CLINICAL ANAESTHESIA
Anaphylaxis
Jessica Chapman
Abdul G Lalkhen
Abstract
Anaphylaxis is a severe, life-threatening, generalized or systemic
hypersensitivity reaction. The pathophysiology of anaphylaxis can be
described as immunologic and non-immunologic. Classification can
be based on the time course of the anaphylactic reaction which may
be uniphasic, biphasic or protracted. There are many triggers for
anaphylaxis; the most commonly identified are food, drugs and
venom. Perioperative anaphylaxis is a serious complication reported
in up to 1 in 13,000 anaesthetics. It can be caused by neuromuscular
blocking agents (NMBAs), antibiotics, blood and blood products,
dyes, chlorhexidine and natural rubber latex. The presence of other
comorbidities and concurrent medications impacts on the severity of
symptoms and the response to treatment in patients with anaphylaxis.
The diagnosis of anaphylaxis is mostly clinical; however it can be
supported by various laboratory tests like serum tryptase levels,
plasma histamine levels and the mature b-tryptase levels. The basic
principles of management of anaphylaxis are the same in all age
groups. The use of the Resuscitation Council Anaphylaxis Algorithm
aids in the recognition and treatment of an anaphylactic reaction.
Keywords b-Tryptase; biphasic anaphylaxis; pathophysiology of
anaphylaxis; plasma histamine; tryptase; uniphasic
Royal College of Anaesthetists CPD Matrix: 1BO1, 2A06, 2C04
Anaphylaxis
The first recorded episode of anaphylaxis can be found in hi-
eroglyphic recordings from 2640 BC of the death of an Egyptian
pharaoh after a wasp sting. A more modern description of
anaphylaxis is described in a study from 1902 involving pro-
tocols for immunizing dogs with jellyfish toxin. The injection of
small amounts of toxin in some animals, rather than generating
protection, precipitated a rapid onset of fatal or near-fatal
symptoms. The term ‘anaphylaxis’ is derived from the Greek
roots ‘ana’ (backward) and ‘phylaxis’ (protection or immunity).
Definition and classification
The European Academy of Allergy and Clinical Immunology
(EAACI) Nomenclature Committee proposed the following
definition: Anaphylaxis is a severe, life-threatening, generalized
Jessica Chapman FRCA is a Specialist Registrar in Anaesthesia in
the Northwestern Deanery and Advanced Pain Trainee at Lancashire
Teaching Hospitals NHS Foundation Trust, UK. Conflicts of interest:
none declared.
Abdul G Lalkhen MSc FRCA FFPMRCA DP Med is a Consultant in
Anaesthesia and Pain Medicine at Salford Royal NHS Foundation
Trust and is an Honorary Senior Lecturer at the University of
Manchester, UK. Conflicts of interest: none declared.
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Please cite this article in press as: Chapman J, Lalkhen AG, Anaphylaxis, Anaesthesia and intensive care medicine (2016), http://dx.doi.org/
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Learning objectives
After reading this article, you should be able to:
C define and classify anaphylaxis
C describe the pathophysiology of anaphylaxis
C understand the diagnostic criteria and recognize the full
spectrum of signs and symptoms of anaphylaxis
C appreciate the impact that various comorbidities and medica-
tions have on the response to treatment in patients with
anaphylaxis
C describe the immediate and secondary management of a
patient with anaphylaxis
C understand the need for further investigations and appropriate
onward referral
or systemic hypersensitivity reaction. Traditionally Anaphy-
laxis is a term used to describe immunoglobulin E (IgE)-
dependent events and ‘anaphylactoid reaction’ is used to
describe IgE-independent reactions e although both of these
reactions are clinically indistinguishable.
The World Allergy Organization (WAO) has proposed that
this nomenclature be discarded and that anaphylaxis should be
described as immunologic and non-immunologic. The WAO is an
international organization that represents many regional
and international societies dedicated to allergy and clinical
immunology.
 Immunologic anaphylaxis includes:
 IgE-mediated reactions.
