Anaphylaxis

How to recognize, treat, and prevent potentially fatal attacks

Richard Wyatt, MD
VOL 100 / NO 2 / AUGUST 1996 / POSTGRADUATE MEDICINE

This is the third of five articles on allergy

Preview: A severe anaphylactic reaction can be terrifying for the person experiencing it.
Fortunately, reactions are usually mild. But because of the suddenness of attacks, wide spectrum of
causes, and variable clinical course, prompt recognition and treatment can be lifesaving. Dr Wyatt
gives tips on diagnosis, treatment, and prevention.

Anaphylaxis is a life-threatening syndrome triggered by a wide range of antigens and involving

multiple organ systems. The true incidence is difficult to estimate, but in 1973 the Boston
Collaborative Drug Surveillance Program (1) reported six anaphylactic reactions and 0.87 deaths
from anaphylaxis per 10,000 patients. Reactions to insect stings alone are responsible for at least 50
deaths in the United States each year. All physicians need to be aware of the suddenness with which
symptoms, severe reactions, and even death can occur in otherwise healthy persons. Rapid
institution of appropriate treatment is essential for a favorable outcome.

Mechanisms and causes

The release of mediators such as histamine from the mast cells and basophils (figure 1) is
responsible for the immediate clinical manifestations of anaphylaxis. A late-phase response caused
by the recruitment of other inflammatory cells, including eosinophils, can occur hours after the
initial reaction. Anaphylaxis is usually thought of as an IgE-mediated allergic reaction to such
things as foods, insect venoms, drugs, and latex. The mast cell, however, can be induced to react by
other means, including (1) direct activation by exercise, opiates, and possibly radiocontrast agents,
(2) disturbances of arachidonic acid metabolism by cyclo-oxygenase inhibitors such as aspirin and
nonsteroidal anti-inflammatory drugs (NSAIDs), and (3) complement activation by immune
complexes, caused by reactions to blood products and resulting in production of C3a and C5a (2).

Some patients have repeated anaphylactic episodes without the cause being determined. In a recent
study of 266 patients referred for evaluation when obvious causes (eg, insect stings,
immunotherapy) had been eliminated,3 37% were determined to have idiopathic disease (figure 2).
In patients in whom a cause was identified, common triggers included foods (eg, peanuts, fish, nuts,
eggs), drugs (NSAIDs, aspirin, penicillin, cephalosporins, insulin, sulfonamides, blood products,
vaccines, and enzymes such as trypsin, chymopapain, and streptokinase), exercise, and latex.

Clinical features
The clinical manifestations of anaphylaxis can occur within seconds of antigen exposure. With fatal
reactions, the respiratory and cardiovascular systems are often affected initially. Severe upper
airway obstruction by angioedema can lead to asphyxia, while lower airway obstruction with
wheezing and chest tightness is caused by bronchospasm. Severe hypotension is usually caused by a
massive shift of fluid from the intravascular to the extravascular space. Profound losses of

intravascular volume can occur quickly as a result of increased vascular permeability. Patients
compensate through maximal vasoconstriction initiated by the release of catecholamines and
angiotensin.
Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal pain. Flushing,
urticaria, and angioedema are cutaneous signs. Patients may experience a feeling of impending
doom and light-headedness and sometimes sense a metallic taste in the mouth. In most cases, the
slower the onset of symptoms, the less severe the reaction. Some patients experience recurrence of
symptoms hours after apparent remission of the initial reaction (late-phase anaphylaxis). In patients
taking beta blockers, anaphylaxis is often severe and may be refractory to conventional
management (4).

Differential diagnosis
When a patient presents with sudden symptoms of dizziness, syncope, or flushing, rapid assessment
is essential so that an appropriate course of management can be determined. Many conditions need
to be considered (table 1). The vasovagal reaction is the one most commonly confused with
anaphylaxis (5). It usually follows a painful intervention such as an injection and is manifested by
pallor, light-headedness, nausea, profuse diaphoresis, and syncope. Symptoms improve promptly
with recumbency and disappear altogether without treatment in 20 to 30 minutes. The lack of
pruritus in the presence of a slow pulse rate and normal blood pressure distinguishes a vasovagal
attack from anaphylaxis.
Table 1. Conditions to consider in differential diagnosis
of suspected anaphylaxis
Cardiac arrhythmia
Myocardial infarction
Food aspiration
Seizure disorder
Insulin reaction
Pulmonary embolism
Flushing syndromes
Globus hystericus
Vasovagal reactions
Fictitious allergic reactions

Ingestion of spoiled fish from the tuna family may result in urticaria, pruritus, flushing,
gastrointestinal upset, and headache. The cause of this reaction is a histaminelike substance
(saurine) produced through bacterial contamination. Other factors, such as the presence of a
carcinoid tumor or a reaction between alcohol and chlorpropamide, can cause flushing-type
reactions. Psychosomatic conditions can present as vocal cord dysfunction or outright fictitious
anaphylaxis. The measurement of mast cell tryptase in the blood confirms the diagnosis of
anaphylaxis.

