Received: 1 October 2018 | Revised: 7 July 2019 | Accepted: 9 July 2019

DOI: 10.1111/pan.13703

E D U C AT I O N A L R E V I E W

An update on allergy and anaphylaxis in pediatric anesthesia

Bojana Stepanovic1 | David Sommerfield1,2 | Michaela Lucas2,3 |

Britta S. von Ungern‐Sternberg1,2,4

1
Department of Anaesthesia and Pain
Medicine, Perth Children's Hospital, Perth, Abstract
Western Australia, Australia Childhood allergy is common, and increasing. Many children are incorrectly labeled
2
Medical School, The University of Western
as having allergy or adverse drug reactions. This can pose a dilemma for anesthetists
Australia, Perth, Western Australia, Australia
3
Department of Immunology, Perth
and lead to a change in practice or drug selection. We review the pathophysiology of
Children's Hospital, Perth, Western hypersensitivity reactions and the implications for anesthesia of food allergy, atopy,
Australia, Australia
4
and family history of allergy in children. The epidemiology of anaphylaxis is discussed.
Telethon Kids Institute, Perth, Western
Australia, Australia We discuss the common triggers of perioperative anaphylaxis in children and explore
emerging triggers including chlorhexidine and sugammadex. Accurate data on pedi‐
Correspondence
Britta S. von Ungern‐Sternberg, Department atric perioperative anaphylaxis is limited worldwide, with marked geographic varia‐
of Anaesthesia and Pain Management, Perth tion. This highlights the need for accurate local, district and/or nationwide incident
Children's Hospital, 15 Hospital Avenue,
Nedlands, WA 6009, Australia. reporting. The clinical features, diagnosis, and management of anaphylaxis under
Email: Britta.regli-vonungern@health. anesthesia are discussed. We review the process of expert allergy testing following
wa.gov.au
a suspected case of anaphylaxis to guide future safe anesthesia administration. The
Funding information preoperative consultation is an opportunity for referral for allergy testing to allow
Frank Callahan Estate; Stan Perron
Charitable Trust; Perth Childrens' Hospital de‐labeling. This has the potential for improved antibiotic stewardship and more
Foundation effective treatment with first‐line therapeutic agents.
Section Editor: Francis Veyckemans
KEYWORDS
allergy, anaphylaxis, outcome, pediatric anesthesia

1 | I NTRO D U C TI O N 2 | S E A RC H M E TH O D

Anesthetists are often confronted with a child with food allergy, The databases Ovid Medline and PubMed were used. The follow‐
atopy, a family history of allergy, or a child labeled as having an ing search terms were used: anesthesia, anaphylaxis, perioperative,
allergic reaction to a drug.1 Epidemiological data suggest that the pediatric, child, allergy, drug allergy, including articles published
2
incidence of drug‐induced anaphylaxis overall is increasing high‐ from 2005 to 2018.
lighting the need for improvement in allergy reporting systems.1
Allergy de‐labeling is a growing area of research interest with a
potential to improve patient care perioperatively. 3 The common 3 | M EC H A N I S M O F A LLE RG I C
triggers, diagnosis, management, and follow‐up testing of periop‐ R E AC TI O N S
erative anaphylaxis are reviewed in this article. Concern over
anaphylaxis risk has been shown to alter anesthetists’ clinical Allergic reactions are classified by Gell and Coombs, as summarized
practice 4 and follow‐up allergy testing is crucial to the diagnosis in Table 1. The term drug hypersensitivity reaction is often used in
and prevention of further events. this context. Drug hypersensitivity reactions may be allergic or not

Pediatric Anesthesia. 2019;00:1–9. wileyonlinelibrary.com/journal/pan

© 2019 John Wiley & Sons Ltd | 1
2 | STEPANOVIC et al

TA B L E 1 Gell and Coomb's classification of hypersensitivity reactions adapted from source65

Classification Mechanism Clinical presentation

Type 1‐ Immediate hyper‐ IgE antibody to specific antigens, mast cell stimulation, Wheeze, hay fever, eczema, food allergy, urticaria,
sensitivity reactiona and release of inflammatory mediators laryngeal edema, angioedema, anaphylaxis
Type 2‐ Antibody‐mediated Cytotoxic antibody: IgM, IgG bind specific antigens on Haemolytic transfusion reaction from ABO incompat‐
cytotoxic reactions cell membrane, complement activation, phagocytosis ibility, autoimmune hemolytic anemia
Type 3‐ Immune complex‐ IgM and/or IgG Immune complex deposition in re‐ Serum sickness, vasculitis, glomerulonephritis, rheuma‐
mediated reactions sponse to soluble antigen; complement activation toid arthritis
Type 4‐ Delayed type Cell mediated by T‐lymphocytes Contact dermatitis, tubercular lesions, graft rejection
hypersensitivity
Other Various Nonspecific rash severe cutaneous adverse reactions
(SCAR, eg, Stevens Johnson Syndrome, toxic epidermal
necrolysis)
a
Non‐IgE‐mediated reactions mimicking Type 1 reactions may also occur, for example, direct histamine release caused by drugs for example, mor‐
phine, atracurium, vancomycin (red man syndrome)

