) Some food sensitivities, such as peanuts, tree nuts, and seafood,however, seem to be life long and are termed fixed food allergies [9].

Anaphylactic reactions to venom from insects in the Hymenoptera orderoccur in approximately 0.5% to 3% of the population in the United States[8]. Stinging insects in the Hymenoptera order include honey bees, hornets,wasps, yellow-jackets, and fire ants [2]. Adults with a history of anaphylaxiscaused by Hymenoptera stings who do not receive immunotherapy have upto a 60% risk of another episode of anaphylaxis from future stings, ascompared with a 3% risk in those who receive immunotherapy [8].

Many forms of exercise, with or without the ingestion of certain foods,can cause an anaphylactic reaction. Vigorous anaerobic activity is morelikely to precipitate an event than less strenuous activities. Fortunately, thenumber of episodes tends to stabilize or decrease over time. Treatmentconsists of exercise modification and avoidance of any food precipitants thatcan be identified as cofactors.

Of the small number of incidences of anaphylaxis that occur in physicians’offices, skin testing for type I (IgE-mediated) sensitivities and immunother-apy shots are common inciting events. A prospective study of 27 otolaryngicallergy practices over a 1-year period (1,144,000 injections) disclosed 0.005%major systemic reactions, of which 87% occurred within 20 minutes ofantigen exposure [10]. Of affected patients, 46% had a history of asthma. Inanother prospective study of 10,000 patients seen in the offices of generalallergists (513,368 injections), major systemic reactions occurred in 0.02%of skin tests and in 2.9% of immunotherapy injections; none were fatal [11].

Table 1

Mediators of anaphylaxis

Immediately released mediators Late-phase reactants

Histimine Prostaglandins

Chymase Leukotrienes

Heparin Platelet activating factor

Tryptase

Chondroitin sulfate


The problem of latex allergy has increased dramatically since 1987 whenthe Centers for Disease Control and Prevention issued recommendationsthat all hospitals adopt universal precautions to prevent the spread of theHIV to health care workers. The allergen in latex comes from the rubber tree,Hevea brasiliensis. Rubber gloves first became implicated as an allergen in1933, with contact dermatitis reported [12]. Certain subsets of persons areat high risk for latex sensitization, including patients with spina bifida orcongenital urinary tract abnormalities, patients who have undergone mul-tiple surgeries, and health care workers. Sensitization is usually secondary tofrequent exposure to latex products in the form of urinary catheters,neurosurgical shunt tubes, and surgical gloves. The incidence of latex allergyis as high as 67% in patients with spina bifida, 6.5% in patients who haveundergone multiple surgeries, 17% in health care workers (although mostreactions are minor), and up to 6% in the general population (again, mostreactions are minor) [8,13]. Exposure to latex in a sensitized individual maycause symptoms ranging from dermatitis to anaphylaxis. Avoidance of latexin a sensitized individual is important but may be difficult because of themany household and health care products that contain latex (Boxes 1, 2).More than 40,000 types of consumer products contain latex [8]. Latex-freeclinics and hospitals, including the surgical suites, have become a priority,however, and some hospitals have now become latex-free.

A wide variety of medications have been reported to cause anaphylaxis.Beta-lactam antibiotics, nonsteroidal anti-inflammatory agents, opioidanalgesics, and aspirin are some of the more common inciting medications.Among hospitalized patients, 2% to 3% experience allergic drug reactions,

Box 1. Health care products potentially containing latex

Blood pressure cuffsStethoscopesGlovesSurgical capsCathetersOral and nasal airwaysTourniquetsIntravenous tubingSyringesElectrode padsBand aidsRubber tops of multidose vialsDental mouth guardsSurgical drainsAnesthesia facemasksEndotracheal tubes


and 1 patient in 2700 experiences a severe reaction [8,14] Penicillin typeantibiotics are the most frequent single causative agent and account forapproximately 75% of fatal cases in the United States each year [8]. Theparenteral route of medication administration is more far immunogenicthan the oral route, but either may lead to a life-threatening reaction.

