Downloaded from pmj.bmj.com on September 8, 2012 - Published by group.bmj.

com

Review

Anaphylaxis: current state of knowledge for the

modern physician
Krzysztof Rutkowski, Shelley Dua, Shuaib Nasser

Allergy Department, Cambridge ABSTRACT DEFINITION

University Hospitals NHS Anaphylaxis is a severe, potentially fatal, Historically, the definition of anaphylaxis has been
Foundation Trust, Cambridge, an area of contention because it is a condition with
UK hypersensitivity reaction of rapid onset. It may trigger
life-threatening cardiopulmonary compromise, often a variety of underlying mechanisms presenting
Correspondence to with skin and mucosal changes such as urticaria and with a spectrum of clinical features. However, the
Dr Shuaib Nasser, Department angioedema. The prevalence of anaphylaxis is current consensus is that anaphylaxis is a severe
of Allergy, Cambridge University increasing and the number of cases of fatal hypersensitivity reaction of rapid onset that, if left
Hospital, Hills Road, Cambridge
CB2 0QQ, UK; Shuaib.nasser@ anaphylaxis appears to be rising. Food, insect stings, untreated, may cause death.2 There is usually
addenbrookes.nhs.uk and drugs are the most common triggers. Novel a swift progression of skin changes and develop-
triggers are increasingly seen and include delayed ment of life threatening airway, respiratory or
Received 2 December 2011 anaphylaxis to red meat, food-dependent cardiovascular compromise, or any combination of
Accepted 10 March 2012 these three features.
exercise-induced reactions and anaphylaxis to
Published Online First
30 March 2012 monoclonal antibodies. Anaphylaxis is usually IgE
mediated, but other mechanisms also play a role for
example direct mast cells activation. Differential EPIDEMIOLOGY
diagnosis is discussed including asthma, syncope and Prevalence rates reported in the literature vary, and
shock; excessive endogenous histamine, food related population based estimates are not always reliable
syndromes, and some rare diagnoses. Intramuscular due to misdiagnosis, underreporting, and incorrect
epinephrine is first line treatment. The role of other clinical coding. However, most reports suggest
drugs is reviewed. Timed and serial serum tryptase lifetime prevalence rates within the range of
measurements help to confirm the diagnosis. Long- 0.5e2%.3
term management is necessary to minimise the risk of The prevalence has been increasing for reasons
recurrence and includes identification of the trigger(s), that are not yet clear. A UK study illustrated
management of risk factors, education on avoidance a sevenfold increase in the number of hospital
and a formalised treatment plan with an epinephrine admissions for anaphylaxis over a period of 15 years
auto-injector if appropriate. Every patient who has (1990e2005).4 In younger age groups the prevalence
experienced anaphylaxis should be referred to an of food induced anaphylaxis has increased dispro-
allergy clinic for appropriate management. This is portionally. An Australian study detected a fivefold
endorsed by many national guidelines (eg, UK NICE). increase in hospital admissions for food mediated
Anaphylaxis is often misdiagnosed or miscoded as, for anaphylaxis over a 10 year period in children aged
example, asthma or food allergy. Most doctors will 0e4 years.5 Additionally, the number of cases of
encounter a patient with anaphylaxis in their career and fatal anaphylaxis is believed to be rising.6 7 In the UK
should to be familiar with the clinical features, 20 deaths per year from anaphylaxis are reported,
management and mechanisms of this potentially fatal although this may underestimate the true rate.8
condition.
CLINICAL FEATURES
Anaphylaxis presents with a range of clinical
symptoms of varying severity, many of which can
present in other conditions associated with severe
INTRODUCTION systemic compromise. The diagnosis is therefore
Anaphylaxis is an acute systemic allergic reaction made by the typical pattern of clinical features
which may be life threatening. The incidence of with rapid progression of symptoms, often with
anaphylaxis is increasing.1 Most doctors will a history of a preceding trigger. However, the clin-
encounter a medical emergency due to anaphy- ical presentation varies considerably depending on
laxis at some point in their careers. Early recog- individual hypersensitivity, the dose and route of
nition of the signs and symptoms along with trigger delivery, as well as individual traits such as
prompt initiation of acute treatment is crucial. the presence of asthma. The diagnosis of anaphy-
However, once the acute reaction has resolved, laxis should be made if a patient develops an acute
clinical management should focus on preventing illness (within minutes of exposure to the trigger)
further similar episodes. We aim to provide doctors with rapidly progressing skin changes, and life
with a better understanding of the condition threatening airway and/or breathing and/or
by discussing the aetiology and mechanisms cardiovascular compromise. Anaphylaxis
of anaphylaxis. In addition, we review the frequently produces signs and symptoms within
current recommendations for its acute and long 5e30 min after exposure to a trigger, although
term management, including recently published sometimes symptoms may not develop for several
guidelines.1 hours (figure 1).