allergic in nature with the term drug allergies being reserved for im‐
4 | A LLE RG Y H I S TO RY TA K I N G
munological‐mediated hypersensitivities. For this review we use the
term drug allergy throughout.
Allergic reactions are classified based on their pathophysiology Children are frequently labeled as having multiple drug allergies
where antibody mediated reactions characterize Type 1 to Type 3 without definitive testing.9 There is limited data for the prevalence
reactions while Type 4 reactions are cell mediated (Table 1). of drug allergy labeling in children, however recent studies from
Western Australia quoted a rate of 5%‐7% at a tertiary pediatric cen‐
tre.9,10 Up to 20% of adult inpatients are labeled as having antibiotic
3.1 | Pathophysiology of anaphylaxis
allergy,11,12 with only 10% of those patients having a true allergy.12
Anaphylaxis is a systemic allergic reaction of sudden onset after Having an antibiotic allergy label is associated with inappropriate an‐
exposure to an allergen, which manifests as life threatening com‐ tibiotic prescribing11 and increased hospital readmission compared
promise of the airway, respiratory, or circulatory function with or to unlabeled patients.12 Conversely, de‐labeling of antibiotic aller‐
5,6
without dermatologic findings. gies may reduce the use of broad spectrum antibiotics and prevent
Medications can trigger anaphylaxis through an IgE‐dependent surgical site infections due to inadequate prophylactic cover from
mechanism as well as direct mast cell activation. Following an initial second‐line agents.3
sensitizing exposure, IgE antibodies are produced by B lymphocytes The anesthetist is met with the difficulties of parental recall
that bind to the high‐affinity FcεRI receptors present on mast cells of adverse drug events, preoperative time constraints, and lim‐
and basophils.5 Further drug exposure leads to the antigen–antibody ited institutional resources for allergy testing. Parents often mix
complex inducing mast cell activation. There is release of preformed up common drug side effects or intolerances as immune‐mediated
mediators including histamine, tryptase, heparin, and inflammatory allergies.
mediators, such as cytokines like TNF‐alpha, leukotrienes, prostaglan‐ Accurate allergy history taking and documentation is important
dins leading to immediate allergic symptoms. This leads to recruitment to distinguish a true drug allergy from a simple adverse drug reac‐
and activation of additional inflammatory cells producing an amplified tion. Immediate allergic reactions are usually present within 1 hour
response over several hours.5 of exposure with the occurrence of urticaria, laryngeal edema, and
Some drugs can trigger anaphylaxis via direct mast cell or baso‐ bronchospasm and may lead to anaphylaxis.3 Non‐IgE‐mediated
phil activation, with no prior sensitization necessary. This has been drug reactions may be delayed and present with maculopapular or
identified with opioids, radiocontrast media, and some antibiotics morbilliform rash, gastrointestinal effects, headache, or pruritis.3 If
6
such as vancomycin. Both triggering mechanisms can present the clinical symptoms are suggestive of an immediate allergic reaction,
same way and are clinically indistinguishable.4 the patient should be referred for allergic evaluation prior to the pro‐
Sensitization does not always correlate with the presence of cedure if possible13 in relation to elective surgery and the causative
7
clinical allergy or anaphylaxis. The development of anaphylaxis fol‐ agent should be avoided until further guidance by formal testing.
lowing an exposure is influenced by immunological, hormonal, and Consensus recommendations from European and UK bodies recom‐
environmental factors.8 To develop an allergy the patient has to have mend preoperative allergy testing for patients who have described
been exposed to the allergen before (knowingly or not knowingly). a history of severe reaction consistent with anaphylaxis during pre‐
Previous tolerance of a medication does not predict lifelong toler‐ vious anesthesia.4 The child with documented anaphylaxis to a med‐
ance as sensitization to a medication with regard to an IgE reaction ication should be referred for a MedicAlert bracelet to convey the
can occur at any time. risk if found unconscious or unaccompanied by an adult.
STEPANOVIC et al | 3

5 | CO M M O N A LLE RG Y‐ R E L ATE D 6 | A N A PH Y L A X I S
D I S E A S E S I N C H I LD H O O D
6.1 | Epidemiology
5.1 | Atopic disease
In the general population, the incidence of perioperative anaphylaxis
Atopic diseases include atopic dermatitis, food allergy, allergic rhi‐ is estimated as 1:10 000 in the recent UK‐wide NAP 6 survey4 and
nitis, and allergic asthma. Children with one of these illnesses are at Australian data. 25,26 The true incidence of perioperative anaphylaxis
a significant risk of developing another.14 The most basic underlying is unclear as data are compiled from institution‐based case series,
mechanism is the development of IgE antibodies directed against al‐ administrative databases, or voluntary reporting systems in many
lergens that are usually harmless.14 Up to 40% of children progress countries27 rather than formal reporting systems.
from eczema to asthma and/or rhinoconjunctivitis, mostly before The incidence of perioperative anaphylaxis in the pediatric
5 years of age.14 A family history of atopic disease is a major risk population is not comprehensively reported worldwide. The NAP
factor.14 The propensity to atopy is hereditary, for example, if both 6 survey reported 11 cases of grade 3‐4 anaphylaxis in pediatric
parents have an atopic disease, this will also manifest in 40% of off‐ anesthetics delivered, with an estimated incidence of 1:37 000,4
14,15
spring. However, it is a common myth that specific drug allergies the 2017 APRICOT study reported an incidence of 1:10 00028 , and
are hereditary; that is, if a mother is has anaphylaxis to a certain a French national database reported an incidence of 1:20 000. 29
trigger the child will not necessarily be allergic to the same allergen Australian mortality data demonstrate a 300% increase in inci‐
(eg, penicillin).15 dence and mortality from drug induced anaphylaxis from 1997 to
2005. 2
It is important to note that anaphylaxis is the leading cause of “pri‐
5.2 | Food allergy mary anaesthesia mortality” in Australia and New Zealand, and that all
deaths occurred in adults.30 One pediatric cardiac arrest and no deaths
Food is the leading cause of anaphylaxis overall in children.16
were reported in the French analysis,29 and no deaths in NAP 6.4
Common food allergy triggers are milk, eggs, peanuts, fish, soybeans,
wheat, and tree nuts.1 The prevalence of food allergy is greatest in
6.2 | Risk factors
the first years of life then falls in adulthood.1 Longitudinal studies
17 18
have found a resolution rate of 79% for milk, 68% for egg, 65% Several risk factors occur more frequently in children who develop
for wheat,19 50% for soy20 allergy compared to 20% for peanut 21 perioperative anaphylaxis including a history of asthma, food allergy,
and less than 10% for tree nut. 21 Fish and shellfish allergy persist multiple operations, and a family history of atopy.31 There is no sex
1,22
into adulthood difference in children, but the incidence of anaphylaxis is greater in
Food allergies do not pose a contraindication to any anesthetic adult females. 29 As the above factors are highly prevalent in the gen‐
agents. There is no contraindication to propofol use in children aller‐ eral population, they are not useful as screening tools.32
13,23
gic to egg, soy, or peanut. There is no cross reactivity between The clinical features of anaphylaxis are shown in Table 2. 29 In
seafood or crustacean antigens and iodinated drugs such as povi‐ children, severe anaphylaxis most commonly presents with broncho‐
done iodine and contrast agent,13 as although these agents all con‐ spasm or high airway pressure.4 “Resistant bronchospasm”, that is
tain iodine, this is not the allergenic determinant.13 In addition, no refractory to initial epinephrine administration, is more common due
allergic reactions to protamine have been reported in fish allergic to increased airway reactivity from underlying asthma and respira‐
patients. 24 tory tract infections.33