 IgG-mediated reactions.
 Immune complex/complement-mediated reactions.
 Non-immunologic anaphylaxis is caused by agents or events
that induce sudden and massive mast cell or basophil
degranulation in the absence of immunoglobulins.
Definitions and incidence
Uniphasic anaphylaxis is the most common type accounting for
80e90% of all episodes. The uniphasic response peaks within 30
e60 minutes after exposure to allergens and tends to resolve
either spontaneously or with treatment within the next 30e60
minutes.
Biphasic anaphylaxis has an estimated incidence of 1e23% of
all anaphylactic reactions. These reactions are characterised by a
uniphasic response, followed by an asymptomatic period of an
hour or more and the subsequent recurrence of symptoms
WITHOUT re-exposure to the antigen. These reactions can occur
at any age.
Protracted anaphylaxis has an unknown incidence. These
anaphylactic reactions last hours, days or even weeks in extreme
cases without resolving completely.
Epidemiology
The incidence of anaphylaxis is underestimated in various
studies in the UK owing to the problems of recognizing it. The
criteria for inclusion vary in different studies and countries.
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 CLINICAL ANAESTHESIA
Incidence
The American College of Allergy, Asthma and Immunology
Epidemiology of Anaphylaxis Working Group concluded that the
overall frequency of episodes of anaphylaxis is between 30 and
950 cases per 100,000 persons per year.
Lifetime prevalence
The same group provided data indicating a lifetime prevalence of
between 50 and 2000 episodes per 100,000 persons or 0.05e2%.
More recent UK primary care data concur, indicating a lifetime
age-standardized prevalence of a recorded diagnosis of anaphy-
laxis of 75.5 per 100.000 in 2005. Calculations based on these
data indicate that approximately 1 in 1333 of the British popu-
lation have experienced anaphylaxis at some point in their lives.
Pathophysiology
Immunologic reactions
IgE-mediated: this reaction is classically initiated by the antigen
(allergen) interacting with the allergen-specific IgE bound to the
receptor Fc on the mast cells and/or basophils. The B cells
differentiate into IgE-producing cells via the activity of CD4-
Helper T cells (Th2 cells). This occurs in the peripheral
lymphoid tissues. The cytokines interleukin-4 and interleukin-13
along with their receptors contribute to the IgE response. Once
produced, allergen-specific IgE diffuses into the tissues and
vasculature and occupies the receptors on the mast cells and
basophils. When the allergen diffuses into the proximity of a
mast cell or basophil, it interacts with the surface bound IgE that
is specific for that allergen. This interaction causes the receptors
to initiate intracellular signalling. Certain allergens are able to
interact on two or more surface receptors of IgE and thus are
capable of cross-linking. If signalling is robust enough it will
activate mast cells and basophils and cause degranulation. The
result is the release of preformed mediators, enzymes and cyto-
kines (tryptase, histamine and tumour necrosis factor) and the
production of additional mediators, cytokines and enzymes.
These mediators either act directly on tissue or indirectly by
activating eosinophils to cause the symptoms of allergy.
IgG-mediated anaphylaxis has not been demonstrated in
humans. However, human IgG receptors are capable of activating
macrophages and neutrophils to secrete platelet activating factor
(PAF) which activates mast cells causing immune complex
ecomplement mediated anaphylaxis. This type of anaphylaxis
has been implicated in life-threatening reactions to many drugs
like protamine.
Non-immunologic reactions
The potential mechanisms by which mast cells and basophils
are activated without the involvement of IgE or immune
complexes are:
 Activation of complement in the absence of immune complex
formation. This mechanism has been implicated in peanut-
induced anaphylaxis, use of drugs dissolved in Cremophor
EL including older preparations of propofol and paclitaxel.
 Direct activation of the mast cells and/or basophils. The