458 Postgrad Med J 2012;88:458e464. doi:10.1136/postgradmedj-2011-130634

 Downloaded from pmj.bmj.com on September 8, 2012 - Published by group.bmj.com

Review

Cutaneous manifestations are most common, affecting over Table 1 Mechanism of anaphylaxis9 13 28 51e54

90% of reported cases.9 These features include flushing, pruritus, Mechanism Trigger
urticaria, and angioedema. Other clinical features of anaphylaxis
IgE mediated Food (eg, nuts, milk, shellfish), insect venom,
include bronchospasm, laryngeal oedema, hypotension, and b-lactams, NMBA (eg, suxamethonium), latex,
cardiac arrhythmias. Some patients also describe gastrointestinal occupational allergens (wheat flour in bakers),
symptoms of nausea, diarrhoea, and abdominal pain. An over- semen, aeroallergens
whelming feeling of ‘impending doom’ is common.10 In severe Non-IgE immune mediated (IgM or Radio-contrast media, dextran, gelatin, NSAID,
IgG mediated cytotoxicity, immune some biologics
anaphylaxis rapid cardiovascular compromise and shock can complexes, leukotrienes, activation
occur without preceding cutaneous features. For example, in of complement, kalikrein-kinin and
intraoperative anaphylaxis, cardiovascular compromise may be coagulation cascade)
the only presenting sign.11 Special attention should be paid to Direct, non-immune mediated mast Exercise, cold, drugs (vancomycin, opioids)
cell activation
infants who may be unable to describe their symptoms.
However, some presenting features such as flushing, hoarseness IG, immunoglobulin; NMBA, neuromuscular blocking agents; NSAID, non-steroidal anti-
inflammatory drugs.
after a crying spell, and vomiting after feeding may be evident in
healthy infants, leading to misdiagnosis.
These reactions have a tendency to be more severe and can
Anaphylaxis and the heart occur with the first recognised exposure.23 Moreover, nuts are
Anaphylaxis may be complicated by myocardial ischaemia and often hidden in foods and accidental exposure is sometimes
arrhythmias even without underlying cardiac pathology and in difficult to avoid. Geographic variation affects which foods
the absence of epinephrine administration.12 Tachycardia is the predominate as causes of anaphylaxis. Buckwheat and rice are
norm in anaphylaxis. However, when volume depletion exceeds more common causes in parts of Asia and sesame in parts of the
20e30%, tachycardia may be followed by bradycardia (two Middle East.24 25
phase physiological response to hypovolaemia). Therefore, heart
rate does not always differentiate between anaphylaxis and Insect stings
vasovagal reaction.13 14 Moreover, bradycardia may occur in Insects of the order Hymenoptera can cause anaphylaxis, namely
response to the drug taken or may be associated with bees (honey bees, bumble bees), vespids (yellow jackets, hornets,
a conduction defect. Vasodilatation during anaphylaxis impairs wasps), and stinging ants. Systemic allergic reactions to insect
venous filling, leading to empty vena cava syndrome if the stings are reported by up to 3% of adults and up to 1% of
patient suddenly assumes an upright position. Pulseless electrical children.26 27 The onset of anaphylaxis following insect stings
activity ensues, followed by myocardial ischaemia and can be rapid.
subsequently epinephrine-unresponsive shock due to lack of
circulatory volume.15 Drugs
The most common classes of drugs triggering anaphylaxis
Fatal anaphylaxis include antibiotics, usually b-lactam antibiotics, and non-
Fatalities are rare and estimated to occur in <2% cases.16 Predis- steroidal anti-inflammatory drugs (NSAIDs).28 Biological agents
posing factors for fatal anaphylaxis include coexistent asthma increasingly are identified as causes of anaphylaxis, resulting
and in particular poorly controlled asthma.17 This is especially from their growing in use in clinical practice. The estimated rate
relevant in the context of food allergy such as peanut and tree nut of anaphylaxis and immunoglobulin E (IgE) mediated reaction to
allergy.18 A delay in administration of epinephrine is an important infliximab, for example, is 2e3%.29 For accurate diagnosis of
risk factor for death and is seen in 80e87% of fatal cases.19 20 anaphylaxis following drug administration a thorough history is
vital, including the exact timing of when the agent was
CAUSES OF ANAPHYLAXIS administered, the interval to the reaction, medications that
There are a wide variety of triggers for anaphylaxis and their
frequency varies according to age. In children, food is the most
common cause whereas drugs are more common in adults.20 21
Table 2 Major mediators of anaphylaxis9 13 18 44 50e52 57

Food Mediators / cells Action

Nuts are frequently associated with food mediated anaphylaxis,
Histamine (via H1‒H4 Pruritus, tachycardia, rhinorrhoea, bronchospasm (H1)
with peanut being the most common cause in the USA.22 histaminergic Endothelial release of nitric oxide (NO) leading to
receptors) vasodilatation and hypotension (H1)
Hypotension, flushing and headache (H1, 2)
Inhibitory presynaptic (H3)drelease endogenous
epinephrine
Chemotaxis and mast cell cytokine release (H4)
Tryptase Activates: complement, coagulation and kalikrein‒kinin
system leading to angioedema, hypotension, and
disseminated intravascular coagulation
Respiratory and gastrointestinal tract mast cells
contain less tryptase than connective tissue mast
cells (tryptase may not increase in food anaphylaxis)
Platelet activating Responsible for systemic mast cell activation;
factor (PAF) high concentration of PAF and low concentrations of
PAF-acetylhydrolase may predispose to severe reaction
Low serum ACE concentrations may also contribute
to severe anaphylaxis
Figure 1 Timing of fatal anaphylaxis in relation to different triggers. Eosinophils Pro-inflammatory (release mediators from their granules)
IV, intravenous. Adapted from Pumphrey.8 Anti-inflammatory (metabolise vasoactive substances)