TA B L E 2 Clinical grading of
Grade Symptoms
anaphylaxis adapted from Mertes et al33
I (Mild) Cutaneous signs:
Generalised erythema, urticaria, peripheral angioedema
II (Moderate) Measurable but not life‐threatening symptoms:
Cutaneous signs
CVS: Hypotension, tachycardia
Respiratory disturbance: cough, dyspnoea
GI: difficulty swallowing, nausea, abdominal pain
CNS: irritability, confusion, sense of impending doom
III (Life threatening) Life threatening symptoms:
Severe hypotension, tachycardia or bradycardia, arrhythmias
Bronchospasm, high airway pressure
IV (Cardiac arrest) Cardiac and/or respiratory arrest
Most commonly presents as pulseless electrical activity
4 | STEPANOVIC et al

TA B L E 3 Differential diagnoses for anaphylaxis under neuromuscular blocking drugs as the commonest perioperative
anesthesia adapted from ANZCA guideline33 anaphylaxis triggers in children. The adoption of a latex‐free en‐

Symptoms Differential diagnoses vironment in many countries has drastically reduced sensitivity to
and hence anaphylaxis to this trigger. 35
Cutaneous signs: Direct histamine release
Hives, flushing, erythema, Venous obstruction
urticaria, angioedema
Head down position 6.3 | Antibiotics
C1‐esterase deficiency Antibiotic allergy is commonly reported in 5%‐10% of children and
Mastocytosis may manifest as an immediate IgE‐mediated (Type 1) or delayed T‐
Cold‐induced anaphylaxis cell‐mediated (Type 4) reaction.10 However, this is complicated by
Hypotension Hypovolemia the fact that 90% of patients are incorrectly labeled as having an
Peripheral vasodilation by drugs/ antibiotic allergy.36 This exposes patients to the risk of alternative
neuraxial blockade agents, higher rates of surgical site infection, antibiotic resistance,
Sepsis nosocomial infection, and prolonged hospital stay.3,36
Embolism: thrombotic, air, amniotic Cephalosporins, followed by penicillins are commonly reported
Vasovagal triggers of perioperative anaphylaxis in Europe34 and Australia.
Cardiogenic shock Cephalosporins are commonly used in antibiotic prophylaxis, which

High airway pressure/ Circuit malfunction

poses a challenge for anesthetists. In general, cross reactivity between
Respiratory compromise: penicillin and cephalosporin allergy is rare, however, independent ceph‐
Misplaced/kinked airway device
Wheeze, stridor, dyspnea alosporin allergies can still occur.3 Penicillins and cephalosporins share
Tension pneumothorax
a beta‐lactam ring,36 which is rapidly degraded and rarely antigenic.3
Asthma/Bronchospasm
Potential cross reactivity is due to similarities of the R1 side chains at‐
Airway foreign body
tached to the beta‐lactam ring.3 For example, cephazolin has a unique
Aspiration
side chain structure and does not react with penicillins 3, whereas am‐
picillin shares an R1 group side chain with cefaclor and cephalexin.36
TA B L E 4 Triggers for perioperative anaphylaxis (adults and Severe T‐cell‐mediated delayed allergic reactions such as toxic epider‐
children) adapted from NAP 6 4 mal necrolysis require referral for expert allergy consultation as cross
reactivity between penicillins and cephalosporins may occur.3
Percentage of cases with
Trigger identified trigger agent Current recommendations by the American Academy of Allergy
on cephalosporin use in the setting of proven penicillin allergy suggest
Antibiotics 46%
that a convincing history of Ig‐E mediated allergy should mandate for‐
NMBAs 33%
mal allergy testing37 and avoidance of the particular antibiotic class.
Chlorhexidine 10%
Consensus opinion suggests that in adult patients without a history of
severe reaction and no testing, cephalosporins may be given in a full
Diagnosis of anaphylaxis under anesthesia is challenging for a dose or graded oral challenge.38 These recommendations are debated
number of reasons. Symptom onset is usually sudden and severe and do not apply to the perioperative setting where an intravenous
due to intravenous drug delivery. However, onset may be delayed bolus dose of antibiotic is administered on induction of anesthesia.
from skin exposure to antiseptic or impregnated lines. As peripheral Data in the perioperative setting are limited to retrospective studies
perfusion is reduced in shock, cutaneous features may be absent ini‐ prone to selection bias and suggests very low incidence of anaphylaxis
tially in more severe grades of anaphylaxis. Patients may be draped to cephazolin in penicillin allergic patients.3 Vorobeichik et al review
making the airway access and physical examination more difficult. this topic in detail.3
The presenting symptoms are nonspecific with a broad list of differ‐ Of note, NAP 6 identified teicoplanin as the commonest anaphy‐
ential diagnoses (Table 3). Anaphylaxis should be suspected in any laxis trigger,4 which illustrates geographical differences in sensitivity
case of patient deterioration under anesthesia especially if unre‐ and local drug preferences. Vancomycin reaction under anesthesia is
sponsive to treatment. largely caused by nonimmune‐mediated histamine release leading to
Table 4 lists common triggers for perioperative anaphylaxis “red man syndrome” if rapidly administered.
identified in NAP 6, however, this varies among countries. 34 Of
the 11 pediatric cases identified in NAP 6, the trigger agents
6.4 | Neuromuscular blocking drugs (NMBDs)
were atracurium in three cases, and one case each of suxame‐
thonium, aprotinin, cefuroxime, and cryoprecipitate.4 Ibuprofen Neuromuscular blocking drugs are one of the most common
caused a nonallergic adverse reaction and no trigger was found causes of perioperative anaphylaxis in the general population with
in three cases.4 The findings above are in contrast to Mertes' geographical regional differences with higher rates in Europe and
study from 1997 to 2004 which identified latex, antibiotics, and Australia than observed in North America, implicated in 33%‐58%
STEPANOVIC et al | 5