exact mechanism is by activation of MRGPRB2 and
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MRGPRX2. This mechanism is implicated in the ‘red man
syndrome’ reaction to vancomycin and degranulation by
drugs such as opiates.
 Angiotensin-converting enzyme (ACE) inhibitors cause
rare anaphylactic reactions or isolated angioedema due
to the excessive production and/or accumulation of
bradykinin.
 Over-sulphated chondroitin sulphate (OSCS) which is a
compound contaminating heparin supplies in 2007e2008
caused direct activation of the kinin-kallikrein pathway
which generated bradykinin, C3a and C5a.
Diagnostic criteria
The diagnostic criteria for anaphylaxis were published by a group
of experts in 2005 and 2006 to aid clinicians in the recognition of
the full spectrum of signs and symptoms.
Anaphylaxis is highly likely if ONE of the following criteria is
fulfilled:
Criterion 1 e Acute onset (minutes to several hours) involving
skin, mucosal tissue or both (generalized hives, urticaria, pruri-
tus and flushing, swollen lipsetongueeuvula) and at least one
of the following:
 Respiratory compromise (bronchospasm, wheeze, stridor,
hypoxaemia, reduced peak expiratory flow).
 Reduced blood pressure (BP) or associated symptoms
and signs of end-organ dysfunction (collapse, syncope,
incontinence).
Criterion 2 e Two or more of the following that occur rapidly
after exposure to a likely allergen for that patient (minutes to
several hours):
 Involvement of skin and mucosal tissue as described
above.
 Respiratory compromise as described above.
 Reduced BP or associated signs and symptoms of reduced
BP.
 Persistent gastrointestinal signs and symptoms (crampy
abdominal pain, nausea, vomiting).
Criterion 3 e Reduced BP after exposure to a known allergen
for that patient (minutes to several hours):
 Reduced BP in adults is defined as a systolic BP (SBP) of
less than 90 mmHg or 30% decrease in that patient’s
baseline.
 In infants and children, reduced BP is defined as low sys-
tolic BP (age specific) or greater than 30% decrease in SBP.
Symptoms and signs
Common symptoms and signs include the following:
 Skin-mucosal signs and symptoms, which occur in up to
90% of all episodes include generalized hives, pruritus,
flushing swollen lipsetongueeuvula, periorbital oedema,
conjunctival swelling.
 Respiratory symptoms and signs, which occur in up to
70% of episodes. These include nasal discharge, nasal
congestion, change in voice, choking sensation, stridor,
wheeze, cough and shortness of breath.
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 CLINICAL ANAESTHESIA
 Gastrointestinal symptoms and signs, which occur in up to
45% of episodes. These include nausea, vomiting, diar-
rhoea and abdominal cramps.
 Cardiovascular symptoms and signs, which occur in 45%
of all episodes. These include collapse, syncope, inconti-
nence, tachycardia, hypotension and dizziness.
Anaphylaxis may present as mild and resolve spontaneously
due to the endogenous production of compensatory mediators (e.g.
adrenaline, angiotensin II) or it may be severe and may progress
within minutes to respiratory or cardiovascular compromise and
death. The factors that determine the course of progression are
not fully understood. It is worth noting that in perioperative
anaphylaxis, the most common presenting features are cardio-
vascular collapse and bronchospasm; skin changes are less
common in this group when compared to all-cause anaphylaxis.
Triggers and mechanisms
Anaphylaxis can be precipitated by various triggers. Those most
commonly identified include food, drugs and venom.
Allergen triggers (IgE-dependent mechanism)
 Foods and additives like walnuts, peanuts, shellfish, fish,
milk, eggs, strawberries and spices.
 Insect stings (Hymenoptera venom) and insect bites
(mosquitoes, horse flies, ants).
 Medications (e.g. Beta-lactam antibiotics e penicillin,
cephalosporin, vancomycin, NSAIDS).
 Contrast media (iodinated, technetium, fluorescein).
 Anaesthetic drugs (e.g. suxamethonium, atracurium,
rocuronium, sugammadex).
 Occupational allergens (natural rubber latex, hair dye).
