Perioperative anaphylaxis.pdf

Perioperative anaphylaxis
Onnicha Chaisetsumpan, MD
Division of Allergy, Immunology and Rheumatology Unit,
Department of Pediatrics
King Chulalongkorn Memorial Hospital

Outline
• Introduction
• Pathophysiology
• Clinical manifestation
• Differential diagnosis
• Investigation
• Important causes of POH
• Management and prevention

Introduction
• Most challenging clinical problems in drug allergy investigation
• Combination of effects of anesthetic drugs, surgical procedure, simultaneous
administration of several drug, hidden exposures and numerous differential diagnoses
• Periorperative = in relation to anesthesia
• General anesthesia (GA) or regional anesthesia (RA) or sedation or anesthesia care
under the care of an anesthesiologist
Perioperative anaphylaxis
Perioperative immediate hypersensitivity (POH)
Garvey LH, et al. Allergy. 2019 Oct;74(10):1872-84.
Cook TM, et al. British Journal of Anaesthesia. 2018 Jul 1;121(1):124-33.

Incidence
• Estimated incidence of perioperative immediate hypersensitivity are wide variations
from 1 in 1,250 to 1 in 20,000
• Influenced by the heterogeneity of studies (multicentre/single centre,
prospective/retrospective) and by differences in terminology, local practice and drug use
• Mortality is higher than from other causes of anaphylaxis ranging 3-9%
Long E, et al. AIMS Medical Science. 2022 Mar 1;9(1):32-50.

Incidence of suspected perioperative
anaphylaxis in China 2018-2019
Incidence
Zhang P, et al. British Journal of Anaesthesia. 2022 Jan 1;128(1):45-54.
Charuluxananan S, et al. Journal of the Medical Association of Thailand. 2005 Nov 1;88:S14-29.
• Prospective descriptive study of occurrence
screening in 20 hospitals in Thailand
• Data collected during preanesthetic
evaluation, intraoperative period and 24
hours postopertive period
• Total 163,403 cases recorded for 12
months
• Anaphylaxis or anaphylactoid reactions
2.1:10,000
THAI Study of anesthetic outcome 2005

Pathophysiology
1
2 3

Pathophysiology
IgE-mediated anaphylaxis
Dewachter P, et al. BJA education. 2019 Oct 1;19(10):313-20.

Clinical manifestations
• Presumptive diagnosis is based on combination of
• Clinical signs, symptoms and severity
• Timing of the reaction in relation to possible culprit drugs
• Life-threatening reactions are more likely to be confirmed to be IgE-mediated
• Majority of POH reactions occur during anesthetic induction, but may occur during
any phase of the perioperative course

• Signs and symptoms vary from mild skin symptoms to life-threatening anaphylaxis.
Involving several organ systems
• Isolated cardiovascular collapse or cardiac arrest may be presenting features
• Hypotension occurs unexpectedly
• With or without tachycardia
• Unresponsive to vasopressor
• Cutaneous signs can be absent during severe hypotension
• May reappear after restoration of adequate circulation
POH should be considered

NAP6 study in UK

Cross-sectional multicenter
study in China
Zhang P, et al. British Journal of Anaesthesia. 2022 Jan 1;128(1):45-54.

Grading systems
• The Ring and Messmer scale
• Adapted for the perioperative setting
in 1980s
• Consists of 4 grades based on
symptoms severity
• Alternative 3-grade system in
Australia and New Zealand

Grade Skin GI Respiratory Cardiovascular
I Itch, flush, urticaria,
angioedema
- - -
II (not obligatory) Nausea
Cramps
Rhinorrhea
Hoarseness
Dyspnea
Tachycardia
Respiration changes
Arrhythmia
III (not obligatory) Vomiting
Defecation
Laryngeal edema
Broncospasm
Cyanosis
Shock
IV (not obligatory) Vomiting
Defecation
Respiratory arrest Cardiac arrest
Clinical manifestations: grading system
The Ring and Messmer scale

Differences between perioperative anaphylaxis and other settings
Manifestation Other settings Perioperative settings
Upper respiratory
system
Throat tightness, voice change • Difficulty to intubation
• Postextubation stridor
Lower respiratory
system
Shortness of breath, wheezing, cough • Ventilatory pressure, difficult to inflate lungs
• EtCO2
• SaO2
Cardiovascular
system
Dizziness, collapse • Cardiovascular collapse (1st detected in 50%)
• Arrhythmia, cardiac arrest
Skin Flushing, itching, urticaria (>90% of cases) • Absent or present skin lesions but may be hidden by
surgical drapes

Differential diagnosis

Differential diagnosis
• Anesthesia related
• Airway irritation from misplaced ET tube
• Airway edema
• Subcutaneous emphysema
• Aspiration
• Inadequate depth of anesthesia
• Pharmacological effects
• Overdose
• Hypotension from vasodilation induced by
spinal/epidural, drugs
• Bradycardia and hypotension after opioids
• Malignant hyperthermia
• Drugs interactions: ACEI
• Procedure related
• Major blood loss
• Amniotic fluid embolism
• Overdose of oxytocin
• Autonomic parasympathethic effects
• Patient comorbidity related
• Hyperreactive airways: uncontrolled asthma,
smokers, viral infection
• Pulmonary embolism
• Cardiac disorders: MI, CHF, arrhythmia
• Septicemia
• Chronic urticaria or angioedema exacerbation
• Mast cell disorders

Important causes
Criteria of possible culprits
• IV exposure within 1 hour of onset
• Other exposure within 2 hours of onset
• intramuscular, subcutaneous, spinal, epidural, other local exposure
• Timing should not be used to guess the culprit as it was imprecise

