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emedicine.medscape.com

Pediatric
Anaphylaxis
Updated: Sep 15, 2016
Author: Jeffrey F Linzer, Sr, MD, FAAP, FACEP,
MICP; Chief Editor: Kirsten A Bechtel, MD

Overview
Anaphylaxis is an acute, potentially life-threatening
syndrome — with multisystemic manifestations due
to the rapid release of inflammatory mediators. In
children, foods can be a significant trigger for
immunoglobulin E (IgE)-mediated anaphylaxis.
Milk, eggs, wheat, and soy (MEWS) as a group are
the most common food allergens; however, peanuts
and fish are among the most potent. In fact,
children can develop anaphylaxis from the fumes of
cooking fish or residual peanut in a candy bar.

Other common triggers include preservatives (in

food and drugs), medications (antibiotics), insect
venom (bee sting), and bioactive substances (eg,
blood, blood products). Environmental allergens
such as pollens, molds, and dust mites are a less
common and infrequent cause of anaphylaxis. Non-
IgE triggers include infection, opiates, radiocontrast
dye, and exercise.

To see complete information on Anaphylaxis,

please go to the main article by clicking here.

Anaphylaxis vs anaphylaxis syndrome

Although the clinical presentation and management
are the same, the term anaphylaxis generally refers
to IgE-mediated reactions, whereas the term
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to IgE-mediated reactions, whereas the term

anaphylactoid generally refers to non–IgE-mediated
reactions. The term anaphylaxis syndrome is best
used to describe clinical symptoms and signs.

Pathophysiology

IgE- and Non–IgE-Mediated Reactions

Both IgE and non-IgE activation of mast cells and
basophils ignites a cascade that results in the
release and production of several inflammatory and
vasoactive substances. These bioactive materials
include histamine, tryptase, heparin, prostaglandins
(PGD2, PGF2), leukotrienes (LTC4, LTD4, and
LTE4), cytokines (TNF‑α), and platelet-activating
factor (PAF). In anaphylaxis, these substances
most commonly involve the skin, respiratory,
cardiovascular, and gastrointestinal systems. As a
result, urticaria, angioedema, bronchospasm,
bronchorrhea, laryngospasm, increased vascular
permeability and decreased vascular tone, and
bloody diarrhea can develop.

The most common cause of mediator release is

due to an IgE-mediated reaction. A previously
sensitized B lymphocyte produces IgE against a
specific antigen. The IgE resides on the mast cells
and basophils. When the specific antigen, or one
similar to it, binds to the high affinity FcεRI-α
receptor of the immunoglobulin, mast cell and
basophil degranulation occurs.

Non-IgE mediator release can be triggered by

several different mechanisms including stimulation

of the complement cascade to produce C3a, C4a,

and C5a anaphylatoxin, neuropeptide and cytokine
activity, and direct stimulation of the kallikrein-kinin
system by certain agents (eg, opiates, radiocontrast
media).

Activation of Histamine Receptors

Many of the clinical presentations seen in

anaphylaxis are due to activation of multiple
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anaphylaxis are due to activation of multiple

histamine receptors.[1] For example, acute
bronchospasm (wheezing, dyspnea) is a result of
the interaction between H1 and H2 receptor activity;
bronchial smooth muscle constriction and increased
mucus viscosity from H1 receptor activity and H2
activity causes increased mucus production. The
combination of H1 and H2 receptor stimulation
results in increased vascular permeability, flushing,
hypotension, tachycardia, and headache. H1 and
H3 activity results in cutaneous itch and nasal
congestion.

Other Precipitating Agents in

Anaphylaxis
Histamine, however, is not the only agent to cause
symptoms in anaphylaxis.[2] Prostaglandins,
leukotrienes, and PAF all contribute to the
bronchoconstriction, vascular changes, and
changes in vascular capacitance (increased
vascular permeability and vasodilatation). One
study showed an inverse correlation between PAF
acetylhydrolase activity and the severity of
anaphylaxis.[3] Compared with a placebo group,
patients with anaphylaxis due to peanuts who had
low PAF acetylhydrolase activity were more likely to
have a fatal outcome.

