1. Review
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Management of anaphylaxis in
the emergency setting
Expert Rev. Clin. Immunol. 6(1), 89–100 (2010)
Allison Worth, Jasmeet
Soar and Aziz Sheikh†
Author for correspondence
Allergy & Respiratory Research
Group, Centre for Population
Health Sciences: General
Practice Section, University of
Edinburgh, 20 West Richmond
Street, Edinburgh EH8 9DX, UK
Tel.: +44 131 651 4151
Fax: +44 131 650 9119
aziz.sheikh@ed.ac.uk
†
Anaphylaxis is a life-threatening emergency that appears to be increasing in frequency. It affects
males and females of all ages and ethnic groups. The most common triggers include foods, drugs
and venom from stinging insects, although any of a number of other triggers may also be
implicated. Death, when it occurs, tends to be due to respiratory and/or cardiovascular compromise,
but most of these fatalities can be prevented by appropriate avoidance measures and emergency
management. The management of anaphylaxis is hampered by scientific and clinical uncertainty.
KEYWORDS : adrenaline • allergy • anaphylaxis • antihistamines • corticosteroids • emergency management
• epinephrine • long-term management
Anaphylaxis is a potentially lethal allergic emergency. Time is of the essence as, when fatal, death
usually occurs very rapidly after exposure to the
trigger. The management of anaphylaxis is often
hindered by scientific and clinical uncertainty.
There is, for example, no universally agreed definition of anaphylaxis, and its true incidence is
therefore unknown. Emergency management
has furthermore been described as based mainly
on extrapolation and anecdote rather than
robust scientific evidence [1,2] . There is considerable variation in international guidelines on
emergency management [3–7,101] , and these discrepancies reflect this scientific uncertainty [8,9] .
A recent comparison of international guidelines
[9] found consensus on the use of epinephrine
(adrenaline), but little agreement on the role of
other approaches, with differences on the use of
corticosteroids, antihistamines, oxygen, bronchodilators and patient positioning. The authors
called for the strength of evidence underpinning
guideline recommendations to be made much
more explicit. Clinical decision making is also
reported to be flawed, with misdiagnosis and
a lack of knowledge about the correct course
of action and correct administration of rescue
medication commonplace [10–12] . This review
aims to present the best available evidence to
support the effective, systematic management
of anaphylaxis in the emergency setting.
Definition
Descriptions of anaphylaxis date back to
the Ancient Egyptian period, but it was not
until just over a century ago that Richet and
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10.1586/ECI.09.73
Portier first coined the term ‘anaphylaxis’ to
describe the fatal reactions they induced when
trying to immunize dogs to the venom of sea
anemone. The term anaphylaxis was used to
indicate that, rather than offer protection, they
had inadvertently induced an inappropriately
exaggerated response.
There are a number of available working
definitions of anaphylaxis [13] and important
international differences in criteria for diagnosis. For example, the European Academy
of Allergy & Clinical Immunology (EAACI)
definition, modified by the Resuscitation
Council (London, UK) [6,101] emphasizes the
nature of the reaction and suggests that the
most important clinical features are respiratory and/or cardiovascular involvement. The
working definition is:
“Anaphylaxis is a severe, life-threatening, generalised or systemic hypersensitivity reaction. This
is characterised by rapidly developing life-threatening airway and/or breathing and/or circulation
problems usually associated with skin and mucosal
changes” [101] .
By contrast, the second National Institute
of Allergy and Infectious Disease and Food
Allergy and Anaphylaxis Network (NIAID/
FA AN) symposium on the definition and
management of anaphylaxis [3] , on which US
guidelines are based, suggested the following
broad definition:
“Anaphylaxis is a serious allergic reaction that is
rapid in onset and may cause death’’.
We discuss international differences in clinical
criteria for recognizing anaphylaxis later.
© 2010 Expert Reviews Ltd
ISSN 1744-666X
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Worth, Soar & Sheikh
Epidemiology
Recognition & differential diagnoses
The incidence of anaphylaxis is widely considered to be underestimated, as many patients experiencing anaphylaxis will not present for medical attention. Even when they do present, they may
be misdiagnosed as suffering from a range of other conditions,
such as asthma. Anaphylaxis is not even always recognized at
postmortem examination [1,101] . A review of international epidemiological studies suggested that incidence lies between 30 and
950 cases per 100,000 persons per year, with a lifetime prevalence of 0.05–2% [14] . Case–fatality ratios have been reported to
be less than 1% in a number of case series, although figures of
up to 5% have been published [15–19] . There are approximately
20 anaphylaxis deaths reported each year in the UK and 1500
in North America, although as noted previously these are widely
believed to be underestimated [20–22,101] . People with poorly controlled asthma have been shown in a number of case series to
have a higher risk of death, particularly if epinephrine use is
delayed [20] . Young people are also at increased risk of severe
and fatal episodes [23–25] , as are those with peanut allergy [26] .
Epidemiological work from the UK, studying cases of anaphylaxis resulting in hospitalization, has revealed quite marked
independent variations in anaphylaxis rate by age, gender, geography and socioeconomic profile, with the usual socioeconomic
gradient of higher admission rates in deprived populations being
reversed [27] .
There are only limited epidemiological data on trends over
time in anaphylaxis and, where available, these suggest there
may be important increases in disease frequency taking place.