of reactions.4,34 The NAP 6 study found suxamethonium to have the 6.7 | Propofol
highest rate of anaphylaxis per 100 000 administrations, followed by
Propofol is a rare cause of anaphylaxis under anesthesia, attributed
rocuronium and atracurium.34 Patients who are allergic to one agent
to well below 1% of cases.4,29 The reported incidence of anaphy‐
are likely to be cross reactive to other NMBDs.39 Suxamethonium
laxis to propofol is 1:60 000.48 Potential allergens include (a) the
has the highest prevalence of cross‐reactivity in patients allergic to
propofol molecule itself via its isopropyl and phenol groups,(b) to
rocuronium or vecuronium, whereas cisatracurium has the lowest.40
the intralipid solution of glycerine, soybean oil, and egg lecithin or
A prior exposure to NMBDs or anesthesia is not required to de‐
(c) preservatives such as disodium edetate (EDTA) or sodium metabi‐
velop allergy to a muscle relaxant. Epitopes containing a quaternary
sulfite. 23 There are a handful of case reports describing propofol al‐
ammonium ion or tertiary amine group are common in drugs, foods,
lergy in children allergic to egg, soy, or peanut.49 Egg allergic patients
cosmetics, and industrial materials, raising the possibility of environ‐
generally have immediate hypersensitivity to ovalbumin, a protein
mental exposure causing cross reactivity with NMBDs.32 Pholcodine
contained in egg whites, although lecithin is contained in the yolk.
is an over‐the‐counter antitussive drug available in Australia, which
Moreover, most cases of egg allergy outgrow this with time.13 Thus,
contains the quaternary ammonium ion epitope. Epidemiological
patients are unlikely to suffer anaphylaxis unless egg anaphylaxis is
studies have correlated pholcodine intake and the incidence of
present. Peanut allergy is considered due to the potential uncom‐
NMBA anaphylaxis. The drug was withdrawn in Norway in 2007,
mon (30%) cross‐reactivity between peanut and soy.50 The potential
with a subsequent fall in perioperative anaphylaxis and IgE sensitiza‐
small amount of soy protein remaining in soy oil after the refining
tion to pholcodine and suxamethonium.41 The immunological mech‐
process is thought to be insufficient, even in a sensitized individual,
anisms behind these observations are still to be clarified.42
to trigger a reaction13, however, no data exist on a threshold dose
The benzolisoquinolinium compounds (atracurium, mivacurium,
of contamination below which no allergic patient is likely to experi‐
cisatracurium) also cause direct mast cell histamine release which
ence symptoms.51 A retrospective review did not find an association
may present as a non‐IgE‐mediated anaphylaxis. A recent discovery
between food allergy and allergic reaction to propofol in children.52
of drug‐receptor interactions between NMBDs and the “MRGPRX2”
A retrospective review of egg, soy, and/or peanut allergic chil‐
mast cell receptor has been postulated as a mechanism for nonaller‐
dren who had received propofol found one child with anaphylaxis to
gic reactions to these drugs.43
egg who developed erythema and urticaria in the recovery room in
43 propofol exposures.49 Other retrospective reviews of adult pa‐
6.5 | Sugammadex tients allergic to egg, soy, or peanut reported no allergic reactions on
exposure to propofol.50,53
Sugammadex is a cyclodextrin compound used for reversal of ste‐
roidal neuromuscular blocking drugs such as rocuronium and ve‐
curonium. Gamma‐cyclodextrins are common food additives.44 6.8 | Nonsteroidal anti‐inflammatory drugs
Sugammadex usage is highest in Japan, with an estimated incidence
of anaphylaxis is 1:34 483.44 The use of this drug is increasing world‐ Nonsteroidal anti‐inflammatory drugs (NSAIDs) induced anaphylaxis

wide, and its availability stimulates increased rocuronium use. Little is most commonly due to a non‐IgE mediated mechanism,54 although

is currently known about the mechanism of sugammadex‐induced immediate IgE and delayed T‐cell reactions can occur.55 NSAIDs in‐

anaphylaxis due to the lack of sugammadex‐specific IgE antibodies hibit cyclooxygenase, increasing production of leukotrienes which

available for testing, and skin prick tests for the drug are still in de‐ can manifest as bronchospasm, urticaria, and angioedema.54

velopment. Emerging case reports in the literature lacked previous Subsequent skin tests are typically negative due to the lack of mast

exposure to sugammadex, suggesting cross‐reactivity between sug‐ cell involvement. NSAIDS are implicated as a leading cause of drug‐

ammadex and another substance 44,45

including a suspected case of induced anaphylaxis in adults56 and children55,57 outside the perio‐

anaphylaxis to the rocuronium‐ sugammadex complex.46 perative setting. Allergy testing is required to differentiate between
specific allergy or cross‐intolerance to all NSAIDs, and to suggest
safe alternatives.55
6.6 | Chlorhexidine
Chlorhexidine is an emerging cause of allergic reactions, ranging
6.9 | Latex
from contact dermatitis to anaphylaxis.47 Chlorhexidine applied
to mucous membranes or skin may produce a delayed reaction, Natural rubber latex is derived from the tropical Hevea brasiliensis
whereas insertion of a chlorhexidine‐impregnated device can lead tree and is widely used in the production of medical devices and eve‐
to a rapid and severe anaphylaxis.4 NAP 6 reported that diagnosis of ryday items. While many urethral and other catheters, sterile gloves,
chlorhexidine anaphylaxis was often not recognized, as it may not be as well as products in the food and hairdressing industry used to
4
obvious that certain products contained the allergen. If anaphylaxis be composed of latex in the past, many products have now been
to chlorhexidine is suspected, such indwelling devices should be re‐ supplanted by nonlatex products. However, patients with a history
moved and replaced with chlorhexidine‐ free alternatives if needed.4 of multiple surgeries, known latex sensitivity and atopy are still at
6 | STEPANOVIC et al