Immunologic triggers (IgE-independent mechanism)
 Coagulation system activation.
 IgG-dependent reactions (e.g. reactions to dextran,
infliximab).
Idiopathic anaphylaxis
 Possibility of mastocytosis or clonal mast cell disorder.
 Possibility of previously unrecognized trigger.
Non-immunologic triggers (direct activation of mast cells and
basophils)
 Medications (like opioids, some NSAIDS).
 Alcohol.
 Physical factors (e.g. cold, heat, exercise, sunlight).
Time course for fatal anaphylactic reactions
Fatal food reactions cause respiratory arrest typically after 30e35
minutes according to a published case series; insect stings cause
collapse from shock after 10e15 minutes. Deaths due to intra-
venous medication occur commonly within 5 minutes. Death
never occurred more than 6 hours after contact with the trigger.
Contributory factors
Factors including exercise, alcohol, non-steroidal anti-inflam-
matory drugs (NSAIDs), acute infections, stress and pre-
menstrual status potentially amplify anaphylaxis by decreasing
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the threshold of allergen exposure needed to trigger anaphylaxis.
Comorbidities and concurrent medications may impact on the
severity of symptoms and signs and response to treatment in
patients with anaphylaxis.
Comorbidities
 Pulmonary diseases (e.g. COPD, asthma).
 Cardiovascular diseases (e.g. ischaemic heart disease,
hypertensive vascular disease, cardiomyopathy).
 Recent intracranial surgery.
 Hyperthyroidism.
Concurrent medications
 b-Adrenergic blockers.
 a-Adrenergic blockers.
 ACE inhibitors.
 Tricyclic antidepressants.
 Recreational drugs (e.g. cocaine, heroin).
 Monoamine oxidase inhibitors.
Mortality
The overall prognosis of anaphylaxis is good. Early injection of
adrenaline in anaphylaxis e defined as injection before arrival at
an emergency department e can significantly reduce the likeli-
hood of hospital admission. Delayed injection of adrenaline has
been reported in a large case series of anaphylaxis-related fatal-
ities in which only 23% of the 92 individuals received it before
cardiac arrest. Risk of death is increased in those with pre-
existing comorbidities, especially asthma. There are approxi-
mately 20 anaphylaxis deaths reported each year in the UK,
although this may be a substantial underestimate.
Trends over time
Data indicates a dramatic increase in the rate of hospital ad-
missions for anaphylaxis; from 0.5 to 3.6 admissions per 100,000
between 1990 and 2004: an increase in 700%. A recent study of
hospital admissions in England and Wales shows a 615% in-
crease in admissions for all-cause anaphylaxis between 1992 and
2012. There was no evidence of an increase in fatal anaphylaxis
over the same period, with a rate of 0.047 cases per million
population. The highest admission rates for food-induced
anaphylaxis occur in very young children (0e4 years), howev-
er the greatest acceleration in the rate of increase is in the age
groups 5e14 years and 15e29 years.
Differential diagnosis
The most common disorders in the differential diagnosis include
acute generalized urticaria and/or angioedema, acute asthma
exacerbations, syncope/faint and anxiety/panic attacks.
Acute disorders
 Acute asthma
 Acute generalized urticaria
 Acute angioedema
 Acute anxiety/panic attacks
 Cardiovascular events (myocardial infarction, pulmonary
oedema)
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 CLINICAL ANAESTHESIA
Flush syndromes
 Carcinoid syndrome
 Hyperthyroidism
 Peri-menopause
 Red man syndrome (vancomycin)
 Phaeochromocytoma
Shock
 Hypovolemic
 Cardiogenic
 Septic
 Distributive (spinal cord injury)
Excess histamine production
 Mastocytosis
 Basophilic leukaemia
Laboratory tests
The clinical diagnosis of anaphylaxis can sometimes be supported
by the elevated concentrations of serum tryptase or plasma his-
tamine. It is important to obtain blood samples for measurement
soon after the onset of symptoms, as elevations are transient.
 Serum total tryptase: ideally the blood sample for serum
tryptase measurement needs to be obtained from 15 mi-
nutes to 3 hours after the onset of symptoms. The normal