Clinical symptoms

The clinical manifestations of anaphylaxis are secondary to the release ofboth the immediate and late mediators from tissue mast cells and peripheralblood basophils (see Table 1). Symptoms may occur within seconds ofantigen exposure and persist in a continuum through the eventual metabolismand clearance of the late-phase mediators. Common, less severe symptoms inthe continuum include weakness, dizziness, flushing, angioedema, urticaria,nausea, and emesis and can progress to more severe symptoms includingrespiratory tract obstruction, hypotension, and vascular collapse. Mildersymptoms do not always precede themore severe manifestations as indicatorsof impending anaphylaxis. The onset of symptoms, however, is a goodindicator of the severity of the reaction. Generally, the sooner the onset ofsymptoms, the more severe the reaction [8]. The type of allergen, however,

Box 2. Household objects potentially containing latex

Automobile tiresCarpetingSwimming gogglesShoesDish washing glovesHot water bottlesEarphonesPantyhoseRubber ballsBalloonsChewing gumCosmeticsBaby bottle nipplesPacifiersRubber bandsErasersAdhesive tapeStampsCondomsElastic in clothes (especially in waistbands)


must be considered when speculating on the time course to anaphylaxis. Onestudy showed a median time to respiratory or cardiac arrest was 30 minuteswhen the allergen was a food, 15 minutes when it was a venom, and 5 minutesfor an iatrogenic reaction (usually intravenously administered medication orradiographic contrast agent) [13]. Another study disclosed that the onset ofsymptoms in 86% of fatal anaphylactic reactions occurred within 20 minutesof initial antigen exposure, and that 51% of the patients died within 1 hour ofthose initial symptoms [15]. That said, arrest has been reported up to 6 hoursafter exposure to a food antigen [8,16]. The clinical symptoms can be biphasicas well, with the late-phase reaction occurring hours after the initialsymptoms without additional antigen exposure, and this later reaction can,on occasion, be more profound than the acute episode [17].

Diagnosis

Prompt diagnosis of anaphylaxis is important because recovery is mostlikely if epinephrine is given within 30 minutes of onset of symptoms [2,18].However, the administration of such medication to patients with cardiacconditions who are not having an episode of anaphylaxis can lead to a fatalevent [16]. The history and physical examination remain the mainstay ofdiagnosis. Elucidating a temporal relationship between onset of symptomsand possible antigen exposure should be the focus of the history ina suspected episode of anaphylaxis (Table 2). Serum analysis of tryptaselevels is valuable in confirming an anaphylactic reaction, although treatmentof a suspected reaction should not be postponed while waiting for assayresults. Tryptase is a preformed mediator released by mast cells on antigenexposure (see Table 1) and has a half-life of several hours. Histamine, on theother hand, has a half-life of minutes and can be measured by immunoassayonly if blood is drawn very early in an acute event [2]. Optimally, a mast celltryptase assay should be taken within the first hour of an attack and thenrepeated at 2, 12, and 24 hours [19].

When anaphylaxis is suspected, an appropriate differential diagnosis mustbe promptly formulated [16]. Conditions to consider include asthma, cardiacarrhythmia, myocardial infarction, aspiration, seizure disorder, hypoglyce-mia, pulmonary embolism, vasovagal reaction, hereditary angioedema,carcinoid syndrome, systemic mastocytosis, panic attack, and psychogenicdisorders [2,6]. A targeted (and quick) history and physical examination andassessment of the objective vital signs will help determine the correctdiagnosis.

Treatment

After the extent and severity of an anaphylactic reaction have beenaccurately assessed, basic life support measures should be taken (Box 3).


As always in a life-threatening medical emergency, one should assess theABCs (airway, breathing, circulation). Attention is first directed to theestablishment or maintenance of a patent airway. Breathing is supported ifnecessary, and circulation is assessed through the physical examination andthe monitoring of vital signs. The rapid and appropriate administration of

Table 2

Signs and symptoms of anaphylaxis*

Mild Onset can take up to 1 hour, and is primarily local

Major wheal/flare at cutaneous site if skin test, allergy shot, or

insect sting; pruritis, rhinorrhea and/or sneezing, flushing,

sweating, globus complaint and/or ‘‘uneasy’’ feeling, tachycardia

Moderate Mild symptoms within 30 minutes, plus more systemic

manifestations

Mild wheeze and/or cough, urticaria and/or angioedema with

hoarseness

Severe Onset usually within 20 minutes, symptoms as above, plus some of

the following:

Pulmonary with status asthmaticus; cutaneous with angioedema

from lips to larynx, with stridor and/or massive urticaria;

gastrointestinal with nausea, vomiting, cramps and/or diarrhea;

genitourinary with cramps and/or incontinence; cardiovascular

with hypotension, arrhythmia, and/or signs of shock; central

nervous systems with a feeling of impending doom and/or loss of

consciousness

* Can involve the skin, respiratory, cardiovascular, gastrointestinal, central nervous, and

genitourinary systems.

Box 3. Steps in managing an anaphylactic reaction in themedical office setting

� CALL FOR HELP (first 20 minutes is critical).� Place patient supine or in Trendelenberg position.� Assess airway, breathing, and circulation.� Administer epinephrine subcutaneously if reaction is obviouslysevere.