A striking increase in the rate of hospital admissions for anaphylaxis in England has been noted, from 0.5 to 3.6 admissions
per 100,000 patients between 1990 and 2004, an increase of
700% [28] . Increases have also recently been noted in a US study,
although the magnitude of the increase is less marked than that
reported in England [29,30] .
Recognition of anaphylaxis can be problematic in an emergency
setting and this can hinder effective treatment. Paradoxically,
it is both under- and over-recognized, with many patients who
are genuinely experiencing anaphylactic reactions not treated
appropriately with epinephrine, whereas in other cases epinephrine may be given inappropriately for mild allergic reactions and
panic attacks, for example [11,29] . Anaphylaxis can be difficult
to recognize if it is the first episode or if a trigger is not apparent [24,29] . Diagnosis is particularly difficult in young children,
who are likely to be experiencing a first episode and who may
furthermore be unable to articulate subjective symptoms [35] .
Skin manifestations can be transient and can be overlooked
in children, among whom respiratory features dominate [1,17] .
Anaphylaxis can begin with apparently minor symptoms and
progress rapidly to a life-threatening reaction, death can occur
within minutes of onset, reactions may also be biphasic (recurrent) or protracted [36] , and its course is therefore difficult to
predict [10] .
Clinical presentation varies, with no single set of criteria able
to identify all anaphylactic episodes; some diagnostic errors
are therefore inevitable [101] . Certain combinations of signs do,
however, make the diagnosis of anaphylaxis more likely [3,37,101] .
Again, however, international experts disagree over the clinical
criteria for recognizing anaphylaxis. The Resuscitation Council
suggests criteria based on the Airway, Breathing, Circulation,
Disability, Exposure (ABCDE) approach, commonly used to
treat medical emergencies in general for the recognition of
anaphylaxis (BOX 1) .
The NIAID/FAAN symposium proposed three clinical criteria for diagnosing anaphylaxis, which they suggest recognize
the varied presentations of anaphylaxis rather than emphasizing respiratory and/or circulation problems (BOX 2) . They suggest
that 80% of cases of anaphylaxis should be identified by criterion 1, which emphasizes skin symptoms, with criteria 2 and 3
picking up those without obvious skin symptoms and with more
unusual presentations.
Less severe systemic allergic reactions with generalized urticaria,
angioedema and rhinitis lack the characteristic life-threatening
airway, breathing and/or circulatory problems, and should therefore not be classed as anaphylaxis. Differential diagnoses include
severe asthma, septic shock, vasovagal reactions, panic attack,
hypotension, numerous causes of skin rashes, hereditary angioedema, ‘restaurant syndromes’ such as scombroid fish poisoning,
syndromes associated with flushing and systemic mastocytosis [1, 4,5,24,38,101] . TABLE 1 considers important differential diagnoses
and reviews features that may help to distinguish these conditions
from anaphylaxis. Care must be taken, however, not to diagnose
dyspnea and bradycardia as anxiety [1] .
Triggers
Anaphylaxis is most commonly triggered by food, drugs and
venom, with latex, immunotherapy, contrast media and exerciseinduced anaphylaxis also being well-known triggers [2,3,31] . Physical
causes, such as heat, cold and UV light, are also recognized. Foodinduced anaphylaxis is most frequent in children – milk, eggs,
peanuts and other legumes, tree nuts, fruit, fish and shellfish are
particularly important triggers. In adults, peanuts, tree nuts, fish
and shellfish are common causes [26] . Medicines are the most common triggers in older people; specifically, muscle relaxants used
during anesthesia, antibiotics, nonsteroidal anti-inflammatory
drugs and aspirin [32] . The venom of stinging insects such as wasps
and bees is also an important seasonal trigger. In many cases,
particularly in adults, however, no trigger can be identified: anaphylaxis was judged to be idiopathic in 59% of 601 cases reviewed
retrospectively in one very large US-based case series [33] . The role
of cofactors such as inter-current illness, stress, alcohol and exercise is also important in that the presence of these factors may
reduce the threshold of exposure needed to trigger a reaction – this
phenomenon has been labeled as ‘summation anaphylaxis’ [34] .
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Pathophysiology
Although IgG- and IgM-dependent immunological reactions
have been described, in most cases anaphylaxis involves the
release of a range of inflammatory mediators from mast cells
and/or basophils following allergen interaction with cell-bound
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3. Management of anaphylaxis in the emergency setting
Review
IgE. Historically, these type 1 immediate
Box 1. UK guidelines on the recognition of anaphylaxis.
hypersensitivity or ‘anaphylactic reactions’,
as they were known, were distinguished “A diagnosis of anaphylaxis is likely if a patient who is exposed to a trigger (allergen)
from the less common, but nonetheless develops a sudden illness (usually within minutes of exposure) with rapidly progressing
important, ‘anaphylactoid reactions’, skin changes and life-threatening airway and/or breathing and/or circulation problems.
The reaction is usually unexpected” [101] .
which involve non-IgE-mediated or even
nonimmune release of mediators. This Features suggestive of anaphylaxis:
Anaphylaxis is likely when all of the following three criteria are met:
mechanistic distinction is largely now
1. Sudden onset and rapid progression of symptoms AND
seen as redundant in clinical practice, as 2. Life-threatening airway and/or breathing and/or circulation problems AND
the clinical picture and emergency treat- 3. Skin and/or mucosal changes (flushing, urticaria or angioedema)
ment of anaphylaxis are similar regardless The following supports the diagnosis:
of trigger factor or pathophysiological • Exposure to a known allergen for the patient
mechanisms [39] .
