Perioperative anaphylaxis

PERIOPERATIVE
ANAPHYLAXIS
N AT T H I YA P H O L M O O , M D

INCIDENCE
• The incidence of anaphylactic reactions during
procedures or surgery has shown wide variations from
1 in 1,250 to 1 in 20,000.
• The mortality is higher than from other causes of
anaphylaxis and ranges from 3% to 9%.
GeraldW.Volcheck, David L. Hepner, Identification and Management of Perioperative Anaphylaxis,
The Journal of Allergy and Clinical Immunology: In Practice, 2019

PATHOPHYSIOLOGY
• IgE : Approximately 60% of intraoperative anaphylaxis
reactions are thought to be mediated by IgE.
• Nonspecific complement activation
• Mas-Related G-Protein-coupled Receptor X2 can activate
mast cells independent of IgE with exposure to opioids
and neuromuscular blockers.

DELAY IN DIAGNOSIS
• Delay in diagnosis
– Intubated
– Sedated
– Draped
Early skin signs and typical symptoms (eg, pruritus, feeling
faint, and dyspnea) are not easily delineated.

CLINICAL PATTERNS
• Isolated hypotension or cardiovascular collapse without
any skin symptoms may be the initial presentation of
intraoperative anaphylaxis.
• In the surgical setting, it is important to consider
anaphylaxis when hypotension or bronchospasm does
not respond to usual therapy or cardiovascular collapse
occurs unexpectedly.

CLINICAL PATTERNS

CLINICAL PATTERNS
• Grade I : skin manifestations
• Grade II
- mild
- multiple system involvement
- reactions are not life-threatening
- more commonly associated with non-IgE-mediated reactions
• Grade III : life-threatening symptoms
• Grade IV : cardiac and/or respiratory arrest reactions
- more commonly associated with IgE-mediated reactions
• Grade V : Death

DIFFERENTIAL DIAGNOSIS
• Any condition predisposing to shock can lead to
hypotension as the initial presentation.
– Myocardial ischemia
– Cardiac arrhythmias
– Pulmonary embolism
– Hemorrhage
– Sepsis
– Hypovolemia

DIFFERENTIAL DIAGNOSIS
• Upper airway mimickers of anaphylaxis
– Airway swelling as a result of a difficult intubation
– Angiotensin converting enzyme inhibitor related angioedema
– C1-esteraseedeficient hereditary and acquired angioedema
– Airway manipulation in patients with underlying airway hyperreactivity, or with
undiagnosed or insufficiently treated asthma, can also lead to bronchospasm
– Bronchospasm can also present in patients with chronic obstructive pulmonary
disease following intubation or due to light anesthesia.
– Histamine release from medications, mucus plugs, mechanical obstruction,
pulmonary aspiration, pulmonary edema, pulmonary embolism, and
pneumothorax.

Garvey LH, Ebo DG, Mertes PM, Dewachter P, Garcez T, Kopac P, Laguna JJ, Chiriac AM, Terreehorst I, Voltolini
S, Scherer K. An EAACI position paper on the investigation of perioperative immediate hypersensitivity
reactions. Allergy. 2019 Oct;74(10):1872-1884. doi: 10.1111/all.13820. Epub 2019 Jun 18. PMID: 30964555.

MIMIC
• The anesthetics can cause cardiovascular changes that
can mimic early anaphylaxis and make early recognition
difficult.
• Inhaled anesthetics cause a decrease in systemic
vascular resistance and consequently a drop in mean
arterial pressure.
• Inhaled anesthetics can cause an increase in heart rate.

MIMIC
• Isoflurane and desflurane, are pungent and can irritate
the airways when used at higher levels.
– may be exacerbated in patients with reactive airway
disease, leading to bronchospasm.
• Propofol : causes a dose-dependent decrease in blood
pressure that may be associated with a compensatory
tachycardia.

ETIOLOGIES
• Neuromuscular blocking agents (NMBAs)
• Antibiotics
• Latex
• Disinfectants : chlorhexidine, povidone iodine, bacitracin
• Dyes
• Sugammadex
• Hypnotics
• Opioids
• Colloids
• Blood products
• Oxytocin
• Ethylene oxide

NEUROMUSCULAR BLOCKING AGENTS
• Most common cause : 50% to 70% of perioperative anaphylaxis events
• Both an IgE-mediated mechanism and a non-IgE-mediated mechanism
via direct nonspecific mast cell activation.
• The IgE recognition site for the neuromuscular blockers is their
substituted ammonium ions and molecular environment.
• Ammonium structures : materials containing tertiary and quaternary
ammonium groups including
; over-the-counter drugs, cosmetics, disinfectants, and food products
• In Norway : consumption of pholcodine, opioid antitussive