Postgrad Med J 2012;88:458e464. doi:10.1136/postgradmedj-2011-130634 459

 Downloaded from pmj.bmj.com on September 8, 2012 - Published by group.bmj.com

Review

the patient had received previously, and the response to Table 3 Differential diagnosis of anaphylaxis1 2 9 12 25 28 52 54 59

therapy.30 Common diagnoses Acute exacerbation of asthma

Syncope, CVA, epilepsy
Panic attack
Anaphylaxis at the time of anaesthesia Aspiration
The reported incidence of anaesthetic induced anaphylaxis varies CVS pathology (MI, PE)
between 1 in 4000 and 1 in 25 000. The mortality rate has been Shock (hypovolaemic, cardiogenic, septic, etc)
Excessive endogenous histamine Systemic or indolent mastocytosis
suggested as 4%.31 32 Neuromuscular blocking agents are the Basophilic leukaemia
most common triggers.33 The diagnosis of anaphylaxis during Food related syndromes Scombroid fish poisoning
anaesthesia poses challenges. Patients are unable to report (‘restaurant syndromes’) Food poisoning
symptoms and the first signs are often profound hypotension or Flushing syndromes Menopause related
Medullary thyroid carcinoma
difficulty in inflating the lungs. Additional diagnostic problems Carcinoid syndrome
occur due to the concomitant administration of several anaes- Pheochromocytoma
thetic agents, antibiotics and intravenous fluids such as gelofu- Autonomic epilepsy
sine. Other potential agents such as chlorhexidine, patent blue Red man syndrome (vancomycin)
Other drugs: niacin, bromocriptine
and latex should also be considered. ‘Pseudo-anaphylaxis’ Hyperventilation
Vocal cord dysfunction
Munchausen’s (by proxy) syndrome
Exercise induced anaphylaxis Other HAE
In some patients exercise alone can trigger anaphylaxis. Many ACE inhibitor induced angioedema
patients, however, require one or more co-factors to be present (ruptured) hydatid cyst
in order to develop symptoms. Food dependent, exercise CVA, cerebrovascular accident; CVS, cardiovascular system; HAE, hereditary angioedema;
MI, myocardial infarction; PE, pulmonary embolism.
induced anaphylactic reactions are becoming more prom-
inent.34 Foods most commonly implicated include wheat,
shellfish, tomatoes, peanuts, and corn. They are usually DIAGNOSIS AND INVESTIGATION OF ANAPHYLAXIS
ingested 4e6 h before exercise.35 Other reports suggest that the It is sometimes difficult to establish whether anaphylaxis has
combination of any solid food and exercise may trigger a reac- actually occurred.
tion.36 NSAID, alcohol, menstruation or seasonal pollen expo- The diagnosis relies on the patient’s recollection and
sure in pollen sensitised individuals have also been implicated as adequate accident and emergency (A&E), ambulance or
co-triggers.36e38 Typically, exposure to the trigger precedes the primary care documentation. A meticulous history is essential.
exercise which then provokes symptoms of anaphylaxis. Physicians should aim to ascertain a list of all foods and
Changes in plasma pH and osmolality redistribution of medications consumed in the 6 h preceding the event. In
splanchnic blood flow, increased tissue transglutaminase (tTG) addition, details regarding the time of the episode, the setting
activity, increased gastrointestinal permeability, and facilitated in which it occurred, and the treatment required should be
epitope recognition/allergen binding may all be responsible for sought. A history of potential cofactors is relevant, including
food dependent, exercise induced anaphylaxis, but they warrant any associated exercise, exposure to heat or cold, or co-existent
further studies.34 36 37 infections.

Idiopathic anaphylaxis Serum tryptase

Rarely, a trigger cannot be identified and therefore by exclusion It is useful when diagnosing anaphylaxis to look for objective
a diagnosis of idiopathic anaphylaxis can be considered. evidence of mast cell activation. Serum tryptase concentrations
However, in the rapidly moving field of allergy with the emer- peak at 1e2 h after the onset of anaphylaxis, and elevated
gence of new diagnostic tests and increasing knowledge of values can persist for several hours. It is recommended that
allergenic mechanisms, triggers can be identified in patients serum tryptase should be measured as soon as possible after
previously considered to have an idiopathic label. A recent emergency treatment has started, and ideally a second timed
example is the delayed anaphylaxis to red meat caused by the sample taken at 1e2 h and no later than 4 h after the onset of
galactose-a 1,3-galactose allergenic epitope.12 35 39 Furthermore, symptoms.40 Serial samples improve the sensitivity and speci-
a baseline serum tryptase concentration should be measured in ficity of the test.41 In addition, a baseline level should be taken
all patients with anaphylaxis to exclude an underlying diagnosis at 24 h, or when the patient attends a specialist clinic for
of mastocytosis, which would itself increase the risk of future follow-up. Although the positive predictive value is excellent,
reactions. not all anaphylactic reactions are accompanied by a rise in

Table 4 First line treatment of anaphylaxis12 28 60 61

Drug Recommended dose Comment

Intramuscular epinephrine (0.01 mg/kg of 1:1000) Adult: 0.5 ml Repeat every 5e15 min
>12 years: 0.5 ml (0.3 ml if small or pre-pubertal)
>6e12 years: 0.3 ml
<6 years: 0.15 ml
Oxygen Highest possible concentration 6e8 l/min (WAO)
Intravenous fluids (intra-osseous route possible) 0.9% NaCl Correct hypovolaemia (NaCl remains in intravascular space
Hartmann’s solution longer than glucose and contains no lactate)
1e2 litres usually needed in first 5 min (adult);
children 30 mg/kg in the first hour
Anaphylaxis to colloids described
WAO, World Allergy Organisation.