Remember:
The release of histamine and other
• Skin or mucosal changes alone are not a sign of an anaphylactic reaction
inflammatory mediators are responsible for
• Skin and mucosal changes can be subtle or absent in up to 20% of reactions (some
the vasodilation, capillary leak and bronchopatients can only have a decrease in blood pressure, that is, a circulation problem)
spasm that can lead to shock, edema and
• There can also be gastrointestinal symptoms (e.g., vomiting, abdominal pain
wheeze in patients with anaphylaxis.
or incontinence)
Although diagnosis is clinical, serum Reproduced from Resuscitation Council (UK) [101].
mast cell tryptase measurements can be
useful in cases of diagnostic uncertainty at follow-up. Tryptase which clinicians in any setting might find particularly useful as
is the major protein component of mast cell secretory granules it applies the ABCDE approach commonly used for other medical
and can lead to markedly increased blood tryptase concentra- emergencies to recognizing and treating anaphylaxis [101] . This
tions in anaphylaxis and mast cell degranulation [40,101] . Mast ABCDE approach involves the assessment of:
cell tryptase levels can, therefore, be useful in confirming the • Airway: airway swelling, hoarseness and stridor
diagnosis of anaphylaxis once the initial treatment phase is
complete. The optimal timing of measurement is between 1 • Breathing: shortness of breath, wheeze, tiredness, confusion
due to hypoxia, cyanosis and respiratory arrest
and 2 h after the onset of the reaction; mast cell tryptase has a
short half-life and thus serial measurements over a 24-h period • Circulation: signs of shock, tachycardia, hypotension, faintness,
from the onset of the reaction are recommended if possible.
collapse, loss of/decreased consciousness, ECG changes and
Serum tryptase is, however, generally not raised in food-induced
cardiac arrest
anaphylaxis; the role of other biomarkers including mast cell
carboxypeptidase and platelet-activating factor acetylhydol- • Disability: confusion, agitation and loss of consciousness
ase for the diagnosis of anaphylaxis are the subject of ongoing • Exposure: skin and/or mucosal changes – erythema, urticaria
investigation [24] .
and angioedema
Clinical features
Virtually any organ system can be affected. As noted previously,
the UK guidelines indicate that involvement of the cardiovascular and/or respiratory systems are essential for diagnosis, but not
all experts agree, and the NIAID/FAAN guidelines emphasize
skin changes more than respiratory and cardiovascular symptoms. Cutaneous symptoms are particularly common, affecting
the vast majority of affected individuals. BOX 3 details the main
clinical features that tend to occur in anaphylaxis.
It is important to note that, although shock has been considered an essential feature of anaphylaxis, this is no longer the
case as it is now recognized that many people develop important
symptoms but do not manifest symptoms of shock.
Emergency management
Compared with the previous situation in which there were different algorithms depending on first responder, the most recent
Resuscitation Council guideline on the emergency treatment of
anaphylactic reactions simplifies this to an ABCDE approach,
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The anaphylaxis algorithm sets out the keys steps in treatment
(FIGURE 1) .
Assessment
Anaphylaxis is a dynamic process, requiring prompt intervention and then periodic reassessment [1,7,31,38] . Life-threatening
features typically manifest early, but may become apparent up
to an hour after the onset of symptoms. Anaphylaxis should be
considered wherever upper airway obstruction, bronchospasm or
hypotension is present, and the diagnosis is supported by skin/
mucosal features as outlined before [1,101] . The priority is the
assessment of physiological compromise to determine the severity
of the reaction and rapid treatment of life-threatening symptoms [1,10] . Once these are managed, assessment should include
the removal of possible triggers, obtaining a detailed history and,
in particular, information on possibly relevant exposures, and a
detailed examination. Careful recording of this information is
often helpful in later confirming if the diagnosis is correct and
guiding future management [1] .
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Worth, Soar & Sheikh
Box 2. National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network clinical
criteria for diagnosing anaphylaxis.
Anaphylaxis is highly likely when any one of the following three criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue or both (e.g., generalized hives, pruritus
or flushing, swollen lips/tongue/uvula), and at least one of the following:
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF or hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope or incontinence
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush or swollen lips/tongue/uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF or hypoxemia)
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope or incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain or vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP *
b. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that person’s baseline
*
Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 1 year of age, less than (70 mmHg + [2 × age]) from 1 to 10 years of age,
and less than 90 mmHg from 11 to 17 years of age.
BP: Blood pressure; PEF: Peak expiratory flow.
Reproduced from [3].
Previous history of anaphylaxis is a risk factor for recurrence [41] .
Patients with a history of atopy and asthma are also at increased
risk of severe anaphylaxis [25,33] .
Core principles of emergency anaphylaxis management
Emergency treatment of anaphylaxis begins with an ABCDE
assessment and the instituting of basic and advanced life-support
measures if necessary. Epinephrine injected intramuscularly is
the key treatment for anaphylaxis and subsequent interventions
depend on the patient’s response to it [7,10,25] . Rapid treatment is
very important to ensuring the best possible outcome [7,10] .