TA B L E 5 Initial management of pediatric anaphylaxis under TA B L E 5 (Continued)

anesthesia, adapted from ANZCA Guidelines33
Resistant Consider norepinephrine and vasopressin infu‐
Manage according to advanced life saving hypotension sion according to local pediatric protocol
guidelines: Consider isoprenaline and glucagon in beta‐
blocked patients
Start CPR
Consider other differential diagnoses
Epinephrine 10 mcg/kg (0.1 mL/kg of 1:10 000)
Paediatric car‐ After Consider hydrocortisone 2‐4 mg/kg (max
Crystalloid 20 mL/kg, repeat as needed (avoid
diac arrest stabilization 200 mg)
gelofusion)
Consider whether to proceed or postpone
Recognition Unresponsive hypotension or bronchospasm
surgery
Remove potential triggers for example, synthetic
Postoperative monitoring in intensive care/ high
colloid, chlorhexidine, latex
dependency unit
Stop procedure
Use minimal volatile if general anesthesia
increased risk of anaphylaxis. Perioperative anaphylaxis to latex has
Airway Intubate early especially if:
markedly decreasing.34
Airway edema
CVS/ Respiratory compromise
Breathing FiO2 100%
6.10 | Rare reactions
Consider treatment of resistant bronchospasm: Anaphylaxis to intravenous gelatin containing colloids has an es‐
Inhaled salbutamol 100 mcg/puff (6 puffs < 6 y, timated incidence of 1:16 000,4 however, they are rarely used in
12 puffs > 6 y) children. Opioids, particularly morphine and pethidine may cause
IV salbutamol infusion per local protocols (eg direct histamine release manifesting as pruritis, urticaria, and mild
1‐5 mcg/kg/min)
hypotension.58
Magnesium sulfate 50 mg/kg to max 2 g over IgE‐mediated anaphylaxis to benzodiazepines and local anes‐
20 min
thetic agents are rare.
Aminophylline 10 mg/kg over 1 h (max 500 mg)
Hydrocortisone 2‐4 mg/kg (max 200 mg)
Circulation Rapid fluid bolus 20 mL/kg crystalloid, repeat
7 | M A N AG E M E NT
as needed
Plan for large volume resuscitation, obtain large 7.1 | Immediate
bore IV access
Early recognition, administration of epinephrine and fluid, and resus‐
Epinephrine Initial IV Epinephrine Bolus (Pediatric)
citation are the mainstay of anaphylaxis management. The immedi‐
Dilution 1 mg in 50 mL = 20 mcg/mL
ate management of anaphylaxis is summarized in Table 5. Children
Moderate anaphylaxis (Grade 2): 0.1 mL/kg that
over the age of 12 are treated according to adult dosing. Following
is, 2 mcg/kg
stabilization, patients should be observed in intensive care for
Life threatening anaphylaxis (Grade 3):
0.2‐0.5 mL/kg that is, 4‐10 mcg/kg 24 hours as anaphylaxis may persist or exhibit a biphasic response.

Give dose every 1‐2 min prn, increase if The Australia and New Zealand College of Anaesthetists anaphy‐
unresponsive laxis guidelines promote the use of cognitive aids in the form of a
If no IV access series of anaphylaxis cards to assist in crisis resource management.

IM Epinephrine (Pediatric) The cards are intended to be stored in an emergency “anaphylaxis

box” in theatre along with information on local infusion protocols
1:1000 1 mg/mL lateral thigh
and collection tubes for tryptase testing. The anesthetist is the team
<6 y = 0.15 mL (150 mcg)
leader directing theatre staff, with cards assigned to different team
6‐12 y = 0.3 mL (300 mcg)
members to emphasize key tasks. Anaphylaxis drills should be prac‐
>12 y = 0.5 mL (500 mcg)
ticed regularly to ensure familiarity with local guidelines and prompt
Every 5 min as required
management.4
Pediatric epinephrine infusion
1 mg Epinephrine in 50 mL (20 mcg/mL)
7.2 | Diagnosis and follow‐up testing
Commence at 0.3 mL/kg/hr (0.1 mcg/kg/min)
Titrate to max 6 mL/kg/hr (2 mcg/kg/min) Mast cell tryptase (MCT) is a serum protease released from mast
cells activated during an Ig‐E mediated hypersensitivity reaction.
(Continues) There are two main types of MCT, alpha and beta MCT. 59 Alpha
STEPANOVIC et al | 7