Common Triggers of Pediatric

Anaphylaxis
Foods are the most common trigger of anaphylaxis
in children, with peanuts being the most frequent
primary cause.[4] The following list is only meant to
be illustrative of the more common anaphylactic
triggers and therefore should not be considered an
exhaustive listing. These triggering agents may
cause an IgE- or non–IgE-mediated anaphylaxis:

Foods (most common cause in children) –

Milk, eggs, wheat, soy, fish, shellfish,
legumes (peanuts), tree nuts[5]

Medicinals – Antibiotics (penicillins,

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cephalosporins), local anesthetics

(lidocaine), analgesics (aspirin, nonsteroidal
anti-inflammatory drugs [NSAIDS]
[ibuprofen], opiates [codeine, morphine]),
dextran, radiocontrast media

Biologics – Venoms (bee sting, ant or snake

bite), blood and blood products, vaccines,
allergen extracts

Preservatives and additives – Metabisulfite,

monosodium glutamate

Other – Latex

Unknown, idiopathic causes

Epidemiology of Anaphylaxis in
Children
Although Bohlke and colleagues estimated the rate
of anaphylaxis in children at 10.5 per 100,000
person-years,[6] the Rochester Epidemiology
Project showed a rate of 75.1 per 100,000 person-
years in children aged 9 years and 65.2 per
100,000 person-years in children aged 10-19-years
old.[7] Furthermore, anaphylaxis appears to be
more common in boys until the age of 15 years; a
female preponderance then continues through
adulthood.[8, 9] Infants younger than 12 months of
age with anaphylaxis will more often have a history
of atopic dermatitis.[10]

While asthma is more prevalent and has a higher

mortality rate in black children, race does not
appear to affect the likelihood of developing
anaphylaxis.[11]

Evaluation of Pediatric
Anaphylaxis
Signs and Symptoms
Anaphylaxis involves a range of signs and
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Anaphylaxis involves a range of signs and

symptoms from hives, wheezing and angioedema
to cardiovascular collapse and death.[12, 13] More
than 80% of the patients will present with
cutaneous symptoms (eg, hives, pruritus, facial
swelling). Generally, at least 2 organ systems (skin,
respiratory, cardiovascular, gastrointestinal
systems) are involved; however, anaphylaxis can
present with a low systolic blood pressure for age
or decrease in systolic blood pressure by more than
30% after known allergen exposure alone.[14]

The Second National Institute of Allergy and

Infectious Disease (NIAID) / FAAN symposium
proposed diagnostic criteria that would identify at
least 95% of the patients with anaphylaxis.[14] The
primary clinical diagnostic criteria include the acute
onset of skin and/or mucosal symptoms along with
either respiratory compromise (eg, bronchospasm,
stridor, shortness of breath) and/or persistent
gastrointestinal symptoms (crampy abdominal pain,
vomiting) and/or reduced blood pressure or
associated symptoms of end-organ dysfunction (eg,
hypotonia, syncope, incontinence).

Usually, cutaneous symptoms present first. Often, a

history of exposure to a known trigger is given, (eg,
bee sting, peanut ingestion, antibiotic
administration). At times, the inciting agent may be
unknown or unclear. Symptoms may develop slowly
and insidiously over several hours or may rapidly
progress over several minutes. Parenteral agents
generally have a faster onset of symptoms than
ingested ones.

Anaphylaxis may result in respiratory failure, shock,

multiorgan system failure, and disseminated
intravascular coagulation. Between 5% and 20% of
patients may experience a recurrence of
anaphylaxis 8-12 hours after the initial presentation.
[15] Prolonged symptoms can last up to 32 hours
despite treatment.[12]

To see complete information on Anaphylaxis,

please go to the main article by clicking here.

Special challenges

Initial symptoms may include an awareness that

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Initial symptoms may include an awareness that

"something isn't right"; a tingling sensation in the
mouth; itchy, watery nose and eyes; and/or the
feeling of being warm and flushed. However,
children and especially infants may not be able to
verbally express the initial subjective symptoms of
anaphylaxis. Infants may be more likely to have
crying, persistent vomiting and irritability than older
children.[10] Additionally, the verbal child may not
be able to identify the triggering agent (eg, food)
even when known to the parent or caretaker.

Differential Diagnosis
Angioedema

Asthma

Bee and Hymenoptera Stings

Carcinoid Tumor

Exercise-Induced Anaphylaxis

Serum Sickness

Shock

Shock, Cardiogenic

Shock, Hypovolemic

Status Asthmaticus

Syncope

Toxicity, Seafood

Anaphylaxis is essentially a clinical diagnosis. The

primary clinical diagnostic criteria include the acute
onset of skin and/or mucosal symptoms along with
either respiratory compromise (eg, bronchospasm,
stridor, shortness of breath) and/or persistent
gastrointestinal symptoms (crampy abdominal pain,
vomiting) and/or reduced blood pressure or
associated symptoms of end-organ dysfunction (eg,
hypotonia, syncope, incontinence).