Epinephrine
Universal agreement exists on the central role of epinephrine in
the emergency treatment of anaphylaxis and recent guidelines
appear to be moving towards consensus on dose, route of administration and timing of administration [42] . The scientific basis
Table 1. Differential diagnosis of anaphylaxis.
Condition
Distinguishing feature
Acute urticaria
Generalized rash in the absence of
respiratory symptoms and/or hypotension
Angiodema and No flushing, pruritis, urticaria, bronchospasm
hereditary
or hypotension
angiodema
History of C1-esterase inhibitor deficiency
Globus
hystericus
No clinical evidence of upper respiratory
obstruction
No flushing, pruritis, urticaria, angiodema,
bronchospasm, hypotension
Vasovagal
episode
Bradycardia not tachycardia. No urticaria, pruritis,
angioedema or upper respiratory obstruction
Pallor instead of flushing
Nausea without abdominal pain
Adapted from [38].
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for these considerations on dosage, route and timing of administration is weak in humans, with limited supporting evidence
coming from work in canine models [43,44] . Although there are
no randomized, controlled trials assessing the effectiveness of
epinephrine in humans, its use is supported by consistent case
reports and case series of its value in restoring adequate cardiac
output and easing respiratory distress [45] .
Epinephrine has both -adrenergic effects, which result in vasoconstriction, and -adrenergic effects, which result in inotropic
and chronotropic effects on the heart, and bronchodilation; it also
stems the release of inflammatory mediators, therefore helping to
abort the reaction [45,101] .
Epinephrine is indicated for all patients with the life-threatening
features of anaphylaxis. It is best delivered by intramuscular injection. If the patient fails to improve, further doses can be given at
repeated 5-min intervals. The antero-lateral aspect of the thigh is
the optimal site for injection, both in order to maximize the speed
of absorption while also minimizing the risk of adverse effects.
The recommended doses are based on what is considered to be
safe and practical to draw-up and inject in an emergency situation [101] . The most directive guideline is from the Resuscitation
Council [101] , which recommends precise dosing regimens (BOX 4) .
Other guidelines suggest a range, such as 0.2–0.5 ml for adults [3] .
Weight rather than age is an alternative advised method for determining epinephrine dose in children; 0.01 mg/kg intramuscularly
every 5–10 min as necessary [4] .
Intravenous epinephrine administration is not recommended
in the UK guidelines, except when used by experts in specialist
settings (e.g., intensivists, anesthetists and emergency physicians),
and even then only with cardiac monitoring due to the smaller
margin for error and the increased risk of inducing fatal cardiac
arrhythmias, myocardial ischemia and severe hypertension [101] .
The doses of epinephrine given intravenously are much smaller
than the recommended intramuscular doses and require careful titration to avoid these harmful side effects. If a patient with
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5. Management of anaphylaxis in the emergency setting
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anaphylaxis suffers cardiac arrest, standard
Box 3. Clinical features of anaphylaxis.
guidelines for cardiopulmonary resuscitation
should be followed, including intravenous General
epinephrine administration using the much • Anxiety, malaise, weakness, feeling of impending doom
larger doses of intravenous epinephrine • Paresthesia (hands, lips/mouth and tongue), dry mouth, abnormal taste in the mouth
(1 mg in adults) that are recommended for Cutaneous, subcutaneous and mucosal tissues
cardiac arrest treatment.
• Nasal congestion, rhinorrhoea, conjunctival erythema, tearing
It is a matter of concern that, given • Itch – often localized to the palms or soles, groin, armpit, face/eyes or nose
the importance of rapid administration • Flushing (erythema, typically most noticeable on the face, neck and upper trunk),
of epinephrine to prevent mortality and
urticaria (typical skin wheals and erythema), periorbital edema
morbidity, it is under-used by clinicians, • Angioedema of the tongue, lips, ears, neck and other areas of the body
including in emergency settings [12,46–48] . Gastrointestinal/abdominal
In retrospective reviews of the treatment • Nausea, vomiting, abdominal pain including uterine contraction pain or diarrhea
of patients with insect sting allergy and Respiratory
food allergy, only 12% of patients with • Upper airway edema causing difficulty speaking and/or swallowing, hoarse voice, stridor
systemic reactions to insect sting and 16%
• Chest or throat tightness/pain, dyspnea, tachypnea, bronchospasm, cough
of patients with anaphylactic reactions to
• Hypoxemia/central cyanosis
food were treated with epinephrine [12,46] .
• Respiratory arrest
Gaeta et al. found that second-line treatments were more commonly used to treat Cardiovascular
anaphylaxis in US emergency departments • Tachycardia
than epinephrine – that is, antihistamines • Hypotension with either tachycardia or a relative bradycardia
were used for 63% of patients and steroids • Diaphoresis and circulatory failure (capillary refill >2 s) with pallor and/or
peripheral cyanosis
for 61%, but epinephrine for only 50% of
patients [48] . Confusion about the correct • T inversion and/or ST depression in multiple leads (with or without chest pain),
arrhythmias
route of administration is also common;
• Cardiogenic shock and pulmonary edema*
one UK study presenting case studies to
senior house officers (residents) starting • Cardiac arrest
work in emergency departments found Neurological
that 42% would choose to use intravenous • Throbbing headache
epinephrine, and of those using the recom- • Dizziness/presyncope, visual loss, loss of consciousness, incontinence‡
mended intramuscular route, only 20% • Confusion§
suggested using the correct dose. Only *Cardiogenic shock and pulmonary edema appear to be uncommon, and are probably more likely to occur
disease.