Treatment
Treatment of anaphylaxis consists of both short- and long-term management (table 2). The
immediate goal is to maintain an adequate airway and support the blood pressure. Patients having
severe reactions should be given oxygen. Epinephrine should be administered as soon as the
diagnosis is made. The standard dose is 0.01 mL/kg of a 1:1,000 solution, up to a maximum of 0.3

to 0.5 mL, given subcutaneously every 10 to 20 minutes until the patient's condition is stable. In
life-threatening reactions with shock, intravenous administration may be necessary; this route,
however, poses risks of ventricular arrhythmias and myocardial ischemia. For this reason,
intravenous epinephrine is given slowly in low doses. This form of epinephrine is available in 10mL injectable ampules (0.1 mg/mL in a 1:10,000 solution) for bolus infusions. It should be given
over at least a 10-minute period, but the dose is usually limited to 3 mL for an average-sized (70-kg)
adult (6). Continuous infusion may subsequently be needed to sustain the blood pressure. Advanced
Cardiac Life Support guidelines recommend an infusion rate of 1 to 4 micrograms/min in adults
being monitored electrocardiographically (7).
Table 2. Management of anaphylaxis
First-line therapy
Airway maintenance
Oxygen
SC: 0.01 mL/kg, to maximum of 0.3 to 0.5 mL, of 1:1,000 aqueous solution (1
Epinephrine mg/mL)
IV: 1 to 3 mL of 1:10,000 aqueous solution (0.1 mg/mL) given over 10 min, or 1 to 4
micrograms/min (0.25 to 1 mL/min of a solution of 4 micrograms/mL made with 1
mL of 1:1,000 epinephrine in 250 mL fluid)
Fluids

10 to 20 mL/kg of 6% hetastarch in normal saline or 5% human albumin solution, or

5% dextrose in 0.5N saline solution or lactated Ringer's injection
Second-line therapy
Diphenhydramine HCl, 50 mg PO, IM, or IV
Methylprednisolone sodium succinate, 125 mg IV
Bronchodilators: inhaled beta2 agonists, IV aminophylline
Vasopressors: norepinephrine or dopamine HCI
Third-line therapy
Histamine2 antagonists
Glucagon,* 1-mg ampule
Atropine sulfate,* 1 mg IV
Isoproterenol,* 0.1 micrograms/kg per minute initially, with increases at this rate every 10 minutes
until blood pressure is stabilized or heart rate reaches 200 beats per minute (use only in healthy
children and young adults without heart disease) (mix 2.5 mL of 1:5,000 isoproterenol solution [0.2
mg/mL] in 50 mL fluid to equal 10 micrograms/mL)

*Useful in refractory anaphylaxis induced by beta-blocker therapy.

Hypotension should be treated with intravenous fluids to expand the intravascular volume. Colloids
(6% hetastarch in normal saline solution or 5% human albumin), when available, may have an
advantage over crystalloid solutions (5% dextrose in 0.5N saline solution [D5 1/2 NS] or lactated
Ringer's injection), because colloids remain in the intravascular space and potentially attract
extravasated fluid into the vascular space (6).
Antihistamines are useful as second-line therapy when a prolonged course is suspected.
Diphenhydramine hydrochloride can be given orally, intramuscularly, or intravenously at a dose of
1 mg/kg up to a maximum of 50 mg every 6 hours. The combined use of H1 and H2 histamine
antagonists is controversial, but cimetidine has been used in doses of 4 mg/kg.
Corticosteroids may not be helpful in immediate management of anaphylaxis but can be useful in
treating prolonged urticaria or a late-phase response. Methylprednisolone sodium succinate is
usually given in large doses (125 mg) every 6 hours. Bronchospasm should be treated with inhaled
beta2 agonists, with the option of using intravenous aminophylline in resistant cases.
Refractory anaphylaxis in patients receiving beta-blocker therapy requires the use of additional
agents (4). Some success has been achieved with glucagon, which may increase cardiac cyclic
AMP, thereby enhancing cardiac output. This agent is available as a 1-mg ampule that can be given
intravenously as often as every 5 minutes because of its short half-life. Another option for refractory
bronchospasm is 1 mg of atropine sulfate given by intravenous push. Beta blockers act as a
competitive inhibitor of catecholamines, and beta2 agonists given in high doses may counteract this
effect. Isoproterenol hydrochloride is usually given intravenously at an initial rate of 0.1
micrograms/kg per minute and then increased by this amount every 10 minutes until the blood
pressure is stabilized or the heart rate increases to 200 beats per minute (8). This agent should be
avoided when possible in adults, particularly those with heart disease, because myocardial ischemia
can result.