460 Postgrad Med J 2012;88:458e464. doi:10.1136/postgradmedj-2011-130634

 Downloaded from pmj.bmj.com on September 8, 2012 - Published by group.bmj.com

Review

Table 5 Second line treatment of anaphylaxis12 13 51 52 56 60

Table 7 Long term management of anaphylaxis1 12 15 52 54 59 60 65 66

Drug IV/IM dose Action Action Comment

H1-antagonists Chlorphenamine 10 mg Control pruritus, urticaria, Identification of trigger(s) Box 1
(child: 2.5e5 mg) angioedema, nasal/ocular Avoidance and education Avoidance of confirmed trigger cornerstone
symptoms of long term management
H2-antagonists Ranitidine 50 mg Small synergistic effect with Ensure (child’s) relatives and school/nursery
(child: 1 mg/kg) H1-antagonist in limiting staff educated and trained in using
Injected slowly due to above symptoms auto-injectors; verbal, written and online education
potential hypotensive effect Epinephrine autoinjector Prescribed if ongoing risk of fatal
Steroids Hydrocortisone 200 mg Prevent biphasic anaphylaxis and treatment plan reactionsdfor example, insect sting or nut allergy
(child: 25e100 mg) (delayed onset of action) Train to use
b-agonists Salbutamol (albuterol) Relieve wheeze, cough, dyspnoea Written treatment plan is essential
5 mg (child: 2.5 mg) Medic alert bracelet/jewellery Document known triggers (penicillins,
nebulised NSAID, nuts, insect venom etc)
Review of regular medication Replace/discontinue b-blockers, ACE inhibitors,
sedatives, hypnotics, antidepressants unless no
alternative
serum tryptase, particularly in food mediated anaphylaxis and Management of risk factors Age related factors, drugs (table 6)
for severe or fatal anaphylaxis Comorbidities (cardiovascular, asthma, mastocytosis,
sometimes in normotensive patients.42 43 Elevated values of
other clonal mast cell disorders (c-kit mutation), CNS
mast cell tryptase postmortem may also be used to establish impairment)
anaphylaxis as a cause of death.44 However, there have been Referral to allergy specialist See box 1
reports of postmortem elevations in serum tryptase in some CNS, central nervous system; NSAID, non-steroidal anti-inflammatory drug.
non-anaphylactic deaths.45 46 Therefore, high tryptase concen-
trations suggest anaphylaxis, but must be used in conjunction
with the clinical history supplemented by the circumstances of
PAF-acetylohydrolase values seem to correlate with the severity
the death.
of anaphylaxis.49 50
Measurement of plasma histamine has been suggested in the
literature as a possible investigation in the diagnosis of an
anaphylactic reaction. Plasma histamine values begin to rise PATHOGENESIS OF ANAPHYLAXIS
5e10 min after the onset of symptoms and remain elevated for The majority of cases of anaphylaxis are IgE mediated, but other
30e60 min.47 However, histamine has a short half-life, peaking mechanisms have been described (table 1) and the clinical
at 5 min, and is therefore not useful in patients presenting more presentation can be identical. Therefore the distinction between
than an hour after the onset of a reaction. Moreover, plasma anaphylactic (IgE mediated) and anaphylactoid (non-IgE) reac-
histamine is not stable during routine handling and the sample tions is not possible and should be abandoned as it leads to
requires careful treatment. Therefore, an assay of plasma hista- a dangerous assumption that anaphylactoid reactions are always
mine is not routinely available. less severe.12 51 55 56
Elevated total tryptase concentrations are also found in In IgE mediated anaphylaxis allergen/antigen-stimulated B
conditions other than mastocytosis and anaphylaxisdfor lymphocytes produce specific IgE which binds to high affinity
example, in acute myelocytic leukaemia, myelodysplastic IgE receptors (Fc3RI) on mast cells and basophils. Re-exposure to
syndromes, and end stage renal disease with endogenous stem the allergen leads to cross-linking of receptor bound IgE, trig-
cell factor elevation.43 For this reason other ways of measuring gering cell activation and release of preformed (histamine,
mast cell degranulation are being examined. The measurement tryptase, heparin, chymase) and newly synthesised mediators
of mast cell carboxypeptidase has shown particular promise as (leukotrienes, prostaglandins, platelet activating factor PAF,
an investigative technique.12 48 Other markers being studied cytokines IL-6, tumour necrosis factor a (TNFa)) (table 2).12 52
include chymase and platelet activating factor (PAF). PAF and The lungs and the heart are the main shock organs of
anaphylaxis, due to vasodilatation caused by reduced venous
Table 6 Special consideration in acute and long term management of return and hypovolaemia resulting from fluid extravasation (up to
anaphylaxis12 28 52 54 62 63 35% of the intravascular fluid may leak out within 10 min).13 14 58
Group Special considerations
Infants Unable to report symptoms
DIFFERENTIAL DIAGNOSIS OF ANAPHYLAXIS
Some symptoms are physiological: flushing, spitting food Differential diagnosis of anaphylaxis encompasses a wide range
after feeding, etc of conditions. Some of them are common (acute asthma,
Correct epinephrine dose should be calculated
syncope, panic attack) but less common causes should also be
Children Consider developmental delay/behavioural problems
Teenagers Risk taking behaviour (non-compliance with prescribed
considered (table 3).
treatment and avoidance due to denial or peer pressure)
Elderly Consider comorbidities especially involving cardiovascular system
b-blockers and ACE inhibitors commonly used
Memory impairment precludes recognition of life threatening
symptoms; physical impairment (severe rheumatoid arthritis,
hearing/vision impairment) hinders epinephrine (auto-injector) Useful websites
administration
Pregnancy Mother’s health is the priority; use epinephrine as in
non-pregnant patient; position on left side to relieve inferior
UK: http://bsaci.org, http://anaphylaxiscampaign.org;
vena cava compression by gravid uterus; regular fetal monitoring; EU: http://eaaci.net;
consider emergency caesarian section US: http://aaaai.com, http://www.acaai.org,
All age groups Substance/alcohol abusedinterferes with avoidance measures; http://www.foodallergy.org;
impairs recognition of life threatening symptoms and appropriate
self management
Australia: http://www.allergyfacts.org.au.