Antibiotics were the
most common trigger
for anaphylaxis
47%
33%
9%
5%
6%
Antiobiotics
NMBAs
Chlorhexidine
Blue dyes
Others
Important causes

US 2013-2015 UK NAP6 2015-2016 France 2005-2007
Antibiotics (esp. cefazolin) Antibiotics 47% NMBA 47%
NMBA 32% Latex 20%
Chlorhexidine 9% Antibiotics 9%
Patent blue 4.5%
No latex identified
Important causes
Kuhlen JL et al. J Allergy Clin Immunol Pract. 2016;4(4): 697–704.
Guyer AC et a.l J Allergy Clin Immunol Pract 2015;3:94-100
Gonzales-Estrada A et al. J Allergy Clin Immunol Pract 2015;3:101-105.
Harper NJN, et al. 6th National Audit Project (NAP6). British Journal of Anaesthesia. 2018
Dong SW et al. Minerva Anestesiol 2012;78:868-78.

Important causes
•Anonymous reporting
•Suspected causative agents
Lapisatepun W, et al. J Med Assoc Thai. 2008;91:1524-30.

Important causes
Manian DV, et al. Clinical Reviews in Allergy & Immunology. 2022 Jun;62(3):383-99.

Investigation
• When to test or not to test
• Skin testing
• In vitro testing

• All exposures prior to reaction onset may be relevant
• Complete documentation including relevant timelines is essential
• Anesthetic record, anesthetic’s notes
• All drug charts (preoperative, theatre and recovery)
• Details of any surgical or other perioperative exposures (disinfectants, local anesthetic
sprays/gels, dyes, cements)
• Details of all procedures: aterial, venous and urinary catheters, stents
• Not recommended to plan investigations based on information in a referral letter only
Investigation

NAP6 anaesthetic anaphylaxis referral form
• Patientis details
• Details of referring consultant anesthetist and
surgeon
• Date and time at onset of reaction
• Timeline of drug, clinical features and treatment
• Investigation prior to referral
Investigation
Harper NJ, et al. British Journal of Anaesthesia. 2018 Jul 1;121(1):159-71.

Harper NJ, et al. British Journal of Anaesthesia. 2018 Jul 1;121(1):159-71.

When to test
• Aim:
• To identify a culprit drug and safe
alternatives
• To ensure safe future anesthesia, even if
no culprit is identified
• Reaction grade 2-4 should always be
referred for investigation
• All reaction with generalized erythema or
urticaria, grade 1 should be referred

Severity grade VS IgE-mediated reaction
• Clinical manifestations were more severe
in patients with IgE-mediated than in
patients with non-IgE mediated reactions
• Most IgE-mediated reactions were grade 3
• Non-IgE-mediated reactions were mainly
grade 1
When to test
Mertes PM, et al. JACI 2011 Aug 1;128(2):366-73.

• Ideal timing of investigation is not known
• EAACI 2019 recommend that
• Testing takes place 1-4 months postevent
• and at least 4-6 weeks postevent to avoid false-negative results
• British guidelines:
• Investigations can take place immediately after the event
• But negative skin test results before 4 weeks postevent may not exclude allergy
and later re-testing may be needed
When to test

• Transient hypotension, vasodilatation
• Non-specific, transient flushing
• Obvious causes of hypotension
When not to test
When hypotension occurs unexpectedly or unresponsive to vasopressors
Perioperative anaphylaxis should be considered

• Drugs that have been re-administered uneventfully at later date do not need to be
investigated
• Drugs that have been continued or re-administered in the same anesthetic after
recovery should still be considered for testing
• Due to risk of possible refractory phase or antiallergic therapy masking symptoms
• Drugs that have been continued for several days after the antiallergic therapy
has been stopped are less likely causes
• Local anesthetic infusion in epidural, continuous infusion
• However, theoretical risk of desensitization should be considered
When not to test

Culprit is identified
• Planned investigations should still be
completed
• >1 culprits may contribute to the reaction
• Investigate cross-sensitivity, if relevant
• NMBAs: investigate all available NMBAs
• Antibiotics, NSAID, local anesthetics: at
least one safe alternative should be
identified
Negative initial investigation
• Strong clinical suspicion of POH and
significant elevation in serum
tryptase → necessary to reassess
the whole case
• Possible undocumented exposures
• Testing with variety of excipients
may also be warranted
Investigation

When initial investigations are negative
1. Reaction: Non-allergic causes?
• Go through all case notes and chart again
• Discuss alternatives explainations with anesthetist
2. Investigation: performed and interpreted correctly?
• Check skin test dilutions and diagnostic criteria comply
with recommendations
• Additional tests: sIgE, BAT, histamine release
• Drug procation with suspected drugs
• Repeat skin test/in vivo 2-3 months later (if initial
investigations are close to reaction)
Investigation
3. Exposure: all exposures identified?
• Look at all charts: surgeon note, drug charts
• Discuss anesthetist, surgeon, surgical nurse for
undocumented exposures
• Test latex, disinfectants, sterilizing agents
• Test for excipients: PEG, methylcellulose,
mannitol, lidocaine
4. Others
• Consider if the patient could have clonal or non-
clonal mast cell disorder