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Other problems to be considered include

mastocytosis, physical urticaria, "red man
syndrome" (related to the intravenous
administration of vancomycin), and vocal cord
dysfunction.

Diagnosis of Pediatric
Anaphylaxis
Laboratory tests generally are not useful for the
acute diagnosis of this condition, although serum
histamine and tryptase may be of limited help in
confirming the diagnosis retrospectively; other tests
(eg, specific antigen testing following recovery) may
provide some clues to triggering agents.[16]

Serum Histamine and Tryptase levels

Serum histamine level rises quickly with the onset

of symptoms but does not remain elevated after 30-
60 minutes.

Serum tryptase level peaks 60-90 minutes after the

onset of symptoms and remains elevated for up to
5 hours. β-tryptase is released with degranulation of
mast cells, whereas α-tryptase is secreted
constitutively by the mast cells. The ratio of total
tryptase to β-tryptase can help distinguish systemic
mastocytosis from anaphylaxis. A ratio ≤10 implies
anaphylaxis, whereas a ratio ≥20 is consistent with
systemic mastocytosis.[17]

C1INH, VMA, RAST, and Cutaneous

Antigen Testing

Other tests that may be useful in distinguishing

anaphylaxis from the differential diagnosis include
C1 inhibitor functional assay (C1INH) (hereditary
angioedema) and urine vanillylmandelic acid (VMA)
and serum serotonin levels (carcinoid syndrome).

Radioallergosorbent test (RAST) or cutaneous

antigen testing (preferably by a specialist) can be
used after recovery to try to identify the inciting
antigen.
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antigen.

Treatment of Children With

Anaphylaxis
Overview

The early use of epinephrine is the most important

step in managing anaphylaxis.[18, 19]
Administration in the anterolateral thigh appears to
provide superior absorption compared with deltoid
and subcutaneous injections.

Prehospital care should be directed at stabilization

of the airway, breathing, and circulation (the
"ABCs"). In addition, intravenous (IV) access should
be obtained; intraosseous (IO) access should be
considered when IV access cannot be quickly
obtained in unstable patients.

Patients with signs of poor profusion should be

placed in a modified Trendelenburg position with
the legs elevated. Crystalloid fluids should be given
rapidly if the patient is hypotensive or has other
signs of shock.

Emergency department consultation with a pediatric

critical care specialist should be obtained in
unstable patients and those unresponsive to
treatment. Outpatient consultation with an allergist
is appropriate for most patients with anaphylaxis,
especially those with the following factors:

Significant clinical presentation or those

requiring prolonged treatment

History of atopic disease

Unclear trigger or inciting agent

Recurrent episodes of anaphylaxis

Not all patients will present in shock. Most patients

present with skin complaints (eg, urticaria,
angioedema) along with respiratory,
gastrointestinal, or cardiovascular symptoms.
Primary attention is directed at the stabilization of
the patient's airway, breathing, and circulation. If not
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the patient's airway, breathing, and circulation. If not

already given, epinephrine (which acts as a
physiologic antagonist) should be administered as
soon as the diagnosis is suspected.

It cannot be stressed enough that the early use of

epinephrine is the most important step in managing
anaphylaxis.[12, 20, 21] An expert panel convened
by the American College of Allergy, Asthma and
Immunology urged that there are no
contraindications for the use of epinephrine in
treating anaphylaxis. Since delay in administration
may lead to more severe cases, one should
administer epinephrine when patients present with
the possibility any allergic symptoms, whether mild
or moderate in severity.[22, 23]

Antihistamines (H1 and H2 blockers),

corticosteroids, crystalloid fluids, and other
adrenergic agonists can also be beneficial in the
management of this condition.

To see complete information on Anaphylaxis,

please go to the main article by clicking here.

Observation Versus Inpatient Monitoring

Even patients with mild symptoms should be

observed for a minimum period of time. Although
the time of observation should be individualized to
the patient, a minimum of 4-8 hours appears
appropriate.

Children who require fluid resuscitation, multiple

doses of epinephrine, or repeated doses of a
bronchodilator should be hospitalized. At a
minimum, children who require vasopressors or
glucagon should be admitted to a tertiary pediatric
intensive care center (PICU).

Airway Management

If the patient is hypoxic or has respiratory

complaints, high-flow oxygen (warm, humidified air
is preferred) by nonrebreather mask should be
given. In the awake child who is having some
difficulty maintaining their airway, a nasopharyngeal
(NP) airway is better tolerated than an

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oropharyngeal (OP) airway.