Prevention
The most important component of anaphylaxis management is prevention (table 3). Identification
and subsequent avoidance of the offending allergen or other nonimmunologic causes seems an
obvious first step. Since stinging insects cannot be consistently avoided, venom immunotherapy
offers an effective means of preventing life-threatening reactions. Patients receiving allergy
immunotherapy (as well as any high-risk drug) should be observed for 30 minutes after therapy is
given. When possible, drugs should be given orally, since reactions are less severe than with
parenteral administration. Patients with known allergies can wear medical identification tags that
provide vital information about appropriate treatment in the event a patient is unable to
communicate with the physician.
Table 3. Measures to prevent anaphylaxis
Identify and avoid allergens or other causes.
Encourage high-risk patients to wear medical identification containing relevant information.
Provide immunotherapy for venom-sensitive patients.
When possible, use oral route for drugs.
Observe patient for 30 minutes after initial dose of a high-risk drug.
Instruct patients to avoid exercise for 1 hr before and several hours after high-risk
procedures.
Discontinue beta-blocker therapy during periods of high risk.
For patients with sensitivity to radiocontrast agents, provide pretreatment as follows: (1) 50
mg of prednisone given 13, 7, and 1 hr before procedure using radiocontrast material, (2) 50

mg of diphenhydramine HCl given 1 hr before procedure, (3) 25 mg of ephedrine sulfate

given 1 hr before procedure (9).
Consider alternate-day corticosteroid therapy for patients with severe idiopathic anaphylaxis.

Prescribe epinephrine for high-risk patients and instruct them in self-administration.

Exercise can induce anaphylaxis on its own in some patients and in others can create an additional
risk after exposure to allergens such as foods and immunotherapy. Thus avoidance of exercise for 1
hour before and several hours after a high-risk procedure (eg, immunotherapy, injection of
penicillin, procedures using radiocontrast media) is standard.
Beta-blocker therapy should be discontinued during periods of high risk. For example, the agents
should be avoided by venom-sensitive patients during warm seasons, by those receiving
immunotherapy injections, and by persons sensitive to radiocontrast material who are undergoing
procedures using this material. Premedication with corticosteroids, antihistamines, and ephedrine
sulfate can be very effective for patients with a history of reactions to radiocontrast materials who
are undergoing repeated studies (9). Patients with idiopathic anaphylaxis who have life-threatening
reactions can be effectively managed by long-term oral corticosteroid therapy every other morning
(10).
All patients at risk for anaphylactic reactions should be given a prescription for an emergency
epinephrine kit or syringe and instructions on self-administration (see box on page 98). Patients
need to make arrangements to have the kit readily available in the event of a reaction, since a short
delay in administration can be fatal.

Summary and conclusions

Anaphylaxis is a potentially fatal condition. Causes range from bee stings to drugs, foods, and
exercise. Onset is usually sudden, and a delayed reaction may occur hours after the initial reaction.
Treatment consists of airway maintenance and support of the blood pressure with fluid expanders,
epinephrine, and oxygen. Additional agents, such as corticosteroids, antihistamines, vasopressors,
glucagon, atropine sulfate, and isoproterenol hydrochloride, can be useful. Prevention is the most
important part of anaphylaxis management. In patients with known allergies, self-administration of
epinephrine plays a key role in reducing mortality.
Epinephrine for emergency self-administration
Epinephrine for self-administration is vital for patients with a history of anaphylactic reactions. Such
patients should be given a prescription for an emergency epinephrine kit or syringe, and the patient
(or parent) should be instructed in proper administration of the drug. The kit or syringe should be
readily available at all times. Exposure to air and light can cause the epinephrine to oxidize and turn
brown, at which point the syringe should be replaced.
Epinephrine for emergency self-administration is available in several forms. The Ana-Kit (figure 1)
contains a syringe (Ana-Guard Epinephrine), tourniquet, chlorpheniramine maleate tablets, and an
alcohol swab. The syringe has a 25-gauge needle and is operated manually, so there is little chance of
accidental injection. A maximum dose of 0.3 mL of 1:1,000 epinephrine can be delivered at once,
and graduations on the syringe barrel allow delivery of smaller doses for children. A second 0.3-mL
dose can be delivered if symptoms do not improve. The syringe alone costs about $21 and the entire