Investigation: skin testing
• Skin prick test and intradermal testing
• Patients with POH are considered high risk
• Very low risk of anaphylaxis during skin testing, but risk of milder systemic reactions
elicited by IDT increases with higher concentrations, large volumes or multiple tests
• Recommended titrated skin testing for both SPT and IDT using 2-3 dilutions with 20
minutes intervals
• Starting with the lowest concentrations
• Not exceeding the maximum nonirritant concentration
• UK: suggest starting with maximum nonirritant concentration on IDT

Investigation: in vitro testing
• Serum tryptase
• At the time of reaction is
recommended
• Plasma histamine
• Specific IgE (sIgE)
• Basophil activation test (BAT)
• Histamine release (HR)
• Always interprete in context of other test
results and clinical information
• Timing of sampling in close relation as
response decrease over time without
exposure

Serum tryptase
Baseline tryptase should be taken
≥24 hours after reaction and later
for very severe reaction
• Recommend to measure within 1-3 hours after suspected POH
• Consensus formula: peak tryptase ≥ 1.2xbaseline + 2 µg/L
Hours after
onset
Sensitivity Specificity PPV NPV
0.5-2 hours 75% 86% 94% 53%
1-2 hours 78% 91% 98% 44%
Vitte J, et al. JACI In Practice. 2021 Aug 1;9(8):2994-3005.
Beck SC, et al. Frontiers in immunology. 2019 Apr 5;10:494.

Serum tryptase

• Presence of sIgE antibodies to a specific trigger = proof of IgE sensitization
• Not always clinical allergy
• Diagnostic conclusion should not be made based on elevated sIgE without other
confirmatory tests and a relevant clinical history
• Measure on sample taken at the time of reaction but if negative → repeated 4-6
weeks later
• Possible for a limited number of drugs relevant for POH: beta-lactam antibiotics,
NMBAs, natural rubber latex, chlorhexidine, ethylene oxide
• High sensitivity and specificity for natural rubber latex and chlorhexidine
Specific IgE testing

Basophil activation test (BAT)
• In vitro method of assaying the effects of mixing blood containing basophils with
suspected culprit agents
• Not widely available
• Activation is measured by flow cytometry through appearance and/or upregulation of
surface activation and/or degranulation markers: CD63, CD203c
• Can be used to identify both culprit drugs and potential safe alternatives
• BAT with unstandardized drugs should only be performed in experienced laboratory

• Plasma histamine
• Produced by decarboxylation of histidine of mast cells and basophils
• Rapidly metabolized by histamine transferase when released into blood
• Rise within 5 minutes after onset of reaction, last for 30-60 minutes
• Highly sensitivity but low specificity
• Important preanalytic laboratory handling is needed
• Only very few highly specialized centers measure plasma histamine
• Histamine release (HR)
• Quantified by flow cytometry
• Can be done for all drugs and solid materials (divided into small enough pieces) to get
into a test tube
Investigation: in vitro testing

Invesitigation
• Tryptase measurement:
precise for ascertaining mast
cell activation
• Allergy testing (skin testing,
BAT): identify trigger guiding
future anesthetic choices

Investigation

Drug provocation testing (DPT)
• Full-dose DPT = gold standard of investigation immediate hypersensitivity to drugs
• Limited use in POH due to strong pharmacologic effects of perioperative drugs
• Lower maximum doses are used in some centers
• Lack of consensus on the use of drug provocation tests in POH
• Recommendation:
• Performed when skin tests are equivocal or negative with aim to exclude
sensitization to the culprit drugs or to test a safe alternative
• Non-IgE mediated: DPT may be the only reliable test
• Small and less specialized center:
• Possible for allergists to collaborate with local anesthetists
• Individual patients that might benefit from DPT after a careful risk-benefit evaluation

• Drugs
• Neuromuscular blocking agents
(NMBAs)
• Antibiotics
• Sugammadex
• Hypnotics, anesthetic agents
• Opioids
• Local anesthesia
• Natural rubber latex (NRL)
• Antiseptics and sterilizers
• Chlorhexidine, povidone iodine
• Ethylene oxide
• Dyes
• High-molecular weight agents
• Plasma expanders, blood products
Important causes
Manian DV, et al. Clinical Reviews in Allergy & Immunology. 2022 Jun;62(3):383-99.

Neuromuscular blocking agents (NMBAs)
• Most common cause in France, Norway, Belgium, UK, Australia and New Zealand (50-70% of
perioperative anaphylaxis events)
• Less common in USA, Sweden and Denmark (30%)
• Higher incidence in succinyl choline and rocuronium
Volcheck GW, et al. JACI In Practice. 2019 Sep 1;7(7):2134-42.

Depolarizing Non depolarizing
Succinylcholine*
Suxamethonium*
Reversal: Calabadion
Benzylisoquinoline
• Atracurium*
• Cisatracurium*
• Mivacurium
• Doxacurium
Aminosteroid
• Pancuronium*
• Vecuronium
• Rocuronium*
• Pipecuronium
Chlorofumarate
diesters
• Gantacurium
Reversal: neostigmine*,
calabadion
Reversal: neostigmine*,
sugammadex*, calabadion
Reversal: edrophonium,
L-cysteine
Spoerl D, et al. International journal of molecular sciences. 2017 Jun 7;18(6):1223.
*available in KCMH

Pathomechanism
• Occur through IgE or non-
IgE-mediated mechanism
via direct non-specific mast
cell activation
• IgE recognition site for
neuromuscular blockers is
their substituted ammonium
ions and molecular
environment
Ali H. Current Opinion in Immunology. 2021 Oct 1;72:65-71.