5% suggested administering epinephrine in those with underlying cardiacnot always, associated with hypotension and poor cerebral perfusion.
‡
These features are usually, but
§
in accordance with the Resuscitation
Confusion appears to have a strong association with hypoxemia rather than hypotension.
Council guidelines [11] . Factors contribut- Adapted from [1].
ing to the reluctance to administer epinephrine in the emergency setting include clinicians’ perceptions infusion of 500–1000 ml in an adult and 20 ml per kg in a child
of its potential for adverse effects, and lack of experience and should be given, the response monitored and further doses given
knowledge about treating anaphylaxis [22] . These studies sup- as necessary [101] . Crystalloids (e.g., 0.9% sodium chloride or
port the contention that guidelines on anaphylaxis management Hartmann’s solution) are recommended if a colloid is thought
are often not followed in practice [3,10,12,22] .
to be the original cause of the anaphylaxis [3,101] .
Patient positioning
Oxygen
Patients should be placed in a position comfortable to them,
depending on their symptoms. Lying flat with elevated legs
is advised for patients with hypotension, as this may increase
stroke volume and cardiac output in patients with vasodilatory
shock [3,101] . Patients with breathing problems or vomiting may
prefer to sit up, but if the patient feels faint they should not sit
or stand up, as this can cause cardiac arrest and death [3,49,101] .
High-flow oxygen should also be given as soon as possible,
particularly where respiratory distress and/or hypoxia are
apparent [3,101] . Pulse oximetry should be used to guide oxygen
therapy [50] .
Fluids
Intravenous fluids should be given as soon as possible, and this
is particularly important in patients with signs of shock. A rapid
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Antihistamines
H1-antihistamines such as chlorphenamine can be used as a
second-line treatment for anaphylaxis, as the relatively slow
onset of action means they have little impact on the initial
reaction [3,4,101] . They are, however, useful for the symptomatic
treatment of urticaria, angioedema and pruritus [4,39] . The
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6. Review
Worth, Soar & Sheikh
Anaphylactic reaction?
Airway, Breathing, Circulation, Disability, Exposure
Diagnosis – look for:
• Acute onset of illness
• Life-threatening airway and/or breathing and/or circulation problems1
• Usually skin changes
Call for help
Lie patient flat
Raise patient’s legs
Adrenaline2
When skills and equipment are available:
• Establish airway
Monitor:
• High-flow oxygen
• Pulse oximetry
• IV fluid challenge3
• ECG
• Chlorphenamine4
• Blood pressure
• Hydrocortisone5
1. Life-threatening problems:
Airway: swelling, hoarseness, stridor
Breathing: rapid breathing, wheeze, fatigue, cyanosis, SpO2 < 92%, confusion
Circulation: pale, clammy, low blood pressure, faintness, drowsy/coma
Some guidelines do not recommend H2
antagonists such as cimetidine and ranitidine [1,101] ; a US guideline recommends
them cautiously in combination with H1
antagonists [4] ; and an Australian review
recommends oral selective nonsedating
antihistamine use only for the symptomatic
relief of skin symptoms [1] .
Glucocorticoids
Corticosteroids have no role in the acute
management of anaphylaxis, as they may
have no effect for 4–6 h [3] . They are a
possible second-line treatment, which may
help reduce the risk of biphasic reactions
or shorten protracted reactions, and they
may be of use in patients with concurrent
asthma [4,101] . There is little evidence on
which to base the use of steroids in anaphylaxis, with recommendations based on
their use in asthma [1,3] . Steroids are usually
given by slow intravenous or intramuscular
injection; care is needed to avoid inducing further hypotension [101] . An ongoing
Cochrane review of the use of glucocorticoids is examining the evidence base for
their use in anaphylaxis [51] .
Other drugs
Bronchodilators can safely be administered in those individuals experiencing
asthma-like symptoms. Bronchodilators
are best given through the inhaled route,
although intravenous administration may
Stop IV colloid if this
occasionally be necessary [101] .
might be the cause of
anaphylaxis
Some animal work and several case
reports suggest that adding low-dose vasopressin to the emergency treatment regimen of anaphylaxis may, through revers4. Chlorphenamine:
5 Hydrocortisone:
ing the histamine-induced vasodilatation,
(IM or slow IV)
(IM or slow IV)
help reverse cardiovascular collapse in
Adult or child over 12 years of age
10 mg
200 mg
anaphylactic shock and thereby improve
Child 6–12 years of age
5 mg
100 mg
Child 6 months–6 years of age
2.5 mg
50 mg
outcomes [52–57] .
Child under 6 months of age
250 µg/kg
25 mg
Glucagon given as an intravenous infusion may have a role in those with refractory anaphylaxis, particularly in patients
Figure 1. Anaphylaxis algorithm.
taking -blockers, which can attenuIM: Intramuscular; IV: Intravenous; SpO2: Oxygen saturation measured by
ate the effects of epinephrine [5] . This
pulse oximetry.
is because glucagon has inotropic and
recommended route of administration is by slow intravenous or chronotropic effects on the heart that do not rely on the stimintramuscular injection, the dose depending on age [101] . There is, ulation of - and -adrenergic receptors, and its use can thus
however, little robust evidence for their use [39] . Based on animal potentiate the effects of epinephrine. However, the evidence
models, it has been suggested that they may, if administered base in support of glucagon is weak, as with all other treatparenterally, be harmful in anaphylaxis, the main risk being the ments, consisting of only a few case reports in humans and
induction of cardiac arrhythmias [1,9] .
some animal work [58] .