Postgrad Med J 2012;88:458e464. doi:10.1136/postgradmedj-2011-130634 461

 Downloaded from pmj.bmj.com on September 8, 2012 - Published by group.bmj.com

Review

Box 1 Role of allergy specialist in management of Current research questions

anaphylaxis
< How common is anaphylaxis, what are the triggers, and is
Role of allergy specialist anaphylaxis on the increase?
1. Detailed history and elucidation of triggers and co-factors (eg, < New specific and sensitive markers of anaphylaxisd
food dependent, exercise induced anaphylaxis) especially when tryptase is negative.
2. Skin tests, blood tests including relevant specific IgE < What are the likely causes of idiopathic anaphylaxis?
3. Graded challenge and/or provocation if unclear or to identify < Newly discovered allergensdwhat proportion of idiopathic
alternative medication, for example, non-steroidal anti- anaphylaxis can they explain?
inflammatory drug, antibiotic < What is the role of second line drugs in the acute
4. Individualised avoidance plan management of anaphylaxisdfor example, do corticosteroids
5. Written emergency treatment plan prevent the late phase response?
6. Optimisation of asthma treatment
7. Immunotherapy (eg, for insect venom, etc)
8. Desensitisation to a drug if immediately required and no
IM or subcutaneous (SC) injection into the deltoid. Refer to
alternative available
table 4 for dosing.9 12 28 56
9. Education (verbal, written; online resources)
The length of the needle in crucial in ensuring the dose reaches
10. Regular follow-up of patients with ‘idiopathic anaphylaxis’
the muscle. Auto-injectors’ needles may be too short in obese
patients. In the hospital setting standard syringe and needle are
often used allowing for deeper penetration.
The age and sex of the patient often provides the clue: aspi- Intravenous (1:10 000) epinephrine infusion should only be
ration of a nut is more likely in a small child; amniotic fluid used by intensivists experienced in the use/titration of vaso-
embolism during labour and a myocardial infarction in a middle pressors, with continuous haemodynamic monitoring.28 60
aged man.25 52 Intubation and other vasopressors may also be required.
There are no absolute contraindications to epinephrine. Dose
adjustment is almost never required in the setting of acute
MANAGEMENT OF ANAPHYLAXIS
anaphylaxis.60 Occasionally described mild transient side effects
Acute
are the result of physiological action of this drug (pallor,
1. Discontinue exposure to potential trigger (stop intravenous
tachycardia, headache, etc). Erroneous intravenous administra-
(IV) drug/remove insect stinger, etc).
tion or epinephrine overdose may lead to cardiac arrhythmias,
2. Follow the ABCDE rule (Airway, Breathing, Circulation,
pulmonary oedema or even death.12 28 52
Disability, Exposure).
Some drugs interact with epinephrinedfor example, b-
3. Simultaneously with step 2, administer intramuscular (IM)
blockers (including eye drops) may reduce the efficacy of
epinephrine. Lie patient down with legs elevated (to correct
epinephrine and the unopposed stimulation of a receptors may
hypovolaemia/avoid empty vena cava) or place in a position of
trigger bradycardia, hypertension, and bronchoconstriction.
comfort (if vomiting or short of breath). While doing this,
Glucagon and fluid resuscitation are recommended in the
summon help, administer oxygen, and obtain access to give IV
management of anaphylaxis in b-blocked patients. Linezolid,
fluids. Start cardiopulmonary resuscitation (CPR) if needed.
monoamino oxidase inhibitors (MAOIs), and tricyclic antide-
Epinephrine is the first line treatment of anaphylaxis and the
pressants increase the risk of arrhythmias and hypertension in
only one with proven lifesaving properties. Epinephrine vaso-
response to epinephrine.28 59 60
constricts, decreases mediator release and mucosal oedema (via
a1-adrenergic receptor); relieves bronchoconstriction (a1- and
b2-adrenergic receptor), and exerts positive inotropic and
chronotropic effect (b1-adrenergic receptor).12 25 54 56 60
There are no randomised controlled trials, but a large body of
evidence supports prompt use of epinephrine in anaphylaxis. It Key references
should be injected intramuscularly in the mid-anterolateral
thigh (vastus lateralis) which leads to a better absorption than
< Schwartz LB. Diagnostic value of tryptase in anaphylaxis and
mastocytosis. Immunol Allergy Clin North Am 2006;26:
451e63.
< Ewan PW, Clark AT. Long-term prospective observational
study of patients with peanut and nut allergy after participation
Main messages in a management plan. Lancet 2001;357:111e15.
< Kemp SF, Lockey RF. Anaphylaxis: a review of causes and
< Refer all patients who experience anaphylaxis to an allergy mechanisms. J Allergy Clin Immunol 2002;110:341e8.
clinic for further investigation and management. < Ewan PW, Dugue P, Mirakian R, et al. BSACI guidelines for
< Explain allergen avoidance, educate the patient and relatives, the investigation of suspected anaphylaxis during general
and provide a written emergency treatment plan including anaesthesia. Clin Exp Allergy 2009;40:15e31.
epinephrine auto-injector. < Simons FER, Ardusso LRF, Bilo MB, et al. World Allergy
< Serial tryptase measurements are useful in the diagnosis of Organisation guidelines for the assessment and management
anaphylaxis. of anaphylaxis. J Allergy Clin Immunol 2011;127:593e1e23.