range is 1e11.4 ng/ml. A tryptase level in the normal
range does not refute the clinical diagnosis of anaphylaxis.
A serial measurement of total serum tryptase over several
hours increases the sensitivity and the specificity of the
test. If a tryptase level obtained 24 or more hours after the
resolution of symptoms and signs is still elevated, the pa-
tient should be referred to an allergy/immunology
specialist for evaluation of possible systemic mastocytosis
or clonal mast cell disease.
 Plasma histamine e the levels typically peak within 5e15
minutes of the onset of anaphylaxis symptoms and decline
to baseline by 60 minutes. Histamine is rapidly metabo-
lized by N-methyltransferase and diamine oxidase.
 Future tests e a laboratory test for mature beta-tryptase, a
better marker of mast cell activation than total serum
tryptase has been developed but is not widely available. In
a prospective controlled study of emergency department
patients with anaphylaxis, up-regulation of innate inflam-
matory gene networks was reported and may provide new
insights into the potential release of a cascade of mediators
in anaphylaxis.
Management
The basic principles of treatment are the same for all age groups.
The ABCDE approach is used to recognize and treat an
anaphylactic reaction.
The specific treatment of an anaphylactic reaction depends
on:
 Location
Treating an anaphylactic patient in the community will not be
the same as in an acute hospital setting. An ambulance should be
called immediately and the patient transferred to the emergency
department.
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 Training of rescuers
All clinical staff should be able to call for help and initiate
initial treatment in an anaphylactic patient.
 Number of responders
The single responder must ensure that help is coming. If there
are several responders appropriate delegation of tasks can be
undertaken.
 Equipment and drugs available
Resuscitation equipment and drugs to aid rapid initiation of
treatment must be available immediately in all clinical settings.
 Remove trigger agent
Removing the trigger agent may not always be possible. For
example STOP any drug suspected of causing anaphylaxis such
as antibiotics, gelatins; remove the stinger after a bee sting.
 DO NOT DELAY definitive treatment if removing the
trigger agent is not possible.
 Patient positioning
 Patients with airway and breathing difficulties may
prefer to sit up.
 Patients with low blood pressure may need to lie flat or
with elevated legs.
 Patients who are unconscious and breathing should be
laid in recovery position.
 Pregnant patients should lie on their left side to prevent
caval compression.
Cardio-respiratory arrest
Start cardiopulmonary resuscitation (CPR) immediately as per
the recent Advanced Life Support (ALS) guidelines. The intra-
muscular route for adrenaline is not recommended after cardiac
arrest has occurred.
Anaphylaxis algorithm
The key steps in the treatment of an anaphylactic reaction are
shown in Figure 1.
Discharge and follow-up
 Patients who have had a suspected anaphylactic reaction
(ABC problem) should be treated and observed for at least 6
hours. They should then be reviewed by a senior clinician
and a decision made about any further need for observation.
 Patients with response to initial treatment should be
warned of the possibility of an early recurrence of symp-
toms and under some circumstances should be kept for up
to 24-hour observation.
 There is no reliable way of predicting the incidence of a
biphasic reaction; hence the decisions about discharge are
made for each patient by an experienced clinician.
Before discharge from hospital all patients must be:
 Reviewed by a senior clinician.
 Given clear instructions to return to hospital if symptoms
return.
 Be considered for anti-histamines and oral steroid therapy
for up to three days. This is helpful for treatment of urti-
caria and may decrease the chance of further reaction.
 Have a plan for follow-up, including referral to their gen-
eral practitioner.
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 CLINICAL ANAESTHESIA