Mas-related G-protein-coupled receptor
member X2 (MRGPRX2)
• High rate of anaphylactic reactions upon
first exposure
• High rate of cross-sensitization,
demonstrated by positive skin test
results

Sensitization
• Ammonium structures: possible sensitization with
exposure to materials containing tertiary and
quaternary ammonium groups
• Over-the-counter drugs, cosmetics, disinfectants and
food products
• Pholcodine, opioid antitussive: cross-reactivity between
substituted ammonium ions in pholcodine and NMBAs
Brusch AM, et al. British Journal of Clinical Pharmacology. 2014 Jul;78(1):14-23.

17 patients with previously diagnosed NMBA IgE-mediated anaphylaxis
• Selection based on clinical data from anaphylactic reactions and
• Presence of IgE antibodies to suxamethonium and/or positive SPT with NMBAs
Cough syrup containing pholcodine Cough syrup containing guaifenesin
• 10 ml once daily (1/3 therapeutic daily dosage)
• 7 consecutive days
Serum IgE and IgE antibodies to pholcodine, morphine and suxamethonium
at day 0 before, then 4 and 8 weeks after exposure
Harboe T, et al. Allergy. 2007 Dec;62(12):1445-50.

• Patients exposed to pholcodine
had sharp rise in levels of IgE
to pholcodine, morphine and
suxamethonium
• No changes were observed in
guaifenesin group
Harboe T, et al. Allergy. 2007 Dec;62(12):1445-50.

• Group A (Allergics):
• 300 samples from patients tested for suspected allergy
but without any specific knowledge of clinical details
• Performed during April to June each year 2006-2010
• Stratified into subcategories according to total IgE level
• Group M (Medium): IgE levels 1000-5,000 kU/L
• Group H (High): IgE levels > 5000 kU/L
• Pholcodine was withdrawn from Norway in March 2007
• Analyze for IgE to pholcodine, suxamethonium and morphine
• Preliminary anaphylactic reports from NARA
Florvaag E, et al. Allergy. 2011 Jul;66(7):955-60.

• 1-2 years after withdrawing pholcodine: lower levels of IgE and IgE antibodies to
pholcodine, morphine and suxamethonium
• 3 years: decrease incidence of reported suspected anesthetic anaphylaxis significantly both
total number, reactions to NMBAs and IgE antibodies to suxamethonium

Pholcodine in Thailand
• International Narcotics Control Board’s
estimates for world requirements of
narcotic drugs in 2013
• Pholcodine use continued to vary between
countries

• High cross-sensivity between NMBAs
approximately 60-70%
• Variable patterns, only 7% show
sensitivity to all neuromuscular blockers
• Often show cross-sensitivity
• Pancuronium and vecuronium
• Succinylcholine and gallamine
• Cis-atracurium and atracurium

Anaphylaxis to neuromuscular blocking drugs in Western Australia from 2002 to 2011
Sadleir PH, et al. British journal of anaesthesia. 2013 Jun 1;110(6):981-7.

Tacquard C, et al. Acta Anaesthesiologica Scandinavica. 2017 Mar;61(3):290-9.
Li J, et al. British Journal of Anaesthesia. 2019 Jul 1;123(1):e144-50.

Investigation
• Specific IgE test
• Only available in some countries
• sIgE to suxamethonium: poor sensitivity
• Skin test
• Good negative predictive value (up to 96%)
but low specificity
• High false positive: marked irritant effects
• Find alternative drugs
Excellent NPV
Not standardized

• 100% Positive skin test to
NMBA responsible for index
reaction
• 2 patients (8%) reacted with
negative skin tested NMBA
• NPV of skin tests 96%
(95%CI. 88.3-99.9%)
Chiriac AM, et al. British Journal of Anaesthesia. 2018 Jun 1;120(6):1437-40.

Recommendation on
highest non-irritative
concentration by
EAACI Task force
perioperative
hypersensitivity 2019
ANZAAG 2017
Anesth Intensive Care
2017;45:543-555
ENDA 2013
Allergy 2013;68:702-12
GERAP 2011
J investing Allergol Clin
Immunol 2011;21:442-53
BSACI 2010
Clin Exp Allergy 2010;40:15-31
Atracurium SPT 1 mg/ml
IDT 0.01 mg/ml
SPT 1mg/ml
IDT 0.01mg/ml
SPT 1 mg/ml
IDT 0.01 mg/ml
SPT 1 mg/ml
IDT 0.01 mg/ml
SPT 10 mg/ml
ICT 0.01 mg/ml
Cisatracurium SPT 2 mg/ml
IDT 0.02 mg/ml
SPT 2 mg/ml
IDT 0.02 mg/ml
SPT 2 mg/ml
IDT 0.02 mg/ml
SPT 2 mg/ml
IDT 0.02 mg/ml
SPT 2 mg/ml
IDT 0.02 mg/ml
Mivacurium SPT 0.2 mg/ml
IDT 0.002 mg/ml
SPT 0.2mg/ml
IDT 0.002mg/ml
SPT 0.2 mg/ml
IDT 0.002 mg/ml
SPT 0.2 mg/ml
IDT 0.002 mg/ml
SPT 2 mg/ml
ICT 0.01 mg/ml
Rocuronium SPT 10 mg/ml
IDT 0.05 mg/ml
SPT 10 mg/ml
IDT 0.1mg/ml
SPT 10 mg/ml
IDT 0.05 mg/ml
SPT 10 mg/ml
IDT 0.05 mg/ml
SPT 10 mg/ml
IDT 0.05 mg/ml
Pancuronium SPT 2 mg/ml
IDT 0.02 mg/ml
SPT 2 mg/ml
IDT 0.02 mg/ml
SPT 2 mg/ml
IDT 0.2 mg/ml
IDT 0.04 mg/ml healthy volunteers
SPT 2 mg/ml
IDT 0.2 mg/ml
SPT 2 mg/ml
IDT 0.2 mg/ml
Suxamethonium SPT 10 mg/ml
IDT 0.1 mg/ml
SPT 10mg/ml
IDT 0.1 mg/ml
SPT 10 mg/ml
IDT 0.1 mg/ml
IDT 0.5 mg/ml healthy volunteers
SPT 10 mg/ml
IDT 0.1 mg/ml
SPT 50 mg/ml
IDT 0.1 mg/ml