kit about $28.50.

The EpiPen Auto-Injector (figure 2) is a self-injecting syringe that automatically delivers a single
0.3-mL dose of 1:1,000 epinephrine. (A pediatric version, EpiPen Jr, dispenses 0.3 mL of 1:2,000
epinephrine.) This device is popular among patients who are uncomfortable injecting themselves. It
has been useful in schools and daycare facilities, where trained personnel may not be available. It is
simple to use and requires a force of only about 3 lb to the tip to trigger the injection mechanism.
However, caution must be used to avoid accidental injection. The 22-gauge needle is propelled by a
spring that generates 16 lb of force; this could be problematic if the needle were to hit solid tissue
such as bone. EpiPen costs about $39.

The EpiE-Z Pen (figure 2) is a smaller, easy-to-carry version of the EpiPen. A pediatric version,
EpiE-Z Pen Jr, is also available. This device is activated manually, which reduces the likelihood of
accidental injection. The cap can be used as a cover over the exposed needle after it has been used. A
trainer version is included to familiarize the patient with proper technique. EpiE-Z Pen costs about
$40.

References
1. Boston Collaborative Drug Surveillance Program. Drug-induced anaphylaxis. JAMA
1973;224(5):613-5
2. Marquardt DL, Wasserman SI. Anaphylaxis. In: Middleton E Jr, Reed CE, Ellis EF, eds.
Allergy: principles and practice. 4th ed. St Louis: Mosby, 1993:1525-36
3. Kemp SF, Lockey RF, Wolf BL, et al. Anaphylaxis: a review of 266 cases. Arch Intern Med
1995;155(16):1749-54
4. Lang DM. Anaphylactoid and anaphylactic reactions: hazards of beta-blockers. Drug Safety
1995;12(5):299-304

5. Lieberman P. Distinguishing anaphylaxis from other serious disorders. J Respir Dis

1995;16(4):411-20
6. Brown AF. Anaphylactic shock: mechanisms and treatment. J Accid Emerg Med
1995;12:89-100
7. Jaffe AS. Textbook of Advanced Cardiac Life Support. 2d ed. Dallas, Tex: Am Heart Assn,
1990:97-9
8. Lawlor GJ Jr, Rosenblatt HM. Anaphylaxis. In: Lawlor GJ, Fischer TJ, Adelman DC.
Manual of allergy and immunology. 3d ed. Boston: Little, Brown, 1995:244-52
9. Greenberger PA, Patterson R, Radin RC. Two pretreatment regimens for high-risk patients
receiving radiographic contrast media. J Allergy Clin Immunol 1984;74(4 Pt 1):540-3
10. Patterson R, Clayton DE, Booth BH, et al. Fatal and near fatal idiopathic anaphylaxis.
Allergy Proc 1995;16(3):103-8
Dr Wyatt is a member of the department of allergy, Park Nicollet Clinic, Minneapolis; director of
pediatric allergy, Hennepin County Medical Center, Minneapolis; and clinical assistant professor,
department of pediatrics, University of Minnesota Medical School-Minneapolis. Mailing address:
Richard Wyatt, MD, Park Nicollet Clinic, Department of Allergy, 3800 Park Nicollet Blvd,
Minneapolis, MN 55416. E-mail address: [email protected].

Symposium

Introduction
Allergic and nonallergic rhinitis: Directing medical therapy at specific symptoms by
David F. Graft, MD
Urticaria: The diagnostic challenge of hives by Richard J. Sveum, MD
Anaphylaxis: How to recognize, treat, and prevent potentially fatal attacks by Richard
Wyatt, MD
Asthma: Specific preventive strategies by Richard J. Morris, MD
Safe allergen immunotherapy: The correct allergen, the appropriate patient, the
adequate dose by William F. Schoenwetter, MD