• Cross-sensitivity is approximately 60% to 70% among the
neuromuscular blockers.
• Only 7% show sensitivity to all the neuromuscular blockers.
• Often show cross-sensitivity
– pancuronium and vecuronium
– succinylcholine and gallamine
– cis-atracurium and atracurium

• Increased allergic risk
- Succinylcholine
- Rocuronium : most common in UK
• less risk
- Atracurium : most common in UK
- Cis-atracurium
- Pncuronium
• Atracurium is associated with histamine release
: which may lead to bronchospasm and hypotension

Jamma Li, Oliver G. Best, Michael A. Rose, Sarah L. Green, Richard B. Fulton, Marc J. Capon, Benedict A. Krupowicz, Suran L. Fernando,
Assessing cross-reactivity to neuromuscular blocking agents by skin and basophil activation tests in patients with neuromuscular blocking agent anaphylaxis, British
Journal of Anaesthesia, 2019

ANTIBIOTICS
• The most common antibiotics : Cefazolin
• The reactions to the antibiotics occurred
- within 5 minutes : 74%
- between 6 and 10 minutes : 18%
- between 11 and 15 minutes : 5%

LATEX
• Reactions to latex tend to occur later in the surgery, typically after
significant mucosal exposure.
• Latex sensitization has decreased.
• The incidence of cases of latex anaphylaxis has decreased as a result of
- identification of at-risk patients
- the use of preventive measures
: latex-free equipment (primary prevention)
: powder-free gloves

DISINFECTANTS :
CHLORHEXIDINE
• Clean the skin before insertion of epidural catheters, arterial lines, and
central venous lines.
• It is also used on the skin of the abdomen, chest, or other body part
prepared for surgery.
• Urinary catheters are passed using chlorhexidine gel.
• Urologic procedures were most common
• Male predominance

DISINFECTANTS :
CHLORHEXIDINE
• Absorption through mucosal surfaces : urethra and bladder
• Skin : incision and epidural
especially if the chlorhexidine is not dry before the procedure
• Chlorhexidine skin testing has been shown to be predictive of allergic
sensitivity and to correlate with in vitro chlorhexidine specific IgE
testing.
• Sensitization to chlorhexidine can occur from home products such as
mouthwash, toothpaste, dressings, ointments, and over the-counter
disinfectant solutions for cuts and wounds.

DISINFECTANTS :
CHLORHEXIDINE
• Often unrecognized and lack of clear labeling
• Reaction onset in the perioperative setting varies (rapid or delayed)
• Patients with anaphylaxis have a history of mild localized reaction to earlier
exposure
• Lack of standardized testing
• A skin test may have to be read 20–30 mins after SPT and IDT
• Several centres recommend routine testing with Chlorhexidine.
• May be coincident with other drug allergies
Chiewchalermsri, C., Sompornrattanaphan, M., Wongsa, C., & Thongngarm, T. (2020). Chlorhexidine Allergy: Current
Challenges and Future Prospects. Journal of asthma and allergy, 13, 127–133. https://doi.org/10.2147/JAA.S207980

Chiewchalermsri, C., Sompornrattanaphan, M., Wongsa, C., & Thongngarm, T. (2020). Chlorhexidine Allergy: Current
Challenges and Future Prospects. Journal of asthma and allergy, 13, 127–133. https://doi.org/10.2147/JAA.S207980
https://www.mims.com/thailand/
drug/info/chlorsep

DISINFECTANTS :
POVIDONE-IODINE
• Few case reports of reaction to povidone-iodine.
• These are usually associated with the application of the povidone-
iodine to the mucosa or skin.
• These reactions can occur at variable times during surgery.
• Povidone iodine can be safely used in patients with shellfish allergy,
because the allergenic component of shellfish is tropomyosin.

DYES
• Blue dyes are used to identify sentinel lymph nodes in melanoma and
breast cancer.
• The 2 most commonly used dyes are patent blue V and isosulfan blue.
: They are structurally very similar and cross-reactive.
• Methylene blue, however, is structurally different.
: Cross-reactivity would not be expected between methylene blue and
patent blue V, it has been reported.
• Reactions to the blue dyes can be delayed compared with the
intravenously administered medications. This may be due to slow
absorption from the lymphatics and subcutaneous tissue.

SUGAMMADEX
• A reversal agent for neuromuscular blockers
• The incidence : 1 in 2500 at a single Japanese hospital
• Reactions to sugammadex occur late in the surgery because they are
given to reverse neuromuscular blockade.
• The sensitizing trigger to sugammadex is not definitively known.
Cyclodextrin, is found in food additives and cosmetics and this
potentially could be sensitizing.
• There are reports of patients reacting to a sugammadex-rocuronium
complex. Testing to rocuronium and sugammadex individually may
be negative, but when combined result in a positive test result.