� Apply tourniquet above the injection site and administerlocal anesthetic with epinephrine (or half the plannedepinephrine injection) and ice at the injection site if thereaction is secondary to an allergy shot.

� Administer oxygen; secure airway as needed if the patientis unconscious.

� Establish an intravenous line and start rapid infusion.� Use vasopressors, bronchodilators, H1 and H2

antihistamines, steroids, and heparin as needed and asoutlined in Table 3.


Table 3

Medications and their dosages for anaphylactic reactions

Agent Dosage

Vasoactive Agents

Epinephrine Adult 0.3–0.5 cm3 (1:1000) IM or SC

(a- and b- agonist effects):adjust as appropriate for age,

weight, co-existing medical

conditions, habitual

medications

Child 0.01 mg/kg (1:1000) IM or SC

Can use EpiPen, EpiPen Jr (Dey L. P., Napa, CA)

for 1 or 2 premeasured doses

Repeat up to q 10 min as needed (can repeat initial

dose in 3 min if no response secondary to severity

of attack, or obesity with much subcutaneous fat

impairing absorption. Consider tongue,

sternocleidomastoid muscle, or IV (1:10000

solution given 1 lg/min initially, then 2–10 lg/min)

Dopamine 5 cm3 of 80 mg/cm3 in 500 mL IV solution, at

(a-agonist effect) 5 lg/kg/min if blood pressure not responding to

fluids; titrate to effect up to 20 lg/kg/min

(epinephrine appropriate for initial and short-term

effect, but longer-term control requires agent with

fewer adverse effects such as dopamine)

Nitroprusside 50 mg in 250 mL of D5W, 0.3–8 lg/kg/min

If epinephrine has caused

excessive hypertension, be

careful not to overshoot and

cause hypotension; ramp up

IV drip slowly

Antihistamines

Diphenhydramine All ages ¼ 1 mg/kg IV/IM

(H1 and mild H2 receptor

competitive inhibitor)

H2 receptor competitive

inhibitors

Ranitidine 1 mg/kg IM/IV over 2+ min

Cimetidine 4 mg/kg IM/IV over 2+ min

Heparin 100 USP Units/Kg IV (all ages)

Binds histamine and releases

histaminase into circulation;

do not use if bleeding problem

(eg, head injury, ulcers)

Bronchodilators

Albuterol or metaproterenol 2 puffs (all ages), or 0.25–0.5 mL in 2 mL saline for

adults

Aminophylline

only if inhaled agent fails 6 mg/kg IV over 30 min, then 0.5–0.8 mg/kg/hr IV

drip for adults and 1 mg/kg/hr children

Steroids

Hydrocortisone Adult: 250–500 mg IV/IM

Decreases effects of late-phase

reaction

Child: 10–100 mg IV/IM


epinephrine may quickly reverse the symptoms of anaphylaxis. Some casesof anaphylaxis, however, will progress to death even with expeditious andappropriate use of epinephrine. The route of administration of a specificdose of epinephrine determines its plasma concentration. Intramuscularinjection into the thigh is preferred to subcutaneous or intramuscularadministration in the upper arm [20]. The dose of epinephrine is 0.01 mL/kg of 1:1000 solution, up to 0.3 to 0.5 mL, given intramuscularly orsubcutaneously every 10 minutes as needed (Table 3) [1,6]. Autoinjectableepinephrine for emergency self-administration is available in both adultand child dosing (Fig. 2). Inhaled b-agonists are also important to helpreverse bronchoconstriction and may be more important than theadministration of epinephrine in cases of anaphylaxis caused by a foodallergen [16]. Oxygen is necessary because of the hypoxia associated withbronchospasm. Intravenous fluid administration should also be used as

Table 3 (continued )

Agent Dosage

Methylprednisolone 100 mg IV/IM, or 1–2 mg/kg

(consider longer half-life, but

slower onset, Of

dexamethasone IV or po for

control of late-phase

reactions)

Miscellaneous

Intravenous volume expanders

(D5LR, normal saline, others)

Oxygen

Abbreviations: IM, intramuscularly; IV, intravenously; SC, Subcutaneously; PO, by mouth.

Fig. 2. Autoinjectable epinephrine EpiPen Jr. (Photo courtesy of DEY L.P. Napa, CA).


a first-line treatment to expand intravascular volume and combathypotension. As a second-line treatment, intravenous antihistamines mayprove useful in controlling the systemic symptoms of mast cell de-granulation. Diphenhydramine can be given orally, intramuscularly, orintravenously at a dose of 1 mg/kg up to a maximum of 50 mg every 6hours [6]. Corticosteroids may be useful in abating the late-phase responseof anaphylaxis but will not be helpful with the early-phase mediatorsunless given prophylactically well before allergen challenge (as with theadministration of a radiologic contrast agent in a patient with a knownsensitivity to the agent).