462 Postgrad Med J 2012;88:458e464. doi:10.1136/postgradmedj-2011-130634

 Downloaded from pmj.bmj.com on September 8, 2012 - Published by group.bmj.com

Review

Other commonly used drugs in the acute management of Competing interests None.
anaphylaxis should be considered second line, and their admin- Provenance and peer review Commissioned; externally peer reviewed.
istration must never delay treatment with epinephrine (table 5).
4. Measure serum tryptase (see: serum tryptase) and record
timing of sample in relation to onset of symptoms. REFERENCES
1. National Institute for Health and Clinical Excellence. NICE Clinical Guideline
5. Patients with uncomplicated anaphylaxis can be discharged 134. Anaphylaxis: Assessment to Confirm an Anaphylactic Episode and the Decision
after 4e6 h. Some should be observed for 24 h or more (severe to Refer After Emergency Treatment for a Suspected Anaphylactic Episode.
reaction; history of severe asthma and biphasic reaction; likely 2011:1e95.
ongoing absorption of allergen; presenting late evening/night; 2. Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the
definition and management of anaphylaxis: summary report e Second National
vulnerable patients; patients residing in remote areas) (table 6). Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network
Biphasic anaphylaxis has been reported to occur in up to 20% Symposium. J Allergy Clin Immunol 2006;117:391e7.
adults with symptoms recurring within 1e72 h (usually 3. Lieberman P, Camargo CA Jr, Bohlke K, et al. Epidemiology of anaphylaxis:
findings of the American College of Allergy, Asthma and Immunology
8e10 h) after the initial reaction has resolved, despite no further Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol
exposure to the trigger. An experienced clinician should be 2006;97:596e602.
involved in the decision to discharge the patient as there are no 4. Gupta R, Sheikh A, Strachan DP, et al. Time trends in allergic disorders in the UK.
Thorax 2007;62:91e6.
definite predictors of biphasic anaphylaxis. Clear instructions to 5. Poulos LM, Waters AM, Correll PK, et al. Trends in hospitalisations for anaphylaxis,
return to hospital if symptoms recur should to be provided, and angioedema and urticaria in Australia 1993-1994 to 2004-2005. J Allergy Clin
a 1e3 day course of oral steroids may prevent the delayed Immunol 2007;120:878e84.
recurrence of symptoms.1 2 12 60 63 64 6. Shen Y, Li L, Grant J, et al. Anaphylactic deaths in Maryland (US) and Shanghai:
a review of forensic autopsy cases from 2004-2006. Forensic Sci Int 2009;186:1e5,
6. Long term management (table 7). (IIb).
7. Role of allergy specialist (box 1). 7. Liew WK, Williamson E, Tang ML. Anaphylaxis fatalities and admissions in Australia.
J Allergy Clin Immunol 2009;123:434e42.
8. Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal
MULTIPLE CHOICE QUESTIONS (TRUE (T)/FALSE (F); ANSWERS reactions. Clin Exp Allergy 2000;30:1144e50.
AFTER THE REFERENCES) 9. Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy
Clin Immunol 2002;110:341e8.
1. What is the most common cause of anaphylaxis in children? 10. Schmidt-Traub S, Bamler KJ. The psychoimmunological association of panic
A. Radio-contrast media disorder and allergic reaction. Br J Clin Psychol 1997;36:51e62.
B. Stinging insect venom 11. Dewachter P, Mouton-Faivre C, Emala CW. Anaphylaxis and anaesthesia:
controversies and new insights. Anesthesiology 2009;111:1141e50.
C. Antibiotics 12. Simons FE, Ardusso LR, Bilo MB, et al; World Allergy Organization. World Allergy