HYPNOTIC AGENTS
The hypnotic induction
• Propofol : most common
• Ketamine
• Midazolam
• Etomidate
* Reactions to midazolam, etomidate, ketamine, local anesthetics
and inhalational agents appear to be extremely rare.

PROPOFOL
• Allergic reactions to propofol are uncommon and account for less than 2% of all
reactions to general anesthetics.
• Propofol (2-6-diisopropyl-phenol) is currently formulated in a lipid vehicle
containing 10% soybean oil, 1.2% egg lecithin, 2.25% glycerol.
• Recent studies show that propofol is safe to use in children and adults with egg,
soy, or peanut allergy.
• True allergic reactions to propofol are likely to be secondary to the 2 isopropyl
groups.
• Many patients who develop anaphylaxis after first exposure may do so because
of sensitivity to the di-isopropyl radical that is found in many dermatological
products and lipid formulations.
• History of prior use of parenteral nutrition with intralipids and sensitivity to
dermatological products is important.
• Skin tests with 10% intralipid
Koul, A., Jain, R., & Sood, J. (2011). A critical incident report: Propofol triggered anaphylaxis. Indian journal of
anaesthesia, 55(5), 530–533. https://doi.org/10.4103/0019-5049.89898

OPIOIDS
• Incidence of allergic reactions to opioids is 1 in every 100,000 to
200,000 anesthetics.
• IgE‐mediated hypersensitivity to opiates and semisynthetic opioids is
very rare.
• Many opioids (eg, morphine and meperidine) cause the direct release
of histamine, causing dermatologic manifestations including urticaria,
itching, and vasodilation.
• Large doses of morphine used during cardiac anesthesia did not
show any bronchospasm or angioedema.

OPIOIDS
▪ There is little or no evidence of cross‐reactivity between the different
opioid subclasses
– Phenylpiperidines : alfentanil, fentanyl, remifentanil, sufentanil,
meperidine
– Diphenylheptanes : methadone and propoxyphene
– Phenanthrenes : morphine, codeine
▪ Cross‐ reactivity between morphine and codeine is reported.

COLLOIDS
Colloids commonly used in the operating room
• Albumin
• Dextran
• Hetastarch
• Gelatin

COLLOIDS
• Gelatin is the colloid most likely to lead to an allergic reaction.
• Gelatins and dextrans are more likely than albumin or hetastarch to
cause an allergic reaction.
• Albumin is the colloid least likely to lead to an allergic reaction.
• Colloids that belong to the same group such as Hemaccel and
Gelofusin (which are both gelatins) have been proven to have cross-
reactivity.

BLOOD PRODUCTS
• Urticarial reactions are seen in 0.5% of all transfusions with frozen
plasma.
• Allergic reactions to red blood cells and platelets may occur as well.
• The reaction may present as itching, swelling, or a rash. These
symptoms can be avoided with diphenhydramine pretreatment in
patients who previously had severe urticarial reactions.
• True anaphylactic reactions to blood products are infrequent (0.6 per
1000 transfusions)

OXYTOCIN
• Oxytocin and analogues are used widely, but only few cases of
perioperative anaphylaxis are reported.
• As rapid injection and high doses can induce hypotension,
tachycardia, flushing and chest discomfort, a relative over‐dose can
be misdiagnosed as anaphylaxis.

• Ethylene oxide (EO) is a gas used to sterilize most medical devices.
• Reactions are rare in the perioperative setting in general.
• There seems to be increased risk of sensitization in myelomeningocele
patients and patients with ventriculoperitoneal shunts.
• It is rarely possible to completely avoid EO, but an EO minimized
procedure is advised
• Pretreatment with omalizumab has been tried successfully.
ETHYLENE OXIDE

SIGNS AND SYMPTOMS
• When hypotension occurs unexpectedly, with or without tachycardia, or is
unresponsive to vasopressors, perioperative anaphylaxis should be considered.
• Bradycardia or unchanged heart rate may be seen, especially in patients on β‐blockers.
• Paradoxical bradycardia occurring during extreme hypovolaemia has been reported in
patients with perioperative anaphylaxis.
• Bronchospasm is usually a feature in patients with underlying airway hyperreactivity.
• Cutaneous signs, such as urticaria and generalized erythema, are often present in
anaphylaxis, but can be absent during severe hypotension and may reappear after
restoration of adequate circulation.
• Signs from the gastrointestinal tract are absent during general anaesthesia, but may be
present during regional anaesthesia.