pro‐tryptase is constitutively secreted and is the major form of systematic reporting of perioperative anaphylaxis to track local
tryptase in serum, whereas beta tryptase is released rapidly in al‐ trends and inform prevention strategies. Neuromuscular blocking
lergic reactions and elevated in most subjects with systemic ana‐ drugs and antibiotics and are the most common triggers for anaphy‐
phylaxis particularly in drug allergy. 59 Serum MCT is measured at laxis under anesthesia in children.
1 hour, 4 hours, and after 24 hours of the onset of anaphylaxis. Children are more likely to present with resistant bronchospasm
The minimal elevation of the acute total tryptase level that is con‐ and less likely to develop cardiac arrest compared to adults. Timely
sidered to be clinically significant is greater than (2 + 1.2 × base‐ recognition, removal of triggering agent, and administration of fluid
line tryptase levels), allowing detection of mast cell activation and epinephrine are the mainstays of treatment. The use of cognitive
even when the tryptase remains in the normal range. 60 MCT can aids and regular training will assist in the management of this crisis.
be elevated at baseline in rare conditions such systemic mast cell All patients with a suspected allergic reaction under anesthesia
disorders. 61 It is important to note that a MCT within the normal should be referred to a specialized anesthetic allergy testing centre
range does not rule out anaphylaxis if there is a significant rise. 58 for follow‐up.
Following recovery, the patient is referred to a specialized periop‐
erative allergy testing centre to investigate the reaction. The aim is
to ascertain the trigger for anaphylaxis, cross reactivity with other 9 | R E FLEC TI V E Q U E S TI O N S
anesthetic drugs, and formulation of a safe plan for suitable drugs
for future anesthetics. Follow ‐up testing should occur 4‐6 weeks 1. What is the classification of allergic reactions?
after complete resolution of clinical symptoms to allow restoration 2. What are common pediatric anaphylaxis triggers under
of tissue mast cell granules.62 anesthesia?
The consultation includes the review of the nature and tim‐ 3. What are the local protocols for management of perioperative
ing of the clinical reaction and all agents used intraoperatively as anaphylaxis in your institution? Are cognitive aids available, and if
well as tryptase results. Skin prick and intradermal testing induce so, where are they located?
localized mast cell degranulation and a wheal and flare response 4. What are the reporting mechanisms for perioperative anaphy‐
which identifies IgE‐mediated hypersensitivity. 63 International laxis and what are the processes for expert allergy testing in your
guidelines for perioperative allergy testing are published. 63,64 Skin institution?
prick testing is highly sensitive for NMBDs but insensitive for an‐
tibiotics, barbiturates, benzodiazepines, and opiates. 62 False pos‐
C O N FL I C T O F I N T E R E S T
itive results are possible if drug dilutions above the nonirritating
concentration are used. If there is clinical suspicion of anaphylaxis The authors report no conflict of interest
but a negative skin prick test, intradermal testing is considered.
Intradermal testing has a higher sensitivity and is performed rou‐
ORCID
tinely in Australasian centers. Skin tests will not detect the cause
62
of non‐IgE‐mediated anaphylaxis but may yield false negative Britta S. Ungern‐Sternberg https://orcid.org/0000-0002-8043-8541
results.
Drug challenge testing can identify both allergic and nonallergic
hypersensitivity. Drug challenge via graded oral, subcutaneous, or REFERENCES
intravenous exposure may be required for critical drugs such as an‐
1. Longo G, Berti I, Burks AW, Krauss B, Barbi E. IgE‐mediated food
tibiotics, NSAIDS, opioids where skin testing is inaccurate, but the
allergy in children. Lancet. 2013;382(9905):1656‐1664.
drug may be clinically needed in the future. It carries a risk of ana‐ 2. Liew WK, Williamson E, Tang ML. Anaphylaxis fatalities and admis‐
phylaxis and must be performed in a safe setting.36 sions in Australia. J Allergy Clin Immunol. 2009;123(2):434‐442.
It is important to note that a drug with a high clinical suspicion of 3. Vorobeichik L, Weber EA, Tarshis J. Misconceptions surrounding
penicillin allergy: implications for Anesthesiologists. Anest Analg.
causing anaphylaxis but negative testing should be avoided.62
2018;127:642‐649.
4. Harper N, Cook TM, Garcez T, Lucas DN, Thomas M, Kemp H, et al.
Anaesthesia, surgery, and life‐threatening allergic reactions: report
8 | S U M M A RY and findings of the Royal College of Anaesthetists' 6th National
Audit Project: perioperative anaphylaxis (NAP6). Royal College of
Anaesthetists; 2018 May 2018. Contract No.: 1.
Atopy, food allergy, and labels of specific drug allergy are common 5. Demoly P, Adkinson NF, Brockow K, et al. International consensus
in children. There is a need for updated understanding of these is‐ on drug allergy. Allergy. 2014;69(4):420‐437.
sues for anesthetists. The preoperative assessment is an important 6. Simons F, Ebisawa M, Sanchez‐Borges M, et al. 2015 update of the
public health opportunity to refer children with labels of drug allergy evidence base: World Allergy Organization anaphylaxis guidelines.
World Allergy Organ J. 2015;8(1):1‐16.
for testing.
7. Cox L, Williams B, Sicherer S, et al. Pearls and pitfalls of allergy
Epidemiological data on perioperative anaphylaxis in children diagnostic testing: report from the American College of Allergy,
is limited, with marked geographical variation. There is a need for Asthma and Immunology/American Academy of Allergy, Asthma
8 | STEPANOVIC et al