D. Non-steroidal anti-inflammatory drug (NSAID) Organisation guidelines for the assessment and management of anaphylaxis.
E. Food J Allergy Clin Immunol 2011;127:587e93.e1e22.
13. Khan BQ, Kemp SF. Pathophysiology of anaphylaxis. Curr Opin Allergy Clin Immunol
2011;11:319e25.
2. Which drug should be avoided in patients with a history of 14. Fisher MM. Clinical observations on the pathophysiology and treatment of
recurrent anaphylaxis who require an epinephrine auto-injector? anaphylactic cardiovascular collapse. Anaesth Intensive Care 1988;14;17e21.
A. Diltiazem 15. Pumphrey RS. Fatal posture in anaphylactic shock. J Allergy Clin Immunol
2003;112:451e2.
B. Candesartan 16. Moneret-Vautrin DA, Morisset M, Flabbee J, et al. Epidemiology of life-threatening
C. Propranolol and lethal anaphylaxis: a review. Allergy 2005;60:443e51.
D. Metoclopramide 17. Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to
E. Domperidone foods. J Allergy Clin Immunol 2001;107:191e3.
18. Summers CW, Pumphrey RS, Woods CN, et al. Factors predicting anaphylaxis to
peanuts and tree nuts in patients referred to a specialist centre. J Allergy Clin
3. What is the incidence of biphasic anaphylaxis? Immunol 2008;121:632e38.e2.
A. 25e35% 19. Pumphrey R. Anaphylaxis: can we tell who is at risk of a fatal reaction? Curr Opin
Allergy Clin Immunol 2004;4:205e90.
B. 15% 20. Greenberger PA, Rotskoff BD, Lifschultz B. Fatal anaphylaxis: post mortem findings
C. 1e20% and associated co-morbid diseases. Ann Allergy Asthma Immunol 2007;98:252e7.
D. 40e60% 21. de Silva IL, Mehr SS, Tey D, et al. Paediatric anaphylaxis: a 5 year retrospective
review. Allergy 2008;63:1071e6.
E. 100% 22. Furlong TJ, DeSimone J, Sicherer SH. Peanut and tree nut allergic reactions in
restaurants and other food establishments. J Allergy Clin Immunol 2001;108:867e70.
4. The most common agents triggering anaphylaxis at the time of 23. Sicherer SH, Furlong TJ, Munoz-Furlong A, et al. A voluntary registry for peanut and
general anaesthesia are: tree nut allergy: characteristics of the first 5149 registrants. J Allergy Clin Immunol
2001;108:128e32.
A. Neuromuscular blocking agents (NMBA) 24. Shek LP, Lee BW. Food allergy in Asia. Curr Opin Allergy Clin Immunol
B. Opiates 2006;6:197e201.
C. Intravenous fluids (Gelofusin, Hartmann’s) 25. Simons FE. Anaphylaxis: recent advances in assessment and treatment. J Allergy
Clin Immunol 2009;124:625e36; quiz 637e8.
D. Iodine preparation 26. Golden DB. Insect allergy and venom immunotherapy: a model and mystery.
E. Chlorhexidine J Allergy Clin Immunol 2005;115:439e47.
27. Golden DB, Marsh DG, Kagey-Sobotka A, et al. Epidemiology of insect venom
sensitivity. JAMA 1989;262:240e4.
5. Following the onset of anaphylaxis, when do serum tryptase
28. Lieberman P, Nicklas RA, Oppenheimer J, et al. The diagnosis and management of
concentrations peak? anaphylaxis practice parameter: 2010 Update. J Allergy Clin Immunol
A. 0e10 min 2010;126:477e80.e1e42.
B. 1e2 h 29. Baert F, Norman M, Vermeire S, et al. Influence of immunogenicity on the long
term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348:601e8.
C. 3e4 h 30. Ewan PW, Dugue P, Mirakian R, et al. BSACI guidelines for the investigation
D. 20e30 min of suspected anaphylaxis during general anaesthesia. Clin Exp Allergy
E. 4e5 h 2009;40:15e31.
31. Hepner DL, Castells MC. Anaphylaxis during the perioperative period. Anaest Analg
2003;97:1381e95.
Contributors All authors provided written sections for this review. 32. Moss J. Allergic to Anaesthetics. Anaesthesiology 2003;99:521e3.