Prevention

Appropriately treated cases of anaphylaxis can still progress to death;therefore, prevention is a critical treatment strategy in a patient known tohave severe sensitivities. Identification of allergens through thoroughhistory taking and serologic testing is important in guiding those patientsto avoid exposures that can cause reactions. Although patients may well beaware of food allergens that cause an anaphylactic reaction, completeavoidance is not always possible. Studies of fatal reactions caused by foodsdemonstrate that the offending foods were inadvertently ingested in verysmall quantities as part of other foods, such as peanut oil (in a personsensitive to such) used to fry an apparently unrelated food such asa doughnut or French fries. Complete avoidance of insect stings is alsodifficult, and immunotherapy offers an effective means of preventing life-threatening allergy episodes. In general, oral instead of intravenousmedications should be administered whenever possible (especially inpatients with other medication sensitivities), because intravenous adminis-tration is associated with a much higher incidence of anaphylaxis. Patientswith known anaphylactic reactions should wear an identifying bracelet ornecklace listing the offending agent. Patients who must receive agents towhich they have a known allergy, such as a contrast medium for a radiologicexamination or an antibiotic for a life-threatening infection, benefit frompremedication with antihistamines and corticosteroids. b-Blockers act ascompetitive inhibitors of catecholamines, and their use makes treatment ofanaphylactic episodes difficult (Box 4). The use of b-blockers should bediscontinued whenever possible during periods of high risk (eg, in thesummer in patients with known reactions to insect stings) or in all patientsduring immunotherapy.

Special considerations

b-Blockers, such as propranolol, act by competitively inhibiting b-adrenergic receptors, resulting in decreased production of intracellular cyclic


adenosine monophosphate (cAMP) and blunting of the multiple metabolicand cardiovascular effects of circulating catecholamines. These negativeinotropes and chronotropes reduce myocardial contractility and heart rate,which in turn can lower blood pressure and myocardial oxygen demand.These agents are important in the treatment of hypertension but can alsoinhibit the effective treatment of anaphylaxis. b2-receptor blockade inhibitsrelaxation of smooth muscle in blood vessels, bronchi, and the gastrointes-tinal and genitourinary tracts, and as such aggravates the respiratorycompromise caused by the edema, bronchoconstriction, and vascularpermeability from the circulating mediators of anaphylaxis. Becauseepinephrine is both an a- and a b-adrenergic agonist, the unopposeda-adrenergic effect of epinephrine causes vasoconstriction, and severehypertension can result. Because nonselective b-blockers counteract thevasodilatory, inotropic, and chronotropic effects of both epinephrine andmost bronchodilators, treatment of anaphylaxis in these patients requires the

Box 4. b-Blockers and anaphylaxis

� When a patient with an anaphylactic reaction is taking a b-blocker, the a-adrenergic action of epinephrine is uncheckedand can cause hypertension and bradycardia, but thebronchospasm remains because the b effect of epinephrine hasbeen blocked. In such cases, consider these options:

� Give initial epinephrine dose, but monitor blood pressure andreduce subsequent doses (if needed) by one half.(Phentolamine may still be needed for hypertension at dosagesof 5 to 10 mg intravenously every 10 minutes, 0.1mg/kg inchildren.)

� Follow administration of an inhaled b-agonist with ipratropium(2–4 puffs; anti-cholinergic bronchodilation is unaffected by bblockage).

� Administer diphenhydramine, steroids, and heparin as inTable 3.

� Consider administering glucagon (1–5 mg intravenouslyfollowed by 5–10 lg/min) to improve cardiac output.

� Consider administering atropine (0.3–0.5 mg subcutaneouslyevery 10 minutes for a maximum dose of 2 mg) for bradycardiaand/or bronchospasm).

� Consider administeringMgSO4 (1–4 g intravenously) to improvecardiac output. Magnesium is thought to antagonizetransmembrane calcium channels, thereby modifying calciumion flux and promoting airway smooth muscle relaxation.Magnesium may also facilitate binding of ß-agonists to theirreceptors.


use of additional agents such as glucagon, atropine, ipratropium, andmagnesium sulfate (see Box 4).

All physicians should be adept at diagnosing and treating anaphylaxis.Treatment requires knowledge of the clinical signs and symptoms ofanaphylaxis in addition to a well-developed plan to treat the conditionrapidly and with minimal time used to consult references or obtainassistance. This knowledge is especially important for physicians who treatpatients with asthma, perform allergy testing, provide immunotherapy, orcare for hospitalized patients.

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