2. Adrenaline (give IM unless experienced with IV
adrenaline): IM doses of 1:1000 adrenaline (repeat after
5 min if no better)
• Adult
500 µg IM (0.5 ml)
• Children over 12 years of age
500 µg IM (0.5 ml)
• Children 6–12 years of age
300 µg IM (0.3 ml)
• Children under 6 years of age
150 µg IM (0.15 ml)
Adrenaline IV to be given only by experienced specialists
Titrate: adults: 50 µg; children: 1 µg/kg
94
3. IV fluid challenge:
Adult: 500–1000 ml
Child: crystalloid 20 ml/kg
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7. Management of anaphylaxis in the emergency setting
Atropine may be given to treat bradycardia
if this develops [1,4] .
Investigations
Review
Box 4. Recommended doses of adrenaline in anaphylaxis.
Adrenaline im. dose – adults:
• 0.5 mg im. (= 500 µg = 0.5 ml of 1:1000) adrenaline
Guidelines suggest that investigations Adrenaline im. dose – children (the equivalent volume of 1:1000 adrenaline is
appropriate for any medical emergency, shown in brackets):
such as 12-lead ECG, chest x-ray, urea • >12 years: 500 µg im. (0.5 ml) – that is, same as adult dose
and electrolytes, and arterial blood gases, • 300 µg (0.3 ml) if child is small or prepubertal
should be carried out [101] . Diagnosis of • >6–12 years: 300 µg im. (0.3 ml)
anaphylaxis is largely based on clinical • >6 months–6 years: 150 µg im. (0.15 ml)
assessment and a good history. Mast cell • <6 months: 150 µg im. (0.15 ml)
tryptase levels can help to confirm the im.: Intramuscularly.
diagnosis once initial treatment is complete Reproduced from Resuscitation Council (UK) [101].
The provision of epinephrine auto-injectors is a matter of
[101] . Timing of blood samples is crucial, as tryptase concentrations in the blood may not increase significantly until 30 min or some debate, particularly in relation to children, as there is
more after the onset of symptoms, and peak 1–2 h after onset [40] . concern that auto-injectors may have a detrimental psychoThe half-life of tryptase is short ( 2 h), and concentrations may logical effect on children and their carers [62,63] . Furthermore,
be back to normal within 6–8 h. Serial measurement is therefore there are risks associated with the incorrect administration of
recommended if possible, with an initial sample taken as soon as epinephrine, mainly inadvertent injuries to the thumb and finthe resuscitation process allows; a second sample 1–2 h after the ger, emphasising the need for training in correct use of the
onset of symptoms and a third sample at 24 h or later to provide auto-injector device [64] . The Resuscitation Council recommends that prescription of self-injectable epinephrine is given
baseline levels [23,59,101] .
to patients at high risk of further episodes, along with educaMonitoring & discharge
tion on its use [101] . Auto-injectors are not usually required for
Following treatment of initial problems, patients with suspected patients with drug-induced anaphylaxis, as avoidance is likely
anaphylaxis should be observed for at least 6 h in case further to be relatively straightforward, but are necessary for patients
life-threatening symptoms occur [101] . Observation times should with idiopathic or venom- and food-induced reactions [101] .
be individually determined, based on the severity of the reac- Sampson et al. report that consensus indicates auto-injector
tion and a patient’s ability to access care rapidly after discharge prescription for patients who have experienced respiratory or
should a biphasic reaction occur [4] . Biphasic reactions may occur cardiovascular symptoms from exposure to a known allergen
in up to 20% of patients, in most cases within 6–8 h of the pri- in the community, but also point out that this would exclude
mary reaction, but occasionally up to 72 h later [60] . Although a significant proportion of high-risk individuals [3] . Although
unpredictable, with little understanding about their true inci- guidelines generally advocate the prescription of epinephrine
dence, they appear to be most likely in idiopathic anaphylaxis, auto-injectors, many patients leave emergency settings without
in patients with severe asthma, where absorption of the allergen them [48,65] . There is also debate on the number of auto-injectors
may be continuing, and in those with a history of biphasic reac- to be given, with some arguing that two or more auto-injectors
tions [60,101] . In these circumstances, patients should be observed should suffice, so that if the first preparation is not appropriately
for a longer period (e.g., 24 h) or until their symptoms settle [4] . administered, or if there is a failure to respond, the second can
Caution may also be appropriate when considering discharge of then be given [66] . A repeat dose of epinephrine in the treatment
patients at night or where access to emergency care is difficult of food-induced anaphylaxis has been estimated as necessary
[101] . All patients who have experienced severe anaphylaxis should
in up to 20% of cases [67,68] . Others argue that the vast majorbe reviewed by a senior clinician prior to discharge and given clear ity of individuals will respond to the first injection [69] . More
instructions to return to hospital if their symptoms recur [101] .