Postgrad Med J 2012;88:458e464. doi:10.1136/postgradmedj-2011-130634 463

 Downloaded from pmj.bmj.com on September 8, 2012 - Published by group.bmj.com

Review

33. Mertes P, Laxenaire MC. Allergic reactions occurring during anaesthesia. Eur J 54. Simons FE. Anaphylaxis, killer allergy: long-term management in the community.
Anaesthesiol 2002;19:240e62. J Allergy Clin Immunol 2006;117:367e77.
34. Robson-Ansley P, Du Toit G. Pathophysiology, diagnosis and management of 55. Johansson SG, Bieber T, Dahl R, et al. Revised nomenclature for allergy for global
exercise-induced anaphylaxis. Curr Opin Allergy Clin Immunol 2010;10:312e17. use: report of the Nomenclature Review Committee of the World Allergy
35. Romano A, Di Fonso M, Giuffreda F, et al. Food-dependent exercise-induced Organization, October 2003. J Allergy Clin Immunol 2004;113:832e6.
anaphylaxis: clinical and laboratory findings in 54 subjects. Int Arch Allergy Immunol 56. Sheikh A, Shehata YA, Brown SG, et al. Adrenaline for the treatment of anaphylaxis:
2001;125:264e72. cochrane systematic review. Allergy 2009;64:204e22.
36. Shadick NA, Liang MH, Partridge AJ, et al. The natural history of exercise-induced 57. Kajiwara N, Sasaki T, Bradding P, et al. Activation of human mast cell through the
anaphylaxis: survey results from a 10-year follow-up study. J Allergy Clin Immunol platelet-activating factor receptor. J Allergy Clin Immunol 2010;125:137e45.
1999;104:123e7. 58. Brown SG, Blackman KE, Stenlake V, et al. Insect sting anaphylaxis: prospective
37. Harada S, Horikawa T, Ashida M, et al. Aspirin enhances the induction of type I evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg
allergic symptoms when combined with food and exercise in patients with food- Med J 2004;21:149e54.
dependent exercise-induced anaphylaxis. Br J Dermatol 2001;145:336e9. 59. El-Shanawany T, Williams PE, Jolles S. Clinical immunology review series: an
38. Wade JP, Liang MH, Sheffer AL. Exercise-induced anaphylaxis: epidemiologic approach to the patients with anaphylaxis. Clin Exp Immunol 2008;153:1e9.
observations. Prog Clin Biol Res 1989;297:175e82. 60. Resuscitation Council UK. Resuscitation Guidelines. 2010. http://www.resus.org.uk
39. Commins SP, Satinover SM, Hosen J, et al. Delayed anaphylaxis, angioedema or (accessed 19 Sep 2011).
urticaria after consumption of red meat in patients with IgE antibodies specific for 61. Apostolou E, Deckert K, Puy R, et al. Anaphylaxis to gelofusine confirmed by in vitro
galactose-a-1,3-galactose. J Allergy Clin Immunol 2009;123:426e33. basophil activation test: a case series. Anaesthesia 2006;61:264e8.
40. Payne V, Kam P. Mast cell tryptase: a review of its physiology and clinical 62. Gonzalez-Perez A, Aponte Z, Fernandez Vidaurre C, et al. Anaphylaxis epidemiology
significance. Anaesthesia 2004;59:695e703. in patients with and patients without asthma: a United Kingdom database review. J
41. Brown SG, Blackman KE, Heddle RJ. Can serum mast cell tryptase help diagnose Allergy Clin Immunol 2010;125:1098e104.
anaphylaxis? Emerg Med Australas 2004;16:120e4. 63. Tse Y, Rylance G. Emergency management of anaphylaxis in children and young
42. Caughey GH. Tryptase genetics and anaphylaxis. J Allergy Clin Immunol people: new guidance from the Resuscitation Council (UK). Arch Dis Child Educ Pract
2006;117:1411e14. Ed 2009;94:97e101.
43. Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. 64. Tole JW, Lieberman P. Biphasic anaphylaxis: review of incidence, clinical predictors,
Immunol Allergy Clin North Am 2006;26:451e63. and observation recommendations. Immunol Allergy Clin North Am 2007;27:309e26.
44. Yunginger JW, Nelson DR, Squillance DL, et al. Laboratory investigation of deaths 65. Ewan PW, Clark AT. Long-term prospective observational study of patients with
due to anaphylaxis. J Forensic Sci 1991;36:857e65. peanut and nut allergy after participation in a management plan. Lancet
45. Randall B, Butts J, Halsey JF. Elevated post-mortem tryptase in the absence of 2001;357:111e15.
anaphylaxis. J Forensic Sci 1995;40:208e11. 66. Sicherer SH, Simons FE. Quandaries in prescribing an emergency action plan and
46. Edston E, van Hage-Hamsten M. Mast cell tryptase and haemolysis after trauma. self-injectable epinephrine for first-aid management of anaphylaxis in the community.
Forensic Sci Int 2003;131:8e13. J Allergy Clin Immunol 2005;115:575e83.
47. Simons FE. Anaphylaxis. J Allergy Clin Immunol 2008;121(2 Suppl):S402e20.
48. Schwartz HJ. Anaphylaxis: issues in diagnosis. Curr Opin Allergy Clin Immunol
2001;1:357e9.
49. Sanza ML, Gamboab PM, Garcı́a-Figueroac BE, et al. In vitro diagnosis of ANSWERS
anaphylaxis. Chem Immunol Allergy 2010;95:125e40.
50. Vadas P, Gold M, Perelman B, et al. Platelet-activating factor, PAF acetylhydrolase
and severe anaphylaxis. N Engl J Med 2008;358:28e35.
1. A (F); B (F); C (F); D (F); E (T)
51. Lee JK, Vadas P. Anaphylaxis: mechanisms and management. Clin Exp Allergy 2. A (F); B (F); C (T); D (F); E (F)
2011;41:923e38. 3. A (F); B (F); C (T); D (F); E (F)
52. Simons FE. Anaphylaxis. J Allergy Clin Immunol 2009;125:S161e81. 4. A (T); B (F); C (F); D (F); E (F)
53. Lee J, Kim S, Kim M, et al. Anaphylaxis to husband’s seminal plasma and treatment 5. A (F); B (T); C (F); D (F); E (F)
by local desensitization. Clin Mol Allergy 2008;6:13e15.

Online Archive

Visit our Online Archive e available back to 1925. Subscribers may access the entire archive
freely. Non-subscribers have free access to all articles prior to 2006. A simple one-time
registration is required that grants access to all the free archive content, across all of our
specialist titles. To view or to register visit pmj.bmj.com.

464 Postgrad Med J 2012;88:458e464. doi:10.1136/postgradmedj-2011-130634

 Downloaded from pmj.bmj.com on September 8, 2012 - Published by group.bmj.com

Anaphylaxis: current state of knowledge for

the modern physician
Krzysztof Rutkowski, Shelley Dua and Shuaib Nasser

Postgrad Med J 2012 88: 458-464 originally published online March 30,
2012
doi: 10.1136/postgradmedj-2011-130634

Updated information and services can be found at:

http://pmj.bmj.com/content/88/1042/458.full.html

These include:
References This article cites 64 articles, 3 of which can be accessed free at:
http://pmj.bmj.com/content/88/1042/458.full.html#ref-list-1

Email alerting Receive free email alerts when new articles cite this article. Sign up in
service the box at the top right corner of the online article.

Topic Articles on similar topics can be found in the following collections

Collections
Editor's choice (71 articles)

Notes

To request permissions go to:

http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to:

http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to:

http://group.bmj.com/subscribe/