INVESTIGATION
The aims of perioperative anaphylaxis investigation
• Identify a culprit drug
• Identify safe alternatives
• ensure safe future anaesthesia
▪ Reactions grade 2‐4 should always be referred for investigation.
▪ Transient self‐limiting flushing or localized erythema is unlikely to represent
significant hypersensitivity and does not need investigation.

INVESTIGATION
Documentation should include
• anaesthetic record
• all drug charts (preoperative, theatre and recovery)
• anaesthetist's notes
• details of any surgical
• other perioperative exposures (disinfectants, local anaesthetic sprays/gels,
dyes, cements)
• details of all procedures (arterial, venous and urinary catheters, stents).

INVESTIGATION
• All IV exposures given within 1 hour of reaction onset
• All other exposures (intramuscular, subcutaneous, spinal, epidural,
other local exposures) given within 2 hours of reaction onset are
investigated.
• A study on fatal anaphylaxis reported that median times to cardiac
arrest varied with route of administration being
- 5 minutes after IV injection
-15 minutes after SC injection
- 30 minutes after oral intake.

INVESTIGATION
In patients with a past history of perioperative anaphylaxis , but where
details of drug exposures are not available, it may be necessary to test with
• Latex
• Chlorhexidine
• Ethylene oxide
• Simple battery of drugs : propofol, fentanyl, remifentanil and a NMBA
to ensure safe future anaesthesia.

INVESTIGATION
• Drugs that have been continued or re‐administered in the same
anaesthetic after recovery of the reaction should still be considered
for testing due to the risk of a possible refractory phase or
antiallergic therapy masking symptoms.
• Drugs that have been continued for several days after the antiallergic
therapy has been stopped, for example local anaesthetic infusion in
an epidural, or continuous infusion of propofol for several days in
intensive care, are less likely causes.

INVESTIGATION
• The ideal timing of investigations is not known.
• It is recommended that testing takes place 1‐4 months postevent and
at least 4‐6 weeks postevent to avoid false‐negative results.
• British guidelines have suggested that investigations can take place
immediately after the event.
• Negative skin test results before 4 weeks postevent may not exclude
allergy and later re‐testing may be needed.

INVESTIGATION
• Children with perioperative anaphylaxis are investigated using the
same approach as for adults.
• There are no specific data about test sensitivity and specificity in this
age group.
• In small children, IDT may be omitted or carried out after
pretreatment with topical lidocaine, if lidocaine is not a suspected
culprit.

SKIN TESTING

IN VITRO TESTING
• Serum Tryptase
• Plasma histamine
• Specific IgE testing (sIgE)
• Basophil activation test (BAT)
• Histamine release (HR)

SERUM TRYPTASE
• Tryptase, a mast cell protease, is a preformed enzyme that is also
released during mast cell activation.
• Tryptase serum levels peak approximately 15 minutes to 120 minutes
after the anaphylactic reaction onset, and declines under first-order
kinetics with a half-life of approximately 2 hours.

SERUM TRYPTASE
• It is recommended to measure tryptase within 1‐3 hours after a
suspected perioperative anaphylaxis.
• An acute serum tryptase level greater than [1.2 x serum baseline
tryptase] + 2 mcg/L has been recommended to confirm acute mast
cell degranulation.
• Measuring baseline tryptase has an additional purpose, as elevated
baseline levels might be indicative of underlying clonal mast cell
disorders.
• The baseline sample should be taken a minimum of 24 hours after
the reaction.

SPECIFIC IGE TESTING
• β‐lactam antibiotics
• NMBAs
• Latex
• Chlorhexidine
• Ethylene oxide
• Morphine
• Gelatin
• Sensitivity and specificity are high for Latex and Chlorhexidine (near 100%)
assays.
• sIgE can be measured on the sample taken at the time of reaction, but if
negative, it needs to be repeated 4‐6 weeks later.

BASOPHIL ACTIVATION TEST
• BAT can be performed for all drugs.
• BAT can be used to identify both culprit drugs and potential safe
alternatives.

DRUG PROVOCATION TESTING
• Full‐dose DPT represents the “Gold Standard” when investigating
immediate hypersensitivity to drugs.
• It has had limited use in perioperative anaphylaxis due to the strong
pharmacologic effects of perioperative drugs, for example respiratory
depression, paralysis and anaesthesia.
• Consensus on the use of DPT in this setting is lacking.
• DPT can be performed when skin tests are equivocal/negative with
the aim to exclude sensitization to the culprit drug or to test a safe
alternative.

Perioperative anaphylaxis

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