importantly, however, is the need for patients and carers to be
Recording details of the anaphylactic episode is important, appropriately trained in the use of these auto-injectors, which
but often done inadequately [31,48] . In the interests of patient in itself is something of an uphill struggle, as many clinicians
safety, flagging a patient’s case notes or electronic record with are themselves not competent in the use of auto-injectors [64,70] .
a clear warning, particularly when a patient has experienced
There are currently only two preparations of epinephrine autodrug-induced anaphylaxis, should help to reduce accidental re- injector available, namely the 0.15-mg preparation intended for
exposure [61] . Better communication between the emergency children under 30 kg and the 0.3 mg preparation for those weighdepartment, primary and specialist care is needed [7] . Inadequate ing 30 kg and over. This limited range of preparations poses
coding and recording of anaphylactic events contributes to the the potential risk of excessive administration in the very young
lack of knowledge about its prevalence, although this is in part although, on balance, the convenience of using an auto-injector
due to inconsistent definitions [7,48] . The creation of national and pen (as opposed to a parent being asked to draw up a more optiEuropean databases is important to generate better quality data mal dose from a vial in an emergency) is thought to outweigh
and improve the management of anaphylaxis [7] .
the risks [71,72] .
www.expert-reviews.com
95

8. Review
Worth, Soar & Sheikh
Antihistamines and oral steroid therapy may also be prescribed
for up to 3 days to treat urticaria and possibly reduce the chance
of further reactions [101] .
Post-treatment follow-up
Although this review focuses on emergency management, we
would argue that those treating anaphylaxis in emergency settings
have a responsibility to consider long-term management of anaphylaxis, as this can potentially improve patient outcomes [3,31,38] .
Anaphylaxis should be conceptualized as a long-term condition,
with supported patient self-management instigated at the point
of initial diagnosis, which may well be in the emergency setting.
Most cases of anaphylaxis can be managed in the emergency
department as long as follow-up is arranged, including referral to
an allergy clinic and clear discharge information on emergency
care and long-term management [17] .
Before leaving the emergency department, patients who
have experienced anaphylaxis need to know how to recognize
the early symptoms of anaphylaxis and how to use emergency
medication [101] . They should, if possible, also receive information on the allergen responsible, advice on allergen avoidance
and advice about ongoing management, as well as referral for
a more detailed follow-up evaluation [20,22,25,101] . Individual
anaphylaxis management plans are widely advocated as beneficial in reducing episodes of anaphylaxis, although there are no
randomized, controlled trials [73,74] . Management plans should
include a brief, clear emergency action plan and information
about triggers, their avoidance and prevention of emergencies [7,31,38,73–78] . The use of a medical alert system, such as a
MedicAlert ® bracelet, should also be recommended to ensure
first responders in any future emergency have information about
the patient’s condition.
The clinicians’ ability to educate patients and their families
in the recognition of anaphylaxis and management of emergencies is, however, often inadequate [3,23] . Furthermore, failure to
refer to allergy clinics is common. In one Scottish study, 40%
of children with life-threatening reactions attending a pediatric
emergency department received no follow-up, a finding echoed in
other international studies [12,17,65,79] . Patients’ lack of knowledge
contributes to deaths from anaphylaxis [20] and the opportunity
to improve patient care is being lost in the emergency department [3,22] . A study of fatal reactions indicates that the most
important aspects of advice in preventing deaths are allergen
avoidance, optimal management of asthma and patient alertness
to risk [20] . Referral to an allergy specialist for further investigation and an individual management plan is optimum but often
not arranged [65] ; in one Australian study, only 28% of patients
were referred to an allergist from the emergency department and
19% had no follow-up arranged [17] .
Lieberman et al. designed the acronym ‘SAFE’ to improve
ongoing supportive care arranged by emergency department
personnel for patients who have experienced anaphylaxis [22] .
SAFE comprises the essential advice and arrangements to
be discussed with the patient prior to discharge from the
emergency setting:
96
• Seek support: advise on actions to be taken if further reactions
occur
• Allergen identification: emphasize the need for allergen
avoidance and testing, and avoidance strategies
• Follow-up for speciality care: advise or arrange follow-up in
primary care and/or with an allergy specialist
• Epinephrine: prescribe self-injectable epinephrine and
instruction for its use in emergencies
The patient’s primary care physician should be informed of
the event, treatment given and any follow-up arranged. Patient
support organizations such as the Anaphylaxis Campaign in
the UK and the Food Allergy and Anaphylaxis Network in
the USA can provide information and education to support
self-management.
The specialist assessments that should follow any emergency
admission for anaphylaxis will also offer the opportunity to
investigate for potential triggers using either in vitro or in vivo
testing, or a combination of the two. An allergy specialist will
also optimize management of any comorbidity (e.g., asthma) and
review the use of medication, which may increase the risk of poor
outcomes in future reactions (e.g., discontinuing -blockers).
An allergy specialist may also consider the opportunity for
more curative treatment in the form of desensitization therapy,
particularly in those with venom- and aspirin-induced anaphylaxis. Although still early days, oral desensitization therapy also
appears promising in relation to certain foods such as peanuts,
milk and eggs [80–82] .