Continuous positive airway pressure (CPAP) may

be considered before using an advanced airway
(eg, noninvasive pharyngeal airway, endotracheal
intubation) if the child is unable to maintain his or
her airway, has decreased oxygen saturation,
and/or has a decreasing level of consciousness.
The use of noninvasive positive pressure (eg,
CPAP) may help avoid the need for an advanced
airway. In patients with signs of significant hypoxia,
an advanced airway (eg, supraglottic airway device,
endotracheal intubation) should be considered. The
airway should be secured with an endotracheal
tube early in cases of upper airway obstruction.

Nebulized albuterol (2.5-5 mg/dose) may be used

for bronchospasm not responding to epinephrine.
Although the addition of ipratropium to albuterol has
been shown to be beneficial in severe asthma
exacerbations in children, this combination in
anaphylaxis has not been studied. Nebulized
epinephrine has been used for stridor secondary to
laryngeal edema but has not been studied in
anaphylaxis.

Epinephrine Administration

Epinephrine is the first drug of choice. The 1:1000

strength should preferentially be administered
intramuscularly (IM) in to the thigh. Subcutaneous
(SC) administration is no longer recommended.[14,
20, 24] Because of the risk of potentially lethal
dysrhythmias, IV/IO epinephrine (1:10,000) should
be reserved for the patient with uncompensated
shock.

The epinephrine dose may be repeated every 5-15

minutes. Administration in the anterolateral thigh
appears to provide superior absorption compared
with deltoid and SC injections.[25, 26]
Subcutaneous injection is not recommended. For
mild symptoms, diphenhydramine may be given
orally via IM/IV administration.

Nebulized albuterol (2.5-5 mg/dose) may be used

for bronchospasm not responding to epinephrine.

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for bronchospasm not responding to epinephrine.

Although the addition of ipratropium to albuterol has
been shown to be beneficial in severe asthma
exacerbations in children, this combination in
anaphylaxis has not been studied. Nebulized
epinephrine has been used for stridor secondary to
laryngeal edema but has not been studied in
anaphylaxis.

Blood Pressure Management

Patients with hypotension unresponsive to
positioning and epinephrine should receive a 20
mL/kg rapid crystalloid fluid bolus (eg, lactated
Ringer or isotonic sodium chloride). Repeat boluses
up to 60-80 mL/kg may be necessary for correcting
the hypovolemia.

Recall that children are more likely to have

compensated shock in which tachycardia and signs
of hypoperfusion (eg, decreased peripheral pulses,
cool extremities) are present, but the blood
pressure is normal.[27] A systolic pressure of less
than the 5th percentile for age would indicate
uncompensated shock, which correlates to the
following:

< 70 mm Hg in children aged 1-12 months

< 70 mm Hg + (2× age in years) in children

aged 1-10 years

< 90 mm Hg in children aged ≥10 years

Glucagon may help with refractory symptoms in the

patient taking a beta-blocker. In children, administer
20-30 mcg/kg (not to exceed a cumulative dose of 1
mg) IV over 5 minutes, followed by an IV
maintenance infusion and titrated to clinical effect at
5-15 mcg/min.
Treatment for Patients Unresponsive to
Fluid Resuscitation

Patients unresponsive to fluid resuscitation should

receive vasopressors as follows:

Epinephrine (0.1-1 mcg/kg/min IV) should be

considered as the initial vasopressor in
children. Doses at < 0.3 mcg/kg/min will tend

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children. Doses at < 0.3 mcg/kg/min will tend

to have more β-activity, whereas α-action
becomes more pronounced at higher doses.

Dopamine (2-20 mcg/kg/min IV) may be

used in addition to epinephrine. Greater α-
activity is seen at higher doses.

Norepinephrine (0.1-2 mcg/kg/min IV) is a

potent vasopressor. It is usually considered
in children unresponsive to epinephrine.

Treatment of Cutaneous Symptoms

The combination of H1 and H2 antihistamines
appears to be more effective, especially for
cutaneous symptoms.[14, 28] The onset of activity
of these agents is slower than epinephrine and are
considered next-in-line treatment. Second-
generation H1 antihistamines (eg, cetirizine,

loratadine) have not been studied in anaphylaxis.

Diphenhydramine 1 mg/kg (not to exceed 50

mg/dose) may be given IV/IM/PO or ranitidine,
which has a beneficial side effect profile in children,
1 mg/kg (not to exceed 50 mg/dose IV or 150
mg/dose PO) may be given. The oral use of these
agents should be restricted to mild cases.