Drug provocation test
• Should perform if other tests are negative or equivocal
• DPT to safe alternative (negative skin test)
• Full dose VS low dose DPT
• Goal standard = full-dose DPT?
• Limited use due to strong pharmacologic effects
• No consensus on the use of DPT
• Lower maximum doses are used in some centers
• May be performed on the day of surgery
Garvey LH. Trends in Anaesthesia and Critical Care. 2013 Dec 1;3(6):320-6.

Full dose DPT
• Hypersensitivity can only be excluded with
confidence if the total dose of drug reached
• Spanish guideline
• Full dose, in highly specialized centers with
full monitoring and resuscitation facilities
• At level of recovery unit or operating room
• Allergy Anesthetic Unit in Madrid
• 4 steps with increase dose every 15 minutes
Low dose DPT
• Danish Anesthesia Allergy Centre
• Maximum dose of 1/10 of
therapeutic dose
• 3 steps with 10-fold increase with
30 minutes interval
• SE: transient visual
disturbance/tongue movement, no
respiratory difficulty or desaturation
No studies examining whether 1/10 of a full dose is sufficient to rule out IgE-mediated allergy
Garvey LH, et al. British journal of anaesthesia. 2019 Jul 1;123(1):e126-34.
Melchiors BL, et al. Eur J Anaesthesiol. 2018;35(56):318.

Amsterdam University Medical Center, Netherlands
• Provocation test: 1-5-10% of average dose
• Monitoring in PACU with EKG, pulse oximetry, BP under close supervision of anesthesiologist
and allergist
• 8/9 experienced side-effects at 5% test dose, 1/9 at 1% test dose
van Cuilenborg. British Journal of Anaesthesia. 2019 Jul 1;123(1):e153-5.

Antibiotics
• Increasing cause of perioperative anaphylactic reactions
• Most common cause of intraoperative anaphylaxis in US and Spain, accounting for
40-55% of reactions
• Most common antibiotics identified were beta-lactam antibiotics
• Cefazolin is the most common
• The reactions to the antibiotics occurred
• Within 5 minutes: 74%
• Between 6-10 minutes: 18%
• Between 11-15 minutes

Natural rubber latex
• Traditionally identified as one of the more
common cause of perioperative anaphylaxis
• Peak in 1990s in the setting of increased
production of high protein content latex gloves
during HIV epidemic
• Incidence is decreasing
• Improvement of NRL quality
• Substituting other materials for latex and use
of power-free latex gloves

• Reactions to latex tend to
occur later in the surgery (>30
minutes)
• Typically after significant
mucosal exposure
• Risk factors: patients with spina
bifida, health care personnel
• Age, race or sex are not
associated with an increase risk
Vargas A, et al. J Head Neck Spine Surg. 2017;1(1):555552.

• To decrease likelihood of reaction in the latex-allergic individual with a subsequent
surgery, prevention is a goal
• Antigen content in latex products vary significantly: products with immersion process
(gloves) highest levels of allergen > dry rubbers (tires, rubber seals, plugs)
• Main prevention strategies
• Use of latex gloves: main source of allergens in health care settings
• Premedication
• H1-antagonist and corticosteroid: not well-defined studied
• Do not prevent IgE-mediated immune reactions
Hepner DL, et al. Anesthesia & Analgesia. 2003 Apr 1;96(4):1219-29.

• Preoperative period
• Schedule the first case of the day if latex-powdered gloves are being used in the institution
• If not possible, recommend to wash hands especially thoroughly to remove any traces of latex
• Identify patients as allergic and room as latex-free
• Remove all products containing latex
• Cleaning staff should not wear latex gloves
• Aeroparticles from dust stay up to 5 hours, undetectable after removal 24 hours
• Cover all monitoring devices: avoid direct contact with skin
• Rinse products sterilized in ethylene oxide before use
• May cause allergic response in patient allergic to latex

Intraoperative period
• Wear latex-free gloves
• Minimize traffic inside OR
• Do not use penrose drains, latex bands, latex irrigation elements
• Latex-free or glass syringes
• Prefer glass ampoules medication
• If not available, remove the rubber stoppers before preparing the
medication
• Prepare immediately prior administration: decrease contact with
plunger
Postoperative period
• Room prepared for the patients and inform all involved
departments
May contain NRL Now latex free
Gloves Ambu-bag
Drains; penrose Airway mask
Catheters: indwelling,
straight, condom
Endotracheal tubes
Suction catheter
Intravenous bags,
ports
Infusion sets
Elastic bandages
Self-adhesive
bandages, adhesive
tape
Electrode pads

Hepner DL, et al. Anesthesia & Analgesia. 2003 Apr 1;96(4):1219-29.