Expert commentary
Anaphylaxis is an inherently slow-moving field. This is due in
part to the rarity of the condition under study, the fact that episodes tend to be very short-lived, and that conducting research in
the context of a potentially lethal medical emergency is, invariably, extremely difficult. That said, progress is being made, both
in relation to trying to agree on a working definition for anaphylaxis [3] , developing a better understanding of its epidemiology
internationally [13,14] , and identifying the means to risk stratify
and identify those who are at most risk of poor outcomes [24] . The
role of better biomarkers for those at risk is currently also being
pursued internationally. For example, recent work has identified the potentially important role of the inflammatory mediator
platelet-activating factor, and in particular the risks associated
with low levels of platelet-activating factor acetylhydrolase activity in those with fatal outcomes [83] . Recent work has also started
to make explicit the lack of a sound evidence-base for the treatments currently employed to manage anaphylaxis. It is hoped
that such work will, in due course, help stimulate the development of more explicit guidelines for anaphylaxis management
and, more fundamentally, the much needed intervention studies.
These will most probably begin by establishing the efficacy and
effectiveness of second-line agents such as antihistamines and
corticosteroids. Experimental studies on aspects of longer term
management, such as the use of anaphylaxis management plans,
Expert Rev. Clin. Immunol. 6(1), (2010)

9. Management of anaphylaxis in the emergency setting
different alerting mechanisms and oral desensitization, are also
planned and these will, in addition, help to clarify the evidence
with respect to these approaches.
While all of the aforementioned would certainly help in
improving aspects of clinical care, the one issue that would most
probably help in improving outcomes – and in particular reduce
fatalities – is the prompt use of epinephrine where indicated.
Currently, however, there seems to be considerable professional,
patient and carer reluctance to its administration, with the effect
that lives may needlessly be lost.
Five-year view
The biggest change that we anticipate over the next 5 years is the
more widespread use of oral and perhaps cutaneous desensitization therapies in those with food-induced anaphylaxis. By this
Review
time, a clearer idea of the longer term impact of these potentially exciting disease-modifying treatment approaches will, we
believe, also have emerged. We hope that there will also be,
within this period, more consistent use of epinephrine, at least
by professionals, when clearly indicated.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript. This
includes employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or pending,
or royalties.
No writing assistance was utilized in the production of this
manuscript.
Key issues
• Anaphylaxis is a life-threatening emergency that appears to be increasing in frequency.
• Management of anaphylaxis is often hindered by scientific and clinical uncertainty, with no universally agreed definition of
anaphylaxis or knowledge of its true incidence.
• Emergency management is based mainly on expert clinical opinion rather than robust scientific evidence.
• Recognition of anaphylaxis can be difficult in an emergency setting, and this can hinder effective treatment.
• Clinical presentation varies, with no single set of criteria able to identify all anaphylactic episodes, but certain combinations of signs
make the diagnosis of anaphylaxis more likely.
• Emergency treatment of anaphylaxis begins with an intramuscular epinephrine injection and subsequent interventions depend on
the patient’s response.
• Rapid treatment is crucial for recovery and survival.
• Prompt use of epinephrine where indicated would most probably help in improving outcomes and, in particular, fatalities. Currently,
however, there seems to be considerable professional, patient and carer reluctance to the administration of epinephrine.
• Anaphylaxis should be viewed as a long-term condition, with supported patient self-management instigated in the
emergency setting.
• Patients with suspected anaphylaxis should attend an emergency department for assessment and treatment.
• Emergency departments should have arrangements to ensure the further investigation and follow-up of patients with
suspected anaphylaxis.
• Over the next 5 years, the more widespread use of oral and perhaps cutaneous desensitization therapies in those with food-induced
anaphylaxis is likely.
Anaphylaxis Network symposium.
J. Allergy Clin. Immunol. 117, 391–397
(2006).
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12. Review
Worth, Soar & Sheikh
Website
101
Working Group of the Resuscitation
Council (UK). Emergency treatment of
anaphylactic reactions. Resuscitation
Council (UK), London, UK (2008)
www.resus.org.uk/pages/reaction.pdf
••
Most recent guideline on emergency
management of anaphylaxis, aiming to
clarify and simplify guidance on
recognition and treatment for ease of
translation into clinical settings.
100
Affiliations
•
Allison Worth, BSc (Hons), PhD
Research Manager/Senior Research Fellow,
Allergy & Respiratory Research Group,
Centre for Population Health Sciences:
General Practice Section, University of
Edinburgh, 20 West Richmond Street,
Edinburgh EH8 9DX, UK
Tel.: +44 131 650 9463
Fax: +44 131 650 9119
allison.worth@ed.ac.uk
•
•
Aziz Sheikh, MD, FRCP, FRCGP
Professor of Primary Care Research and
Development, Allergy & Respiratory
Research Group, Centre for Population
Health Sciences: General Practice Section,
University of Edinburgh,
20 West Richmond Street,
Edinburgh EH8 9DX, UK
Tel.: +44 131 651 4151
Fax: +44 131 650 9119
aziz.sheikh@ed.ac.uk
Jasmeet Soar, FRCA
Chair, Resuscitation Council UK,
Consultant in Anaesthetics & Intensive
Care Medicine, Southmead Hospital,
North Bristol NHS Trust,
Bristol BS10 5NB, UK
Tel.: +44 117 323 5114
Fax: +44 117 323 5075
jasmeet.soar@nbt.nhs.uk
Expert Rev. Clin. Immunol. 6(1), (2010)

13. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.