and Immunology specific IgE test task force. Ann Allergy Asthma 31. Tam JS, Kelly K, Pongracic JA. A seventeen‐year review of perio‐
Immunol. 2008;101(6):580‐592. operative anaphylaxis in a pediatric hospital. J Allergy Clin Immunol.
8. Munoz‐Cano R, Picado C, Valero A, Bartra J. Mechanisms of anaphy‐ 2011;127(2):AB247.
laxis beyond IgE. J Investig Allergol Clin Immunol. 2016;26(2):73‐82; 32. Mertes PM, Lambert M, Guéant‐Rodriguez RM, et al. Perioperative
quiz 2p following 3. anaphylaxis. Immunol Allergy Clin North Am. 2009;29(3):429‐451.
9. Sommerfield DL, Sommerfield A, Schilling A, Slevin L, Lucas M, von 33. Australia and New Zealand College of Anaesthetists. Perioperative
Ungern‐Sternberg BS. Allergy alerts‐The incidence of parentally Anaphylaxis Management Guidelines. Background Paper [Internet].
reported allergies in children presenting for general anesthesia. 2016 [cited 07/05/2019] from: http://www.anzca.edu.au/docum​
Pediatr Anesth. 2019;29(2):153‐160. ents/bp-anaph​ylaxis-2016.pdf/. Accessed May 07, 2019.
10. Lucas M, Arnold A, Sommerfield A, et al. Antibiotic allergy labels in 34. Tacquard C, Collange O, Gomis P, et al. Anaesthetic hypersensitivity
children are associated with adverse clinical outcomes. J Allergy Clin reactions in France between 2011 and 2012: the 10th GERAP epi‐
Immunol Pract. 2019;7(3):975‐982. demiologic survey. Acta Anaesthesiol Scand. 2017;61(3):290‐299.
11. Trubiano JA, Chen C, Cheng AC, Grayson ML, Slavin MA, Thursky 35. Niggemann B. IgE‐mediated latex allergy–an exciting and in‐
KA. Antimicrobial allergy 'labels' drive inappropriate antimicro‐ structive piece of allergy history. Pediatr Allergy Immunol.
bial prescribing: lessons for stewardship. J Antimicrob Chemothe. 2010;21(7):997‐1001.
2016;71(6):1715‐1722. 36. Har D, Solensky R. Penicillin and beta‐lactam hypersensitivity.
12. Knezevic B, Sprigg D, Seet J, et al. The revolving door: anti‐ Immunol Allergy Clin North Am. 2017;37(4):643‐662.
biotic allergy labelling in a tertiary care centre. Intern Med J. 37. Zagursky RJ, Pichichero ME. Cross‐reactivity in beta‐lactam al‐
2016;46(11):1276‐1283. lergy. J Allergy Clin Immunol Pract. 2018; 6(1):72–81.
13. Dewachter P, Mouton‐Faivre C, Castells M, Hepner D. Anesthesia 38. Solensky R, Khan DA. Drug allergy: an updated practice parameter.
in the patient with multiple drug allergies: are all allergies the same? Ann Allergy Asthma Immunol. 2010;105(4):259‐273.
Curr Opin Anesthesiology. 2011;24:320‐325. 39. Brereton A, Russell WJ. Anaphylaxis to muscle relaxants: an audit of
14. Gold MS, Kemp AS. Atopic disease in childhood. Med J Aust. ten years of allergy testing at the Royal Adelaide Hospital. Anaesth
2005;182:298‐304. Intensive Care. 2012;40(5):861‐866.
15. Cook‐Mills JM. Maternal influences over offspring allergic re‐ 40. Sadleir P, Clarke RC, Bunning DL, Platt PR. Anaphylaxis to neuro‐
sponses. Curr Allergy Asthma Rep. 2015;15(2):501. muscular blocking drugs: incidence and cross‐reactivity in Western
16. Wang J, Sampson HA. Food anaphylaxis. Clin Exp Allergy. Australia from 2002 to 2011. Br J Anaesth. 2013;110(6):981‐987.
2007;37(5):651‐660. 41. de Pater GH, Florvaag E, Johansson SG, Irgens A, Petersen MN,
17. Skripak JM, Matsui EC, Mudd K, Wood RA. The natural his‐ Guttormsen AB. Six years without pholcodine; Norwegians are sig‐
tory of IgE‐mediated cow's milk allergy. J Allergy Clin Immunol. nificantly less IgE‐sensitized and clinically more tolerant to neuro‐
2007;120(5):1172‐1177. muscular blocking agents. Allergy. 2017;72(5):813‐819.
18. Savage JH, Matsui EC, Skripak JM, Wood RA. The natural history of 42. Brusch AM, Clarke RC, Platt PR, Phillips EJ. Exploring the link be‐
egg allergy. J Allergy Clin Immunol. 2007;120(6):1413‐1417. tween pholcodine exposure and neuromuscular blocking agent
19. Keet CA, Matsui EC, Dhillon G, Lenehan P, Paterakis M, Wood RA. anaphylaxis. Br J Clin Pharmacol. 2014;78(1):14‐23.
The natural history of wheat allergy. Ann Allergy Asthma Immunol. 43. Spoerl D, Nigolian H, Czarnetzki C, Harr T. Reclassifying anaphy‐
2009;102(5):410‐415. laxis to neuromuscular blocking agents based on the presumed
20. Savage JH, Kaeding AJ, Matsui EC, Wood RA. The natural history of patho‐mechanism: IgE‐mediated, pharmacological adverse reaction
soy allergy. J Allergy Clin Immunol. 2010;125(3):683‐686. or "Innate Hypersensitivity"? Int J Mol Sci. 2017;18(6):E1223.
21. Skripak JM, Wood RA. Peanut and tree nut allergy in childhood. 44. Takazawa T, Mitsuhata H, Mertes PM. Sugammadex and rocuro‐
Pediatr Allergy Immunol. 2008;19(4):368‐373. nium‐induced anaphylaxis. J Anesth. 2016;30:290‐297.
22. Tsabouri S, Triga M, Makris M, Kalogeromitros D, Church MK, Priftis 45. Tsur A, Kalansky A. Hypersensitivity associated with sugam‐
KN. Fish and shellfish allergy in children: review of a persistent food madex administration: a systematic review. Anaesthesia.
allergy. Pediatr Allergy Immunol. 2012;23(7):608‐615. 2014;69(11):1251‐1257.
23. Harper NJ. Propofol and food allergy. Br J Anaesth. 2016;116(1):11‐13. 46. Yamaoka M, Deguchi M, Ninomiya K, Kurasako T, Matsumoto
24. Levy JH, Adkinson NF Jr. Anaphylaxis during caridac surgery: impli‐ M. A suspected case of rocuronium‐sugammadex complex‐in‐
cations for clinicians. Anesth Analg. 2008;106(2):362‐403. duced anaphylactic shock after cesarean section. J Anesth.
25. Fisher MM, Baldo BA. The incidence and clinical features of ana‐ 2017;31(1):148‐151.
phylactic reactions during anesthesia in Australia. Ann Fr Anesth 47. Moka E, Argyra E, Siafaka I, Vadalouca A. Chlorhexidine: hypersen‐
Reanim. 1993;12(2):97‐104. sitivity and anaphylactic reactions in the perioperative setting. J
26. Gibbs NM, Sadleir PH, Clarke RC, Platt PR. Survival from periop‐ Anaesthesiol Clin Pharmacol. 2015;31(2):145‐148.
erative anaphylaxis in Western Australia 2000‐2009. Br J Anaesth. 48. Koul A, Jain R, Sood J. A critical incident report: propofol triggered
2013;111(4):589‐593. anaphylaxis. Indian J Anaesth. 2011;55(5):530‐533.
27. Harper N, Dixon T, Dugué P, et al. Suspected anaphylactic reactions 49. Murphy A, Campbell DE, Baines D, Mehr S. Allergic reactions to
associated with anaesthesia. Anaesthesia. 2009;64(2):199‐211. propofol in egg‐allergic children. Anesth Analg. 2011;113(1):140‐144.
28. Habre W, Disma N, Virag K, et al. Incidence of severe critical events 50. Asserhoj LL, Mosbech H, Kroigaard M, Garvey LH. No evidence for
in paediatric anaesthesia (APRICOT): a prospective multicentre contraindications to the use of propofol in adults allergic to egg, soy
observational study in 261 hospitals in Europe. Lancet Respir Med. or peanutdagger. Br J Anaesth. 2016;116(1):77‐82.
2017;5(5):412‐425. 51. Bindslev‐Jensen C, Briggs D, Osterballe M. Can we determine a
29. Mertes PM, Alla F, Trechot P, Auroy Y, Jougla E. Anaphylaxis during threshold level for allergenic foods by statistical analysis of pub‐
anesthesia in France: an 8‐year national survey. J Allergy Clin lished data in the literature? Allergy. 2002;57(8):741‐746.
Immunol. 2011;128(2):366‐373. 52. Sommerfield DL, Lucas M, Schilling A, et al. Propofol use in chil‐
30. McNichol L. Safety of Anaesthesia. A review of anaesthesia‐re‐ dren with allergies to egg, peanut, soybean or other legumes.
lated mortality reporting in Australia and New Zealand 2012–2014. Anaesthesia. 2019; [Epub ahead of print]. https​://doi.org/10.1111/
Australian and New Zealand College of Anaesthetists. anae.14693​.
STEPANOVIC et al | 9