Disinfectants
• Chlorhexidine, povidone iodine, bacitracin
• Chlorhexidine is widely used as an antiseptic in
medical, procedural and surgical setting
• Clean skin before insertion of catheters or lines
• Used on skin of body part prepared for surgery
• Urinary catheter using chlorhexidine gel
• Under-recognition, difference in sensitization and
disinfection practice, and lack of standardized
testing
Chiewchalermsri C et al. J Asthma Allergy. 2020.9;13:127-133.

Disinfectants
• Vary reaction onset in the perioperative setting: rapid or delayed
• May be coincidence with other drug allergies
• Sensitization can occur from home products
• Mouthwash, toothpaste, dressing, ointments, over-the-counter disinfectant solutions for cuts
and wounds
• Chlorhexidine exposure is enhanced by absorption through mucosal surface (urethra,
bladder) and skin especially if the chlorhexidine is not dry before the procedure
• No cross-reactivity with povidone iodine
Chiewchalermsri C et al. J Asthma Allergy. 2020.9;13:127-133.

Disinfectants

Disinfectants
Povidone-iodine
• Few case reports of reactions to povidone-iodine
• Usually associated with the application to mucosa or skin
• Can occur at variable times during surgery
• Safely used in patients with shellfish allergy
• Allergic component of shellfish is tropomyosin
• Inconsistent documentation of disinfectants → several centers recommended
routine testing with chlorhexidine or other disinfectants according to local
preferences or availability in all POH patients

Disinfectants
Recommendation on
concentration by
EAACI TF perioperative
ANZAAG 2017 ENDA 2013 GERAP 2011 BSACI 2010
Antiseptics
Povidone iodine SPT 100 mg/ml
No IDT
SPT 100 mg/ml
IDT 1 mg/ml
No advice SPT 100 mg/ml
IDT 10 mg/ml
Chlorhexidine SPT 5 mg/ml
IDT 0.002 mg/ml
(sterile uncoloured
alcohol free solution)
SPT 0.2 mg/ml
IDT 0.0002 mg/ml
SPT 5 mg/ml
ICT 0.002 mg/ml
SPT 0.5 mg/ml
IDT 0.005 mg/ml

Dyes
• Blue dyes are used to identify sentinel lymph nodes in melanoma and breast cancer
• Patent blue V and isosulfan blue: structurally very similar and cross-reactive
• Methylene blue: structurally different
• Cross-reactivity would not be expected between methylene blue and patent blue
• Can be delayed compared with the intravenously administrated medications
• May be due to slow absorption from the lymphatics and subcutaneous tissue
• Preoperative screening for allergy to patent blue has been suggested but is not
generally recommended

Recommendation on
concentration by
Sentinel node dyes
Methylene blue SPT 10 mg/ml
IDT 0.1 mg/ml
SPT 10 mg/ml
IDT 0.01 mg/ml
SPT undiluted
IDT 1:100 diluted
SPT 10 mg/ml
IDT 0.1 mg/ml
Patent blue SPT 25 mg/ml
IDT 0.25 mg/ml
SPT 25 mg/ml
IDT 0.25 mg/ml
SPT 25 mg/ml
2.5 mg/ml
Dyes

Sugammadex
• Reversal agent for amnioateroid neuromuscular
blockers
• Hypersensitivity reactions and IgE-mediated
anaphylaxis have been reported
• Incidence 1:2500 at single Japanese hospital
• Occur late in surgery: given to reverse
neuromuscular blockade
• Sensitizing trigger to sugammadex is not
definitely known
• Cyclodextrin: food additives and cosmetics

Sugammadex-rocuronium complex
• Reactions are reported: negative testing to
rocuronium and sugammadex individually
but positive testing when combined
• Ongoing debate on sugammadex treatment
of rocuronium-induced anaphylaxis
• Encapsulation of rocuronium could prevent
further mediator release from mast cells
• Conflicting evidences
Recommendation on
concentration by
EAACI Task force
perioperative
hypersensitivity
2019
ANZAAG 2017
Anesth Intensive
Care 2017;45:543-
555
Sugammadex SPT 100mg/ml
IDT 10 mg/ml
IDT 1mg/ml
Sugammadex

Opioids
• Incidence of allergic reactions: 1 in
100,000 to 200,000 anesthetics
• Most reactions result from non-specific
mast cell activation (pseudoallergy)
• IgE-mediated hypersensitivity to opioids
and semisynthetic opioids is very rare
• Low cross-reactivity between different
classes
• Phenylpiperidine: fentanyl, alfentanil,
remifentanil, meperidine, sufentanil
• Diphenylheptanes: methadone,
propoxyphene
• Phenanthrene: morphine, codeine
• Cross-reactivity between morphine and
codeine is reported

Opioids
Recommendation on
concentration by
EAACI TF
perioperative
Fentanyl SPT 0.05 mg/ml
IDT 0.005 mg/ml
SPT 0.05 mg/ml
ICT 0.005 mg/ml
SPT 0.05 mg/ml
ICT 0.005 mg/ml
SPT 0.05 mg/ml
ICT 0.005 mg/ml
Alfentanil SPT 0.5 mg/ml
IDT 0.05 mg/ml
SPT 0.5 mg/ml
ICT 0.05 mg/ml
SPT 0.5 mg/ml
ICT 0.05 mg/ml
SPT 0.5 mg/ml
ICT 0.05 mg/ml
Sufentanil SPT 0.005 mg/ml
IDT 0.0005 mg/ml
N/A SPT 0.005 mg/ml
ICT 0.0005 mg/ml
SPT 0.005 mg/ml
ICT 0.0005 mg/ml
Remifentanil SPT 0.05 mg/ml
IDT 0.005 mg/ml
SPT 0.05 mg/ml
ICT 0.005 mg/ml
SPT 0.05 mg/ml
ICT 0.005 mg/ml
SPT 0.05 mg/ml
ICT 0.005 mg/ml
Morphine
High risk of false positive
tests consider provocation in
skin test positive patients
SPT 1 mg/ml
IDT 0.005 mg/ml
SPT 1 mg/ml
ICT 0.00001mg/ml
SPT 1 mg/ml
ICT 0.01 mg/ml
SPT 1 mg/ml
ICT 0.001 mg/ml