Treatment of Late Phase Reaction

Corticosteroids do not have an immediate effect on

the symptoms of anaphylaxis but may help reduce
or prevent a biphasic "late phase" reaction. The
choice of methylprednisolone (IV), prednisone, or
prednisolone (PO) 1-2 mg/kg should be based on
the patient's presentation and condition. The effect
and time of onset are similar among these agents.
The dose may be repeated at 6-hour intervals as
indicated.

No published studies compare dexamethasone with

other corticosteroids in the treatment of
anaphylaxis. However, based on its use in other
allergic conditions, a dose of dexamethasone 0.15-
0.6 mg/kg IV would be appropriate.

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Outcomes in Pediatric
Anaphylaxis
The prognosis is good if anaphylaxis is treated
early. The development of shock, however, is a
poor prognostic indicator. In fact, the risk of death
due to respiratory and cardiovascular complications
is significant in anaphylaxis. Estimates of mortality
from anaphylaxis vary from 100 to more than 500
cases per year in the United States; the estimated
death rate is 0.002%.[29]

Delayed/biphasic anaphylactic response

A delayed or biphasic anaphylactic response may
occur in 1-20% of patients.[30] The literature is
unclear as to which patients are at greatest risk
from having this condition. The secondary response
may be milder, the same, or more severe than the
initial presentation. Patients with greater risk of
biphasic response should be observed a minimum
of 12-24 hours. Severity of symptoms, delay in
receiving epinephrine, and ingested antigen have
been implicated as risk factors.

All patients who had more than mild symptoms

and/or required more than 4 hours of observation

should be given a prescription for an auto-injector

of epinephrine. Patients and families should be
advised to call 911 or seek immediate medical
attention after epinephrine self-administration.

Patients should be continued on H1 and H2

blockers for 3 days after resolution of symptoms. A
second generation H1 may be used as part of
discharge care. A 3-day course of oral steroids may
be warranted.

Patient Follow-up for Pediatric

Anaphylaxis
Patients with anaphylaxis should follow up with their
pediatrician and be given a referral for allergy
evaluation and counseling. Moreover, patients and
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evaluation and counseling. Moreover, patients and

their caregivers should be educated about
exposure risk, early management, and access to
medical care.

Consider discharging patients with an action plan

(such as those from the American Academy of
Asthma, Allergy and Immunology [AAAAI] or Food
Allergy and Anaphylaxis Network [FAAN]).
Exposure to inciting agent, if known, should be

avoided.

For excellent patient education resources, visit

eMedicineHealth's Allergies Center. Also, see
eMedicineHealth's patient education articles Severe
Allergic Reaction (Anaphylactic Shock), Food
Allergy, and Allergy: Insect Sting.

Contributor Information and Disclosures

Author

Jeffrey F Linzer, Sr, MD, FAAP, FACEP,

MICP Professor of Pediatrics and Emergency
Medicine, Division of Pediatric Emergency
Medicine, Emory University School of Medicine;
Associate Medical Director for Compliance and
Business Affairs, EMS/Pre-Hospital Care
Coordinator, Consulting Staff for Children's
Sedation Service, Children's Healthcare of Atlanta

Jeffrey F Linzer, Sr, MD, FAAP, FACEP, MICP is a

member of the following medical societies:
American Academy of Pediatrics, American College
of Allergy, Asthma and Immunology, American
Pediatric Society, American College of Emergency
Physicians, Society for Pediatric Sedation

Disclosure: Nothing to disclose.

Chief Editor

Kirsten A Bechtel, MD Associate Professor of

Pediatrics, Section of Pediatric Emergency
Medicine, Yale University School of Medicine; Co-
Director, Injury Free Coalition for Kids, Yale-New
Haven Children's Hospital
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Haven Children's Hospital

Kirsten A Bechtel, MD is a member of the following

medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Acknowledgements

Kirsten A Bechtel, MD Associate Professor,

Department of Pediatrics, Yale University School of
Medicine; Attending Physician, Department of
Pediatric Emergency Medicine, Yale-New Haven
Children's Hospital

Kirsten A Bechtel, MD is a member of the following

medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate

Professor, University of Nebraska Medical Center
College of Pharmacy; Editor-in-Chief, Medscape
Drug Reference

Disclosure: Nothing to disclose.

Wayne Wolfram, MD, MPH Associate Professor,

Department of Emergency Medicine, Mercy St
Vincent Medical Center

Wayne Wolfram, MD, MPH is a member of the

following medical societies: American Academy of
Emergency Medicine, American Academy of
Pediatrics, and Society for Academic Emergency
Medicine

Disclosure: Nothing to disclose.

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