Anaphylaxis algorithm

Anaphylactic reaction?

Airway, Breathing, Circulation, Disability, Exposure

Diagnosis – look for:

• Acute onset of illness
• Life-threatening airway and/or breathing
and/or circulation problems
• And usually skin changes

• Call for help

• Lie patient flat
• Raise patient’s legs

Adrenaline

When skills and equipment available:

• Establish airway
• High-flow oxygen Monitor:
• IV fluid challenge • Pulse oximetry
• Chlorphenamine • ECG
• Hydrocortisone • Blood pressure

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

2 Adrenaline (give IM unless experienced with IV adrenaline) 3 IV fluid challenge:

IM doses of 1:1000 adrenaline (repeat after 5 minutes if no better) Adult – 500–1000 ml
• Adult 500 micrograms IM (0.5 ml) Child – crystalloid 20 ml/kg
• Child more than 12 years: 500 micrograms IM (0.5 ml)
Stop IV colloid
• Child 6–12 years: 300 micrograms IM (0.3 ml) if this might be the cause
• Child less than 6 years: 150 micrograms IM (0.15 ml) of anaphylaxis
Adrenaline IV to be given only by experienced specialists
Titrate: Adults 50 micrograms; Children 1 µg/kg

4 Chlorphenamine 5 Hydrocortisone
(IM or slow IV) (IM or slow IV)
Adult or child more than 12 years 10 mg 200 mg
Child 6–12 years 5 mg 100 mg
Child 6 months to 6 years 2.5 mg 50 mg
Child less than 6 months 250 micrograms/kg 25 mg

Resuscitation Council (UK). Reproduced with kind permission.

Figure 1

Reporting of a reaction
Adverse drug reactions that include an anaphylactic reaction
should be reported to Medicines and Healthcare products Regu-
latory Agency (MHRA) using the yellow card scheme (www.
mhra.gov.uk). The British National Formulary (BNF) includes
copies of the Yellow Card. All cases of fatal anaphylactic reaction
must be discussed with the coroner.
The 6th National Audit Project of The Royal College of
Anaesthetists is currently collecting information concerning
perioperative anaphylactic events with the aim of enabling the
anaesthetic and allergy communities to collaborate to make
recommendations for the improvement of the quality of patient
care.

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Specialist referral
All patients presenting with anaphylaxis should be referred to an
allergy clinic to identify the cause, and thereby reduce the risk of
future reactions and patient education to manage future epi-
sodes. The list of specialist clinics is available on the British
Society for Allergy and Clinical Immunology (BSACI) and Asso-
ciation of Anaesthetists of Great Britain and Ireland websites
(www.bsaci.org and www.aagbi.org). A Simons FE. Anaphylaxis. J Allergy Clin Immunol 2010; 125: S161.30.
FURTHER READING
Anaphylaxis Foundation and Anaphylaxis Network of Canada.
(www.anaphylaxis.org).
Johansson SGO, Bieber T, Dahl R, et al. Revised nomenclature for
allergy for global use: report of nomenclature review committee of
the World Allergy Organization, October 2003. J Allergy Clin
Immunol 2004; 113: 832e6.
Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mecha-
nisms. J Allergy Clin Immunol 2002; 110: 341.
Online resource. www.uptodate.com/patients.
Resuscitation Council (UK) e Anaphylaxis algorithm. www.resus.org.
uk/pages/anapost1.pdf.
Simons FE, Ebisawa M, Sanchez-Borges M, et al. 2015 update of the
evidence base: World Allergy Organization anaphylaxis guidelines.
World Allergy Organ J 2015; 8: 32.
The American Academy of Allergy, Asthma and Immunology.
www.aaaai.org.
Working Group of the Resuscitation Council (UK). Emergency treat-
ment of anaphylactic reactions: guidelines for healthcare providers.
January 2008, www.resus.org.uk/pages/reaction.pdf.

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