Anesthetic agents
• Hypnotic induction: propofol, ketamine, midazolam, etomidate
• Reactions to barbiturates are now rare due to decreased use
• Propofol is rare
• Midazolam, etomidate, ketamine, inhalational agents are extremely rare
• Local anesthetics are extremely rare

Anesthetic agents
Propofol
• Most frequently used intravenous anaesthetic, but reactions are rare
• Account for less than 2% of all reactions to general anesthetics
• Formulated in lipid vehicle containing 10% soybean oil, 1.2% egg
lecithin and 2.25% glycerol
• Concerns about the use in egg and soy allergic patients due to
trace amounts of egg lecithin and soybean —> no confirmed
connection and avoidance is not recommended
• True allergic reactions secondary to 2 isopropyl groups

Plasma expanders
• Difficult to diagnose since they are administered in hypotensive patients
• Gelatin and Dextran are relatively common > albumin and hydroxylethyl starch (HES)
• Albumin is least likely colloid to lead to allergic reaction
• IgE-mediated anaphylaxis proved by demonstrating IgE antibodies and positive intradermal teat
against gelatin
• Increased circulating IgG dextran-reactive antibodies in patients with dextran anaphylaxis
• No known cross-reactivity between different group of colloids
• Same group (Hemaccel and Gelofusin) which are both gelatins have been proven to have
cross-reactivity

Recommendation on
concentration by
ANZAAG 2017
Plasma expanders
Dextran skin tests not useful. IgG-
mediated mechanism
Hydroxyethyl starch SPT 60 mg/ml
IDT 6 mg/ml
Modified fluid gelatins SPT 40 mg/ml
IDT 4 mg/ml
SPT 35-40 mg/ml
IDT 3.5-4.5 mg/ml
Plasma expanders

Blood products
• True anaphylactic reactions to blood products are infrequent: 0.6 per 1,000
transfusions except in patients with head injury or IgA deficiency
• Urticarial reactions are seen in 0.5% of all transfusion with frozen plasma
• Allergic reactions to RBC and platelets may occur due to small amount of plasma in all
blood products
• In patients who previously has severe urticarial reactions
• Pretreatment with antihistamine: diphenhydramine
• Transfusion with saline washed cells
• Acetaminophen is controversial due to potential toxicity and equivocal benefits

Oxytocin
• Oxytocin and analogues are used widely but only few cases of perioperative
anaphylaxis are reported
• High dose with rapid injection can induce hypotension, tachycardia, flushing and
chest discomfort
• Relative overdose can be misdiagnosed as anaphylaxis

Ethylene oxide
• Ethylene oxide (EO): gas used to sterilize most medical devices
• Heat-sensitive medical equipment
• Reactions are rare in the perioperative setting
• Increased risk of sensitization in myelomeningocele and ventriculoperitoneal shunt
patients
• Extensively exposure to EO during repeated surgical procedures
• Sensitization against EO increases risk of clinical reaction
• IgE-mediated: haptenate with human albumin

• No FDA approved for skin prick test of ethylene oxide
• Skin prick test to glove sterilized with EO and without EO (with gamma rays)
Ethylene oxide
Bache S. Acta anaesthesiologica scandinavica. 2011 Nov;55(10):1279-82.

Ethylene oxide
• Management
• Rarely possible to completely avoid ethylene oxide, but ethylene oxide-minimized procedure
is advised
• Alternative: stream-, gamma-irradiated, hydrogen peroxide gas plasma-sterilized devices
• Extensively rinsed equipment, but may increase microbial colonize
• Pretreatment with omalizumab has been tried successfully
• Patients with IgE antibody to EO without clinical reactions, care should be taken to
minimize EO exposure especially during large procedures

Excipients
• Often overlooked due to rare documentation
• Methylcellulose, macrogols/polyethylene glycols (PEG), polysorbate, mannitol
• Found in gels, spray, hemostatic agents

Management
• When a culprit is found → identify suitable alternative for drug groups with potential
cross-reactivity
• Important to correlate positive test results and clinical reactivity
• To minimize risk of false positive testing → some groups require ≥2 positive tests before
considering the culprit
• Negative tests
• With not elevated serum tryptase + more likely nonallergic explanation: all tested
substances can be used in subsequent anesthesia
• Elevated serum tryptase: re-evaluate
• Inform patient about conclusions and implications for further anesthesia

Management: urgent surgery
• Avoid all previous exposed drugs (60 minutes before anaphylactic onset) except
inhalation anesthetic agents
• Antibiotics: use different classes
• NMBA: best choice is to avoid (high cross-reactivity)
• Avoid possible hidden culprits
• Latex
• Chlorhexidine (medical gel, IV lines or catheters)
• Local anesthetics: use different class (amide, ester)
• Histamine-releasing drugs: morphine
• IV colloids
• Radiocontrast, dyes for lymph node identification