53. Molina‐Infante J, Arias A, Vara‐Brenes D, et al. Propofol adminis‐ 61. Castells M, Butterfield J. Mast cell activation syndrome and masto‐
tration is safe in adult eosinophilic esophagitis patients sensitized cytosis: initial treatment options and long‐term management. J
to egg, soy, or peanut. Allergy. 2014;69(3):388‐394. Allergy Clin Immunol Pract. 2019;7(4):1097‐1106.
54. Kannan JA, Bernstein JA. Perioperative anaphylaxis. Immunol 62. Mills A, Sice P, Ford SM. Anaesthesia‐related anaphylaxis: inves‐
Allergy Clin North Am. 2015;35(2):321‐334. tigation and follow‐up. Continuing Education in Anaesthesia Critical
55. Kidon M, Blanca‐Lopez N, Gomes E, et al. EAACI/ENDA position Care & Pain. 2014;14(2):57‐62.
paper: diagnosis and management of hypersensitivity reactions to 63. Scolaro R, Crilly H, Maycock B, et al. Australian and New Zealand
non‐steroidal anti‐inflammatory drugs (NSAIDs) in children and ad‐ Anaesthetic Allergy Group (ANZAAG) perioperative anaphylaxis in‐
olescents. Pediatr Allergy Immunol. 2018;29(5):469‐480. vestigation guidelines. Anaesth Intensive Care. 2017;45(5):543‐555.
56. Aun MV, Blanca M, Garro LS, et al. Nonsteroidal anti‐inflammatory 64. Mertes PM, Malinovsky JM, Jouffroy L, et al. Reducing the risk of
drugs are major causes of drug‐induced anaphylaxis. J Allergy Clin anaphylaxis during anesthesia: 2011 updated guidelines for clinical
Immunol Pract. 2014;2(4):414‐420. practice. J Investig Allergol Clin Immunol. 2011;21(6):442‐453.
57. Cavkaytar O, Karaatmaca B, Cetinkaya PG, et al. Characteristics of 65. Baldo B, Pham NH. Classification and Descriptions of Allergic Reactions
drug‐induced anaphylaxis in children and adolescents. Allergy and to Drugs. Drug allergy: Clinical Aspects, Diagnosis, Mechanisms,
asthma proceedings. 2017;38(5):56‐63. Structure‐Activity Relationships, (1st edn.). New York, NY: Springer;
58. Volcheck GW, Mertes PM. Local and general anaesthetics imme‐ 2013.
diate hypersensitivity reactions. Immunol Allergy Clin North Am.
2014;34(3):525‐546.
59. Schwartz LB, Min HK, Ren S, et al. Tryptase precursors are prefer‐
How to cite this article: Stepanovic B, Sommerfield D, Lucas
entially and spontaneously released, whereas mature tryptase is re‐
tained by HMC‐1 cells, Mono‐Mac‐6 cells, and human skin‐derived
M, von Ungern‐Sternberg BS. An update on allergy and
mast cells. J Immunol. 2003;170(11):5667‐5673. anaphylaxis in pediatric anesthesia. Pediatr Anesth.
60. Valent P, Akin C, Arock M, et al. Definitions, criteria and global 2019;00:1–9. https​://doi.org/10.1111/pan.13703​
classification of mast cell disorders with special reference to mast
cell activation syndromes: a consensus proposal. Int Arch Allergy
Immunol. 2012;157(3):215‐225.