Management: urgent surgery
• Discuss with the allergist
• Pre-warn the team
• Consider regional anesthesia
• Premedication with H1-antihistamine and steroids: may reduce severity of non-
specific histamine release but not prevent anaphylaxis
• Alternative for NMBA
• Remifentanil + MgSO4 + topical anesthesia
• Adequate depth of anesthesia and adjunct neuraxial block
• Alternative for propofol + GA: inhalation agent, thiopental, etomidate, ketamine

Management
Information gained through tryptase likely
outweighs cost involved in conducting the test
Garvey LH, et al. Allergy: European journal of allergy and
clinical immunology.-Copenhagen. 2020;75(8):all-14226.

v
Garvey LH, et al. Allergy: European journal of allergy and clinical immunology.-Copenhagen. 2020;75(8):all-14226.
In vitro
In vivo

Avoid only substances with relevant timing (highly suggestive of causality)
Management
1
2
3
4
Garvey LH, et al. Allergy: European journal of allergy and clinical immunology.-Copenhagen. 2020;75(8):all-14226.

Prevention
Premedication
• British guideline 2009
• No evidence for premedication with
antihistamine or steroids
• Unlikely to prevent IgE-mediated events
• Spanish guideline 2018
• Premedication with H1-antihistamine,
along with slow injection of incremental
doses of drugs may reduce or prevent
mild reaction caused by nonspecific
histamine release from mast cells and
basophils
Highly recommended: referal for
allergy investigations in patients with
previous episode of POH
• Only risk factor for future POH
• Presence of atopy, food allergy, other
drug allergy, previous uneventful
anaesthetis or family history of
anaesthetic or other drug allergy: not risk
factors for POH

Preoperative screening
• EAACI 2019
• No screening for any drug or drug group in patients WITHOUT a relevant history
of a reaction
• ENDA and EAACI 2011
• General population: not necessary to perform routine screening
• Atopy or history of drug allergy: not necessary to test drugs that are not used
• Role of allergy workup
• Previous diagnosed with anesthetic drugs hypersensitivity
• History suggestive latex allergy: irrespective of exposure circumstance
• History suggestive fruits allergy (avocado, kiwi, banana, chestnut, buckwheat)
Mertes PM et al. J Investig Allergol Clin Immunol. 2011;21(6):442-53.

Spanish guideline 2018
Laguna JJ, et al. JACI 2018, vol. 28, num. 4, p. 216-232. 2018 Jan 1.

Patients with history of POH but unavailable details of drug exposure
EAACI 2019
• Latex
• Chlorhexidine
• Ethylene oxide
• NMBA
• Hypnotics: propofol
• Opioid: fentanyl, remifentanil
Spanish guideline 2018
Garvey LH, et al. Allergy. 2019 Oct;74(10):1872-84
Laguna JJ, et al. JACI 2018.

Perioperative management of patients with mastocytosis
• Mastocytosis: immediate hypersensitivity usually arise after mast cell degranulation
elicited by various nonspecific triggers
• May be associated with occurrence of perioperative immediate hypersensitivity
reactions but incidence is unknown
Dewachter P, et al. Anesthesiology. 2014 Mar;120(3):753-9.

• Understanding disease and its clinical manifestations
• Careful preoperative history: phenotype, previous immediate
reactions
• Close communication between anesthesiologist and surgeon
before surgery
• Avoidance of known and possible factors triggering acute
mediators release
• Management of perioperative mast cell degranulation and
cardiovascular disturbance
Perioperative management of patients
with mastocytosis

Psychological factors
• Emotional factors: psychological stress
and anxiety
• Anxiolysis is recommended
• Schedule as the first of the day when
possible
• Quiet environment in operating room
during anesthesia induction to reduce
preoperative anxiety
Temperature changes
• Extreme of temperature:
hypothermia and hyperthermia
• Monitor patient’s temperature during
all phases of surgical procedure
• Hypothermia management
• Increase operating room’s temperature
• Heat-maintenance devices
• Warmed irrigation and infusion fluids,
solutions and anesthetic gases

Mechanical factors
• Mild trauma of skin lesions; mechanical irritation, tourniquet use and face mask pressure
may induce mast cell degranulation, development of urticaria and blister formation
• Surgery, most likely in GI tract have been reported to induce mast cell degranulation
• Resection of rectal tumor, needle biopsy of pancreas
• GI= rich source of mast cells
• Appropriate positioning and manipulation of patients to avoid bone fractures
• Skeletal pathological findings in systemic mastocytosis: osteopenia, osteoporosis, osteolysis

Pharmacological factors
• Many authors advocate avoiding
certain classes of drugs
• Histamine-releasing drugs: opioids,
neuromuscular blocking agents
• Unless specifically indicated
• Pain: use of analgesics
Perioperative management

What should be done before anesthesia or surgery?
• Baseline tryptase
• Skin test
• No need to perform in patients with mastocytosis prior to anesthetic
• Not risk factor for perioperative drug IgE-mediayed allergic hypersensitivity
• All patients with prior uninvestigated perioperative immediate hypersensitivity should
undergo skin tests with suspected medications
Perioperative management of patients with Mastocytosis

What should be done before anesthesia or surgery?
• Premedication
• Preoperative H1, H2-receptor antagonists and corticosteroid is usually recommended but
has never been evaluated in RCTs
• Best way is to avoid known triggers in prior episodes and potential triggers
• Continue any regular medications used to maintain mast cell stability until the day of surgery
• Ambulatory surgery
• Some authors: should not be candidates for ambulatory surgery because reactions might
delayed for several hours
• No currently available evidences support

Klein NJ, Journal of anesthesia. 2013 Aug;27(4):588-98.

Take home messages

Perioperative anaphylaxis.pdf

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